Effect of autoimmune diseases on risk and survival in female cancers.
Patients with autoimmune (AI) diseases are diagnosed with increased frequencies of some cancers, which may depend on the underlying dysregulation of the immune system or treatment. Data on female cancers are limited. We analyzed systematically risk and survival of female cancers of the breast, uterus, ovary and other genital organs in close to 200,000 patients diagnosed with any of 33 different AI diseases. Standardized incidence ratios (SIRs) for risk and hazard ratios (HRs) for survival were calculated for subsequent incident cancers or cancer deaths up to year 2008. For all breast cancer after any AI diseases, the SIR was 0.94; SIRs were modestly increased after two AI diseases and decreased after nine AI diseases, including Sjogren syndrome (0.46). For cervical cancer, the risk was increased after discoid lupus erythematosus (3.34) and systemic sclerosis (2.43). The HR was 2.12 in chronic rheumatic heart disease patients. The overall SIR for endometrial cancer was 0.85, with low SIR in ankylosing spondylitis (0.37); the HR was 4.05 for Sjogren syndrome. The SIR for ovarian cancer was increased for polymyositis/dermatomyositis (3.26) while the HR was increased for multiple sclerosis (2.43). The overall SIR for other genital cancers was increased to 1.54 and a very high risk of 35.88 was observed in localized scleroderma. Breast, endometrial and ovarian cancers were decreased after all AI diseases and most significant changes after individual AI diseases were towards lower risks. Probably treatment related factors explain the findings. For cervical and other genital cancers all significant changes were increased risks.


The influence of symbiotic bacteria on reproductive strategies and wing polyphenism in pea aphids responding to stress.
Environmental stressors can be key drivers of phenotypes, including reproductive strategies and morphological traits. The response to stress may be altered by the presence of microbial associates. For example, in aphids, facultative (secondary) bacterial symbionts can provide protection against natural enemies and stress induced by elevated temperatures. Furthermore, aphids exhibit phenotypic plasticity, producing winged (rather than wingless) progeny that may be better able to escape danger, and the combination of these factors improves the response to stress. How symbionts and phenotypic plasticity, both of which shape aphids' stress response, influence one another, and together influence host fitness, remains unclear. In this study, we investigate how environmental stressors drive shifts in fecundity and winged/wingless offspring production, and how secondary symbionts influence the process. We induced production of winged offspring through distinct environmental stressors, including exposure to aphid alarm pheromone and crowding, and, in one experiment, we assessed whether the aphid response is influenced by host plant. In the winged morph, energy needed for wing maintenance may lead to trade-offs with other traits, such as reproduction or symbiont maintenance. Potential trade-offs between symbiont maintenance and fitness have been proposed but have not been tested. Thus, beyond studying the production of offspring of alternative morphs, we also explore the influence of symbionts across wing/wingless polyphenism as well as symbiont interaction with cross-generational impacts of environmental stress on reproductive output. All environmental stressors resulted in increased production of winged offspring and shifts in fecundity rates. Additionally, in some cases, aphid host-by-symbiont interactions influenced fecundity. Stress on first-generation aphids had cross-generational impacts on second-generation adults, and the impact on fecundity was further influenced by the presence of secondary symbionts and presence/absence of wings. Our study suggests a complex interaction between beneficial symbionts and environmental stressors. Winged aphids have the advantage of being able to migrate out of danger with more ease, but energy needed for wing production and maintenance may come with reproductive costs for their mothers and for themselves, where in certain cases, these costs are altered by secondary symbionts.


The effect of distal clavicle excision on in situ graft forces in coracoclavicular ligament reconstruction.
Recently, some have suggested that the acromioclavicular articulation confers stability to the construct after coracoclavicular ligament reconstruction for acromioclavicular joint separation. Therefore, it has been suggested that distal clavicle excision should not be performed in this context to protect the graft during healing. Sectioning the acromioclavicular ligaments would significantly increase in situ forces of a coracoclavicular ligament graft, whereas performing a distal clavicle resection would not further increase in situ graft forces. Controlled laboratory study. A simulated coracoclavicular reconstruction was performed on 5 cadaveric shoulders. Static loads of 80 N and 210 N were applied directly to the clavicle in 5 directions: anterior, anterosuperior, superior, posterosuperior, and posterior. The in situ graft force was measured using a force transducer under 3 testing conditions: (1) intact acromioclavicular ligaments, (2) sectioned acromioclavicular ligaments, and (3) distal clavicle excision. For both magnitudes of load, in all directions, in situ graft force with intact acromioclavicular ligaments was significantly less than that with sectioned acromioclavicular ligaments (P < .001). Distal clavicle excision did not further increase the in situ graft forces with load applied to the clavicle in an anterior, anterosuperior, or superior direction. However, in situ graft forces were increased with distal clavicle excision when the clavicle was loaded with 210 N in the posterosuperior direction (60.4 ± 6.3 N vs 52.5 ± 7.1 N; P = .048) and tended to be increased with posterior loading of the clavicle (71.8 ± 6.2 N vs 53.1 ± 8.8 N; P = .125). Intact acromioclavicular ligaments protect the coracoclavicular reconstruction by decreasing the in situ graft force. The slight increase in the in situ graft force only in the posterosuperior and posterior direction after distal clavicle excision suggests only a marginal protective role of the acromioclavicular articulation. Further, the peak graft forces observed represent only a small fraction of the ultimate failure strength of the graft. Distal clavicle excision can perhaps be safely performed in the context of coracoclavicular ligament reconstruction without subjecting the graft to detrimental in situ force. Although the acromioclavicular articulation serves only a marginal role in protecting the coracoclavicular ligament graft, reconstruction of the acromioclavicular ligaments may serve an important role in decreasing in situ graft force during healing.


Deficits in irregular past-tense verb morphology associated with degraded semantic knowledge.
Two distinct mechanisms are often considered necessary to account for generation of the past-tense of English verbs: a lexical associative process for irregular forms like speak-->spoke, and a rule-governed process ("add -ed") for regular and novel forms like talk-->talked and wug-->wugged. An alternative account based on a parallel-distributed processing approach proposes that one complex procedure processes all past-tense types. In this alternative view, neuropsychological dissociations are explained by reduced input from word meaning that plays a greater role in successful generation of the past-tense for lower frequency irregular verbs, and by phonological deficits that disproportionately affect regular and novel forms. Only limited evidence has been available concerning the relationship between knowledge of word meaning and verb-tense processing. The study reported here evaluated the past-tense verb abilities of 11 patients with semantic dementia, a neurodegenerative condition characterised by degraded semantic knowledge. We predicted and confirmed that the patients would have essentially normal ability to generate and recognise regular (and novel) past-tense forms, but a marked and frequency-modulated deficit on irregular verbs. Across the set of 11 patients, the degree of impairment for the irregular past-tense was significantly correlated with the degree of comprehension impairment as measured by verb synonym judgements. These results, plus other features of the data such as the nature of the errors to irregular verbs, are discussed in relation to currently developing theories of the language system.


Effects of biofeedback on biomechanical factors associated with chronic ankle instability: a systematic review with meta-analysis.
Biofeedback may alter the biomechanics of lower extremities in patients with chronic ankle instability (CAI). We aimed to systematically review the literature on the effect of gait-training and biofeedback on biomechanical parameters in individuals with CAI and conduct a meta-analysis. We searched four databases including PubMed, Web of Science, Scopus and Embase from their inception through 30th June 2022. The Downs and Black appraisal scale was applied to assess quality of included studies. Two reviewers screened studies to identify those reporting the effect of biofeedback on biomechanical factors associated with CAI. Outcomes of interest were kinetics and kinematics. Two authors separately extracted data from included studies. Data of interest were study design, number of sessions, intervention, tools, outcomes, number, sex, age, height, and body mass of participants. Thirteen studies with a total of 226 participants were included. Biofeedback was capable of shifting center of pressure (COP) and lateral plantar pressure medially and reducing foot inversion, adduction, propulsive vertical ground reaction force (vGRF), ankle joint contact force, peak pressure and pressure time integral in the lateral mid-foot and forefoot. Auditory biofeedback had agreater impact on modifying plantar pressure in individuals with CAI. The meta-analyses revealed that visual biofeedback reduces peak pressure in lateral mid-foot and pressure time integral at lateral and medial heel and pressure increases under the hallux. Biofeedback can alter pressure, vGRF, and foot inversion associated with CAI. Auditory biofeedback had greater impact on modifying plantar pressure in individuals with CAI. Further studies are required to assess the prolonged effect and clinical consequences of biofeedback or a combination of feedback on CAI in different age groups. Moreover, developing a low-cost and user-friendly device that can be evaluated in high quality RCTs is important prior to implementing the intervention in the clinical setting to reduce symptoms of CAI.


Where a child lives matters: neighborhood deprivation and pediatric obesity.
This article outlines what is currently known regarding the relationship between neighborhood deprivation and pediatric obesity. It discusses the intersectionality between neighborhood deprivation, race, ethnicity, and pediatric obesity. We conclude by proposing several potential solutions to disparities in pediatric obesity related to neighborhood deprivation. Neighborhood deprivation, independent of individual socioeconomic status, is a risk factor for pediatric obesity. The obesogenic characteristics of high deprivation neighborhoods (e.g., lack of safe spaces to be active, easy access to fast food) and the psychological aspects of residing within high deprivation neighborhoods may also contribute to this risk. Intervention strategies and policies designed to address neighborhood related risk for pediatric obesity are needed. Pediatric obesity is a growing problem of complex etiology. Neighborhood risk factors should be considered when assessing risk burden and when designing intervention strategies.


800-kyr land temperature variations modulated by vegetation changes on Chinese Loess Plateau.
The complicity of long-term land surface temperature (LST) changes has been under investigated and less understood, hindering our understanding of the history and mechanism of terrestrial climate change. Here, we report the longest (800 thousand years) LSTs based on distributions of soil fossil bacterial glycerol dialkyl glycerol tetraethers preserved in well-dated loess-paleosol sequences at the center of the Chinese Loess Plateau. We have found a previously-unrecognized increasing early and prolonged warming pattern toward the northwestern plateau at the onset of the past seven deglaciations, corresponding to the decrease in vegetation coverage, suggesting underlying surface vegetation or lack of has played an important role in regulating LSTs, superimposed on the fundamental global glacial-interglacial changes. Our results support that LSTs in semi-humid and semi-arid regions with little vegetation will be more sensitive to the anticipated global temperature rise, while improving vegetation coverage would reduce LSTs and thus ecological impacts.


[Effect of the duration of a reproducible interval on reaction time in man].
The dependence of reaction time (RT) of reproduction of presented standard intervals on their duration (100-5000 ms) was studied on 30 subjects. The intervals were limited by two electrocutaneous stimuli or two clicks and were presented both at random and at a gradual increase or decrease, with a step of 100 ms. They were reproduced by pressing a button. The RTs duration depended on the presented interval within the range from 100 to 2000 ms. Such scatter of the upper limit is due to differences in the methods of presentation of the material and to individual features of the subjects. A presence of two mechanisms of time intervals reproduction is suggested for such experimental conditions: the image of the standard interval might be created either after its presentation or in the process of its presentation. Correspondingly, the RT dependence on the interval duration is manifest in the first case and is absent in the second.


Anti-bacterial efficacy of alcoholic hand rubs in the Kenyan market, 2015.
Hand hygiene is known to be effective in preventing hospital and community-acquired infections. The increasing number of hand sanitizer brands in Kenyan hospitals and consumer outlets is of concern. Thus the main aim of this study was to evaluate the anti-bacterial efficacy and organoleptic properties of these hand sanitizers in Kenya. This was an experimental, laboratory-based study of 14 different brands of hand sanitizers (coded HS1-14) available in various retail outlets and hospitals in Kenya. Efficacy was evaluated using standard non-pathogenic Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 25923) and Pseudomonas aeruginosa (ATCC 27853) as per the European Standard (EN). The logarithmic reduction factors (RF) were assessed at baseline and after treatment, and log reduction then calculated. Ten and 25 healthy volunteers participated in the efficacy and organoleptic studies respectively. Four (28.6%) hand sanitizers (HS12, HS9, HS13 and HS14) showed a 5.9 reduction factor on all the three bacteria strains. Seven (50%) hand sanitizers had efficacies of <3 against all the three bacteria strains used. Efficacy on E. Coli was higher compared to the other pathogens. Three hand sanitizers were efficacious on one of the pathogens and not the other. In terms of organoleptic properties, gel-based formulations were rated far higher than the liquid based formulations brands. Fifty percent (50%) of the selected hand sanitizers in the Kenyan market have efficacy that falls below the World Health Organization (WHO) and DIN EN 1500:2013. Of the 14 hand sanitizers found in the Kenyan market, only four showed efficacies that were comparable to the WHO-formulation. There is a need to evaluate how many of these products with <3 efficacy that have been incorporated into the health system for hand hygiene and the country's policy on regulations on their usage.


Double Dilemma-Management of a Pregnant Patient With a Difficult Airway Presenting With Undiagnosed Placenta Percreta: A Case Report.
Patients with abnormal placentation should undergo planned cesarean delivery with the option for hysterectomy based on severity. We report a case of a multigravida with a known difficult airway presenting for cesarean delivery. She was found to have an undiagnosed placenta percreta at the start of surgery after the epidural was placed. After team discussion, the procedure was aborted and rescheduled electively 2 days later under general anesthesia with preoperative placement of internal iliac artery balloon catheters. This case emphasizes the importance of a multiteam approach toward the management of challenging and unanticipated cases.


Synthesis of α,ω-End Functionalized Polydienes: Allylic-Bearing Heteroleptic Aluminums for Selective Alkylation and Transalkylation in Coordinative Chain Transfer Polymerization.
There are still challenges in the preparation of difunctional stereoregular polydienes, especially for the construction of initiating chain-end functionalization. Coordinative chain transfer polymerization (CCTP) provides a way to achieve the goal but usually requires sophisticated functionalized catalysts as well as expensive chain transfer agents (CTAs). In this work, heteroleptic aluminum with oligo(dienyl) substituents (oligo-Al agents) were readily prepared by living anionic polymerization (LAP) technique. The oligo-Al agents used in Nd-mediated CCTPs of dienes exhibit highly selective alkylation and transalkylation features. Kinetics and transfer efficiency studies using 1H NMR, 13C NMR, 1H-13C HSQC, and Dosy NMR analyses revealed that the resulting polydienes possess substituents at the initiating chain-end that have transferred from the oligo-Al agents. The functionalization efficiency of the initiating chain-end is up to 99%, and the molar mass regulation efficiency of heteroleptic aluminum is higher than the traditional CTA AliBu2H (0.608 vs. 0.410). Based on the experimental results and density functional theory (DFT) calculations, we propose a mechanism in which allylic-Al acts as an efficient alkylating moiety in catalyst preformation and also as an effective transfer agent in polymerization. Taking advantage of these features, di-functionalized polyisoprene, polybutadiene, and poly(isoprene-co-butadiene) can be facilely synthesized.


Cholestasis induced liver pathology results in dysfunctional immune responses after arenavirus infection.
Immune responses are critical for defense against pathogens. However, prolonged viral infection can result in defective T cell immunity, leading to chronic viral infection. We studied immune activation in response to arenavirus infection during cholestasis using bile duct ligation (BDL). We monitored T cell responses, virus load and liver pathology markers after infection with lymphocytic choriomeningitis virus (LCMV). BDL mice failed to induce protective anti-viral immunity against LCMV and consequently exhibited chronic viral infection. BDL mice exhibited reduced anti-viral T cell immunity as well as reduced type 1 interferon production early after LCMV infection. Consistently, the presence of serum from BDL mice reduced the responsiveness of dendritic cell (DC) and T cell cultures when compared to Sham controls. Following fractionation and mass spectrometry analyses of sera, we identified several serum factors to be upregulated following BDL including bilirubin, bile acids, 78 kDa Glucose regulated protein (GRP78) and liver enzymes. Bilirubin and GRP78 were capable of inhibiting DC and T cell activation. In this work, we demonstrate that liver damage mediated by cholestasis results in defective immune induction following arenavirus infection.


How Should Adult Handgrip Strength Be Normalized? Allometry Reveals New Insights and Associated Reference Curves.
Handgrip strength (HGS) is an important indicator of health. Because HGS is strongly associated with body size, most investigators normalize HGS for some measure of body size as a more sensitive indicator of strength within a population. We aimed to 1) identify the optimal body size dimension to remove (normalize) HGS for differences in body size among adults and 2) generate norm-referenced centiles for HGS using the identified body size dimension. Data were from the National Health and Nutrition Examination Survey, a representative sample of the US noninstitutionalized civilian population. Exclusions resulted in a final sample of 8690 adults 20 yr and older. HGS was measured using handheld dynamometry. Body size dimensions included body mass, height, and waist circumference. The most appropriate dimension(s) associated with HGS is identified using allometry. We fitted centile curves for normalized HGS using the generalized additive model for location, scale, and shape. Findings suggest that neither body mass nor body mass index is appropriate to normalize HGS. Incorporating all three body size dimensions of body mass, height, and waist circumference, or the reduced subsets of body mass and height, or height alone, suggests that the most appropriate normalizing (body size) dimension associated with HGS should be a cross-sectional or surface area measure of an individual's body size (i.e., L2, where L is a linear dimension of body size). Given that height was also identified as the signally best body size dimension associated with HGS, we recommend HGS be normalized by height2 (i.e., HGS/HT2). Centile curves for HGS/HT2 by age group and gender were therefore provided. Scaling adult HGS by height2 may help normalize strength for population-based research.


[Little HIV risk behavior in drug users during detention in Dutch penitentiaries].
To assess levels of HIV risk behaviour in injecting drug users during and immediately following prison terms in the Netherlands. Descriptive. Municipal Health Service, Amsterdam, the Netherlands. Injecting drug users taking part in a follow-up study on HIV infection were interviewed on injecting drug use and vaginal and anal sexual contact during their last prison term in the 3 years preceding the interview and on injecting drug use in the week following release from prison. A prison term in the preceding 3 years was reported by 188 (41%) of 463 interviewed drug injectors. The mean age of the 188 was 35.5 years: 146 (78%) were males, 63 (34%) had HIV antibodies, and the mean duration of latest prison term was 3.6 months. Some use of cannabis, heroin, or cocaine in prison was reported by 104 (55%), 69 (37%), and 38 (20%) respectively. Five injectors (3%) reported having injected in prison: in 4 cases once and in 1 case 3 times. No sharing of needles and syringes was reported. Vaginal or anal sex was reported by 2 (1%) of the men and none of the women. Relapse to drug injecting during the week following release from prison was reported by 78/186 (42%) participants, in most cases (34%) on the very day of release. Contrary to findings from other countries, low levels of HIV risk behaviour occur among imprisoned drug injectors in the Netherlands. Although noninjecting drug use in prison is common, drug injecting and the sharing of injecting equipment is rare. There appear to be no grounds for making clean needles and syringes available in Dutch prisons.


Hoof lesions in partly housed pasture-based dairy cows.
Lameness is a symptom of a painful disorder affecting the limbs, which impacts dairy cow welfare and productivity. Lameness is primarily caused by hoof lesions. The prevalence of different lesion types can differ depending on environmental conditions and farm management practices. The aims of this observational study were to establish the cow-level and herd-level lesion prevalence during both housing and grazing periods in a partly housed, pasture-based system, establish the prevalence of lesions always associated with pain ("alarm" lesion), identify the lesions associated with a higher lameness score, determine relationships between lesions, and identify risk factors for digital dermatitis. On 98 farms during the grazing period and on 74 of the same farms during the housing period, every cow was lameness scored (0-3 lameness scoring scale), and the hind hooves of lame cows (score 2 and 3) were examined (maximum 20 cows per visit) and the prevalence of each lesion type recorded. To gather data on potential predictors for the risk factor analysis, a questionnaire with the farmer was conducted on lameness management practices and infrastructure measurements were taken at each visit. Cow-level data were also collected (e.g., parity, breed, milk yield, and so on). Noninfectious lesions were found to be more prevalent than infectious lesions in this system type. The most prevalent lesion types during both grazing and housing periods were white line separation, sole hemorrhages and overgrown claws; all remaining lesions had a cow-level prevalence of less than 15%. The cow-level prevalence of alarm lesions was 19% during the grazing period and 25% during the housing period; the most prevalent alarm lesion was sole ulcers during both periods. We found significantly more foreign bodies within the hoof sole (grazing = 14%, housing = 7%) and overgrown claws (grazing = 71%, housing = 55%) during the grazing period compared with the housing period. Cows with foul of the foot, sole ulcer, white line abscess, toe necrosis or an amputated claw had higher odds of being more severely lame, compared with mildly lame. The strongest correlation between lesions were between toe necrosis and digital dermatitis (r = 0.40), overgrown claws and corkscrew claws (r = 0.33), and interdigital hyperplasia and digital dermatitis (r = 0.31) at herd level. At the cow level, the strongest correlation was between overgrown claws and corkscrew claws (r = 0.27), and digital dermatitis and heel erosion (r = 0.22). The farmers' perception of the presence of digital dermatitis (and lameness) was significantly correlated with the actual presence of digital dermatitis recorded. Additional risk factors for the presence of digital dermatitis were cow track and verge width near the collecting yard, and stone presence on the cow tracks. Results from this study help further our understanding of the causes of lameness in partly housed, pasture-based dairy cows, and can be used to guide prevention and treatment protocols.


13[C]-urea breath test as a novel point-of-care biomarker for tuberculosis treatment and diagnosis.
Pathogen-specific metabolic pathways may be detected by breath tests based on introduction of stable isotopically-labeled substrates and detection of labeled products in exhaled breath using portable infrared spectrometers. We tested whether mycobacterial urease activity could be utilized in such a breath test format as the basis of a novel biomarker and diagnostic for pulmonary TB. Sensitized New-Zealand White Rabbits underwent bronchoscopic infection with either Mycobacterium bovis or Mycobacterium tuberculosis. Rabbits were treated with 25 mg/kg of isoniazid (INH) approximately 2 months after infection when significant cavitary lung pathology was present. [(13)C] urea was instilled directly into the lungs of intubated rabbits at selected time points, exhaled air samples analyzed, and the kinetics of delta(13)CO(2) formation were determined. Samples obtained prior to inoculation served as control samples for background (13)CO(2) conversion in the rabbit model. (13)CO(2), from metabolic conversion of [(13)C]-urea by mycobacterial urease activity, was readily detectable in the exhaled breath of infected rabbits within 15 minutes of administration. Analyses showed a rapid increase in the rate of (13)CO(2) formation both early in disease and prior to treatment with INH. Following INH treatment, all evaluable rabbits showed a decrease in the rate of (13)CO(2) formation. Urea breath testing may provide a useful diagnostic and biomarker assay for tuberculosis and for treatment response. Future work will test specificity for M. tuberculosis using lung-targeted dry powder inhalation formulations, combined with co-administering oral urease inhibitors together with a saturating oral dose of unlabeled urea, which would prevent the delta(13)CO(2) signal from urease-positive gastrointestinal organisms.


[Indometofen causes biochemical changes in the blood cells characteristic for a radioresistant state of the body].
The DNA and RNA contents, RNA/DNA ratio, and spontaneous and latex-induced oxidant activity indices of the whole blood were studied in the nitroblue tetrazolium test of mono- and polymorphonuclear blood leucocytes of intact dogs after injection of lipopolysaccharide pyrogenal. Significant changes in the above parameters were revealed for radioresistant (survived) and radiosensitive (lost) animals exposed to a subsequent prolonged gamma irradiation with a lethal dose of 7.64 Gy (LD75/45). Peroral introduction of 30 mg/kg indometofen (an indole analog of tamoxifen), which is a potential radioprotector, to dogs increased the survival rates of the irradiated dogs up to 93% and aided in the adaptive biochemical changes in the nuclear cell compartment of blood to induce a radioresistant status of the organism.


Electrochemically driven optical and SERS immunosensor for the detection of a therapeutic cardiac drug.
Cardiovascular diseases pose a serious health risk and have a high mortality rate of 31% worldwide. Digoxin is the most commonly prescribed pharmaceutical preparation to cardiovascular patients particularly in developing countries. The effectiveness of the drug critically depends on its presence in the therapeutic range (0.8-2.0 ng mL-1) in the patient's serum. We fabricated immunoassay chips based on QD photoluminescence (QDs-ELISA) and AuNP Surface Enhanced Raman Scattering (SERS-ELISA) phenomena to detect digoxin in the therapeutic range. Digoxin levels were monitored using digoxin antibodies conjugated to QDs and AuNPs employing the sandwich immunoassay format in both the chips. The limit of detection (LOD) achieved through QDs-ELISA and SERS-ELISA was 0.5 ng mL-1 and 0.4 ng mL-1, respectively. It is demonstrated that the sensitivity of QDs-ELISA was dependent on the charge transfer mechanism from the QDs to the antibody through ionic media, which was further explored using electrochemical impedance spectroscopy. We demonstrate that QDs-ELISA was relatively easy to fabricate compared to SERS-ELISA. The current study envisages replacement of conventional methodologies with small immunoassay chips using QDs and/or SERS-based tags with fast turnaround detection time as compared to conventional ELISA.


Differential Activation of Glioprotective Intracellular Signaling Pathways in Primary Optic Nerve Head Astrocytes after Treatment with Different Classes of Antioxidants.
Optic nerve head astrocytes are the specialized glia cells that provide structural and trophic support to the optic nerve head. In response to cellular injury, optic nerve head astrocytes undergo reactive astrocytosis, the process of cellular activation associated with cytoskeletal remodeling, increases in the rate of proliferation and motility, and the generation of Reactive Oxygen Species. Antioxidant intervention has previously been proposed as a therapeutic approach for glaucomatous optic neuropathy, however, little is known regarding the response of optic nerve head astrocytes to antioxidants under physiological versus pathological conditions. The goal of this study was to determine the effects of three different antioxidants, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (Mn-TM-2-PyP), resveratrol and xanthohumol in primary optic nerve head astrocytes. Effects on the expression of the master regulator nuclear factor erythroid 2-related factor 2 (Nrf2), the antioxidant enzyme, manganese-dependent superoxide dismutase 2 (SOD2), and the pro-oxidant enzyme, nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), were determined by quantitative immunoblotting. Furthermore, efficacy in preventing chemically and reactive astrocytosis-induced increases in cellular oxidative stress was quantified using cell viability assays. The results were compared to the effects of the prototypic antioxidant, Trolox. Antioxidants elicited highly differential changes in the expression levels of Nrf2, SOD2, and NOX4. Notably, Mn-TM-2-PyP increased SOD2 expression eight-fold, while resveratrol increased Nrf2 expression three-fold. In contrast, xanthohumol exerted no statistically significant changes in expression levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) uptake and lactate dehydrogenase (LDH) release assays were performed to assess cell viability after chemically and reactive astrocytosis-induced oxidative stress. Mn-TM-2-PyP exerted the most potent glioprotection by fully preventing the loss of cell viability, whereas resveratrol and xanthohumol partially restored cell viability. Our data provide the first evidence for a well-developed antioxidant defense system in optic nerve head astrocytes, which can be pharmacologically targeted by different classes of antioxidants.


Iodination of remote ortho-C-H bonds of arenes via directed S(E)Ar: a streamlined synthesis of tetrahydroquinolines.
A new strategy for the synthesis of tetrahydroquinolines (THQs) via the sequential functionalizations of remote C-H bonds is reported. This method uses a single picolinamide directing/protecting group to effect Pd-catalyzed γ-C(sp(3))-H arylation, metal-free ε-C(sp(2))-H iodination, and Cu-catalyzed intramolecular C-N cross-coupling. The overall sequence is efficient and versatile, and offers a streamlined synthesis of THQs with complex substitution patterns from readily available aryl iodide and aliphatic amine precursors.


Globally convergent algorithms with local learning rates.
A novel generalized theoretical result is presented that underpins the development of globally convergent first-order batch training algorithms which employ local learning rates. This result allows us to equip algorithms of this class with a strategy for adapting the overall direction of search to a descent one. In this way, a decrease of the batch-error measure at each training iteration is ensured, and convergence of the sequence of weight iterates to a local minimizer of the batch error function is obtained from remote initial weights. The effectiveness of the theoretical result is illustrated in three application examples by comparing two well-known training algorithms with local learning rates to their globally convergent modifications.


Comparison of human lung and intestinal mast cells.
Since much of the data on heterogeneity in the rodent systems are based on differential effects of drugs, we compared responses of human lung mast cell and intestinal mucosal mast cell populations to agents that have revealed mast cell heterogeneity in rat models, as well as to other agents that are effective in both rat peritoneal and intestinal mast cell preparations. Disodium cromoglycate and theophylline inhibit histamine release (HR) from rat peritoneal, but not intestinal, mast cells. We found disodium cromoglycate (10(-4) to 10(-8) mol/L) to be ineffective in both human lung and human intestinal mast cell preparations, whereas theophylline (10(-3) to 10(-6) mol/L) inhibited both lung and intestinal mast cell HR. Quercetin (10(-4) to 10(-8) mol/L) and doxantrazole (3 X 10(-4) to 10(-7) mol/L), which inhibit both rat mast cell types, also inhibit HR in both human mast cell preparations. We also examined the actions of indomethacin and exogenous arachidonic acid and found that neither the lung nor the intestinal mast cells demonstrated the enhancement of HR stimulated by these agents in the basophil. In summary, we have found no pharmacologic differences between the human lung and intestinal mucosal mast cell such as exist in the rodent models. This underscores the limitations of applying the data from animal mast cells to the human mast cells, and at the same time demonstrates that human basophils and mast cells are different.


Perceived coercion among jail diversion participants in a multisite study.
Although jail diversion is considered an appropriate and humane response to the disproportionately high volume of people with mental illness who are incarcerated, little is known regarding the perceptions of jail diversion participants, the extent to which they feel coerced into participating, and whether perceived coercion reduces involvement in mental health services. This study addressed perceived coercion among participants in postbooking jail diversion programs in a multisite study and examined characteristics associated with the perception of coercion. Data collected in interviews with 905 jail diversion participants from 2003 to 2005 were analyzed with random-effects proportional odds models. Ten percent of participants reported a high level of coercion, and another 26% reported a moderate level of coercion. Having a drug charge was associated with lower perceived coercion to enter the program. In addition, an interaction between sexual abuse and substance abuse indicated that recent sexual abuse was associated with higher levels of perceived coercion, but only among those without current substance abuse. At the 12-month follow-up (N=398), variables associated with higher perceived coercion to receive behavioral health services included spending more time in jail and higher perceived coercion at baseline. The amount of behavioral health service use was not predicted by perceived coercion at baseline. Rather, being older, having greater symptom severity, and having a history of sexual abuse but no substance abuse and no history of physical abuse were associated with higher levels of outpatient service use. Overall, one-third of jail diversion participants reported some level of perceived coercion. Important determinants of perceived coercion included charge type, length of time in jail, and sexual abuse history. Engagement in treatment was not affected by perceived coercion.


Proteomics Software in bio.tools: Coverage and Annotations.
The large diversity of experimental methods in proteomics as well as their increasing usage across biological and clinical research has led to the development of hundreds if not thousands of software tools to aid in the analysis and interpretation of the resulting data. Detailed information about these tools needs to be collected, categorized, and validated to guarantee their optimal utilization. A tools registry like bio.tools enables users and developers to identify new tools with more powerful algorithms or to find tools with similar functions for comparison. Here we present the content of the registry, which now comprises more than 1000 proteomics tool entries. Furthermore, we discuss future applications and engagement with other community efforts resulting in a high impact on the bioinformatics landscape.


Transcriptome analysis elucidates key developmental components of bryozoan lophophore development.
The most recent phylogenomic study suggested that Bryozoa (Ectoprocta), Brachiopoda, and Phoronida are monophyletic, implying that the lophophore of bryozoans, phoronids and brachiopods is a synapomorphy. Understanding the molecular mechanisms of the lophophore development of the Lophophorata clade can therefore provide us a new insight into the formation of the diverse morphological traits in metazoans. In the present study, we profiled the transcriptome of the Bryozoan (Ectoproct) Bugula neritina during the swimming larval stage (SW) and the early (4 h) and late (24 h) metamorphic stages using the Illumina HiSeq2000 platform. Various genes that function in development, the immune response and neurogenesis showed differential expression levels during metamorphosis. In situ hybridization of 23 genes that participate in the Wnt, BMP, Notch, and Hedgehog signaling pathways revealed their regulatory roles in the development of the lophophore and the ancestrula digestive tract. Our findings support the hypothesis that developmental precursors of the lophophore and the ancestrula digestive tract are pre-patterned by the differential expression of key developmental genes according to their fate. This study provides a foundation to better understand the developmental divergence and/or convergence among developmental precursors of the lophophore of bryozoans, branchiopods and phoronids.


Non-metal with metal behavior: metal-free coordination-insertion ring-opening polymerization.
The "coordination-insertion" ring-opening polymerization (ROP) mechanism has so far been the monopoly of metal catalysts. In this work, we present a metal-free "coordination-insertion" ROP of trimethylene carbonate (TMC) and ε-caprolactone (ε-CL), as well as their sequential block copolymerization, with N-trimethylsilyl-bis (trifluoromethanesulfonyl)imide (TMSNTf2) as the non-metallic initiator/catalyst. TMSNTf2 was proposed to work through an unprecedented metal-free "coordination-insertion" mechanism, which involves the coordination of monomer to the Si atom of TMSNTf2, the nucleophilic attack of the -NTf2 group on the coordinated monomer, and the cleavage of the acyl-oxygen bond of the monomer. The proposed metal-free "coordination-insertion" ROP was studied by NMR, SEC, and MALDI-TOF analyses. In addition, the TMSNTf2-mediated ROP of TMC and ε-CL led to linear and cyclic polymers following two-stage first-order polymerization processes, as evidenced by structural analyses and kinetics study, which further demonstrated the metal-free "coordination-insertion" mechanism.


Thoracic intradural Aspergillus abscess formation following epidural steroid injection.
We report an extremely unusual iatrogenic infection of the spinal canal with Aspergillus fumigatus that resulted in intradural abscess formation following epidural steroid injection in an immunocompetent young individual. Although the imaging findings of the infection were relatively nonspecific, MR imaging not only allowed for a prompt diagnosis, but also helped in surgical localization to the intradural compartment. Complications from the use of these injections are briefly discussed.


Biomimetic antimicrobial cloak by graphene-oxide agar hydrogel.
Antibacterial surfaces have an enormous economic and social impact on the worldwide technological fight against diseases. However, bacteria develop resistance and coatings are often not uniform and not stable in time. The challenge is finding an antibacterial coating that is biocompatible, cost-effective, not toxic, and spreadable over large and irregular surfaces. Here we demonstrate an antibacterial cloak by laser printing of graphene oxide hydrogels mimicking the Cancer Pagurus carapace. We observe up to 90% reduction of bacteria cells. This cloak exploits natural surface patterns evolved to resist to microorganisms infection, and the antimicrobial efficacy of graphene oxide. Cell integrity analysis by scanning electron microscopy and nucleic acids release show bacteriostatic and bactericidal effect. Nucleic acids release demonstrates microorganism cutting, and microscopy reveals cells wrapped by the laser treated gel. A theoretical active matter model confirms our findings. The employment of biomimetic graphene oxide gels opens unique possibilities to decrease infections in biomedical applications and chirurgical equipment; our antibiotic-free approach, based on the geometric reduction of microbial adhesion and the mechanical action of Graphene Oxide sheets, is potentially not affected by bacterial resistance.


Proteomic identification of novel plasma kallikrein substrates in the astrocyte secretome.
Plasma kallikrein (PK) is activated during hemorrhage and has been implicated in cerebral vascular permeability and edema. To further characterize the potential effects of PK on the brain that may follow cerebral vascular injury, we have utilized a proteomics approach to search for novel PK substrates in the astrocyte secretome. Extracellular proteins released by astrocytes are critical mediators of cerebral homeostasis, including roles in synapse function and vascular integrity. We identified 1,108 proteins in astrocyte condition medium and 295 of these were annotated as secreted proteins. The total abundance of nine proteins was changed after treatment with PK. Characterization of the secreted proteins revealed low molecular weight fragments for 59 proteins in conditioned media exposed to PK that were not observed in untreated controls. The most striking finding from this study was the appearance of fragmentation of 26 extracellular matrix-associated proteins including collagen isoforms 1-6 and11, nidogen-1 and -2, lysyl oxidase-like protein 1, and matrix metalloproteinase 19 in the presence of PK. We also demonstrated that PK induced the fragmentation of non-matrix proteins, including apolipoprotein E. This report further characterizes the astrocyte secretome and identifies novel potential targets of PK-induced proteolysis that may contribute to its effects on the brain following vascular injury.


CHD2 variants are a risk factor for photosensitivity in epilepsy.
Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.


Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype.
Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)2D3,theactive form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted "Swiss cheese-like" cribriform morphology (CM) comprising multiple abnormal "back to back" lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors.


Direct activation of forkhead box O3 by tumor suppressors p53 and p73 is disrupted during liver regeneration in mice.
The p53 family of proteins regulates the expression of target genes that promote cell cycle arrest and apoptosis, which may be linked to cellular growth control as well as tumor suppression. Within the p53 family, p53 and the transactivating p73 isoform (TA-p73) have hepatic-specific functions in development and tumor suppression. Here, we determined TA-p73 interactions with chromatin in the adult mouse liver and found forkhead box O3 (Foxo3) to be one of 158 gene targets. Global profiling of hepatic gene expression in the regenerating liver versus the quiescent liver revealed specific, functional categories of genes regulated over the time of regeneration. Foxo3 is the most responsive gene among transcription factors with altered expression during regenerative cellular proliferation. p53 and TA-p73 bind a Foxo3 p53 response element (p53RE) and maintain active expression in the quiescent liver. During regeneration of the liver, the binding of p53 and TA-p73, the recruitment of acetyltransferase p300, and the active chromatin structure of Foxo3 are disrupted along with a loss of Foxo3 expression. In agreement with the loss of Foxo3 transcriptional activation, a decrease in histone activation marks (dimethylated histone H3 at lysine 4, acetylated histone H3 at lysine 14, and acetylated H4) at the Foxo3 p53RE was detected after partial hepatectomy in mice. These parameters of Foxo3 regulation are reestablished with the completion of liver growth and regeneration and support a temporary suspension of p53 and TA-p73 regulatory functions in normal cells during tissue regeneration. p53-dependent and TA-p73-dependent activation of Foxo3 was also observed in mouse embryonic fibroblasts and in mouse hepatoma cells overexpressing p53, TA-p73alpha, and TA-p73beta isoforms. p53 and p73 directly bind and activate the expression of the Foxo3 gene in the adult mouse liver and murine cell lines. p53, TA-p73, and p300 binding and Foxo3 expression decrease during liver regeneration, and this suggests a critical growth control mechanism mediated by these transcription factors in vivo.


Weaker Functional Connectivity Strength in Patients with Type 2 Diabetes Mellitus.
Type 2 diabetes mellitus (T2DM) is related to cognitive impairments and increased risk for dementia. Neuroimaging studies have demonstrated T2DM-related brain structural and functional changes which are partly associated to the cognitive decline. However, few studies focused on the early neuroimaging findingsin T2DM patients. In this study, a data-driven whole-brain resting state functional connectivity strength (rsFCS) methodwas used to evaluate resting functional changes in 53 T2DM patients compared with 55 matched healthy controls (HCs), and to detect the associations between the rsFCSchanges and cognitive functions in T2DM patients. The T2DM patients exhibited weaker long-range rsFCS in the right insula and weaker short-range rsFCS in the right supramarginalgyrus (SG) compared with the HCs. Additionally, seed-based functional connectivity (FC) analysis revealed weaker FC between the right insula and the bilateral superior parietal lobule (SPL), and between the right SG and the bilateral supplementary motor area (SMA)/right SPL in T2DM patientscompared with the HCs. In T2DM patients, negative correlation was found between the long-range rsFCS in the right insula and HbA1c levels; and the FC between the right SG and the bilateral SMA negatively correlated with TMT-A scores. Our results indicated that the rsFCS alteration occurredbefore obvious cognitive deficits in T2DM patients, which might be helpful for understanding the neuromechanism of cognitive declines in T2DM patients.


Cardiac Arrhythmia and Heart Failure Shortly After Starting Romosozumab for Osteoporosis: A Case-Based Review.
Romosozumab is a humanized monoclonal antibody that targets the sclerostin protein, which regulates bone formation and resorption. It is a novel therapy in the treatment of post-menopausal women with osteoporosis. The evidence regarding romosozumab's cardiovascular safety is conflicting. We report the first post-marketing case demonstrating cardiac events (i.e., atrial fibrillation and congestive heart failure) in a female patient with osteoporosis likely triggered by romosozumab. A literature review on romosozumab and cardiovascular disease is discussed extensively. For osteoporotic patients with cardiovascular risk factors (e.g., hypertension, coronary artery disease, and stroke), the benefits of fracture prevention should be weighed against potential cardiovascular risks before prescribing romosozumab. Real-world data on post-marketing surveillance will shed light on the potential safety signals of romosozumab.


Voriconazole exposure and the risk of cutaneous squamous cell carcinoma in allogeneic hematopoietic stem cell transplant patients.
Voriconazole is a commonly used antifungal medication in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. In solid organ transplantation, voriconazole use has been associated with the development of cutaneous squamous cell carcinoma (SCC). We sought to determine if voriconazole use was associated with SCC in patients undergoing allo-HSCT. We retrospectively reviewed consecutive adult patients who underwent allo-HSCT at Mayo Clinic from January 2007 through July 2012. Multivariable Cox models were created to assess the relationship of SCC with two time-dependent voriconazole exposure variables: (i) history of voriconazole exposure (yes/no), and (ii) cumulative days of voriconazole use. In our cohort of 381 allo-HSCT patients, SCC developed in 26 of 312 patients exposed to voriconazole (25 post-voriconazole) and in 1 of 69 patients who received alternative antifungal agent(s). Cumulative incidence of SCC was estimated to be 19% at 5 years post allo-transplant. Cumulative days of voriconazole use was found to be a risk factor for SCC, and this relationship persisted in a multivariable model using previously identified risk factors as covariates (hazard ratio 1.859 for each 180 days of use, P < 0.001). This is the first study, to our knowledge, to identify cumulative days of voriconazole use as a risk factor for SCC development following allo-HSCT, and may help guide appropriate antifungal use in this patient population.


Identifying childhood age groups for exposure assessments and monitoring.
The purpose of this article is to describe a standard set of age groups for exposure assessors to consider when assessing childhood exposure and potential dose to environmental contaminants. In addition, this article presents examples to show how the age groups can be applied in children's exposure assessments. A consistent set of childhood age groups, supported by an underlying scientific rationale, will improve the accuracy and comparability of exposure and risk assessments for children. The effort was undertaken in part to aid the U.S. Environmental Protection Agency (EPA) in implementing such regulatory initiatives as the 1997 Presidential Executive Order 13,045, which required all federal agencies to ensure that their standards take into account special risks to children. The standard age groups include: birth to <1 month; 1 to <3 months; 3 to <6 months; 6 to <12 months; 1 to <2 years; 2 to <3 years; 3 to <6 years; 6 to <11 years; 11 to <16 years; and 16 to <21 years. These age groups reflect a consideration of developmental changes in various behavioral, anatomical, and physiological characteristics that impact exposure and potential dose. It is expected that the availability of a standard set of early-life age groups will inform future analyses of exposure factors data as well as guide new research and data collection efforts to fill knowledge gaps.


Single-cell selectivity and functional architecture of human lateral occipital complex.
The human lateral occipital complex (LOC) is more strongly activated by images of objects compared to scrambled controls, but detailed information at the neuronal level is currently lacking. We recorded with microelectrode arrays in the LOC of 2 patients and obtained highly selective single-unit, multi-unit, and high-gamma responses to images of objects. Contrary to predictions derived from functional imaging studies, all neuronal properties indicated that the posterior subsector of LOC we recorded from occupies an unexpectedly high position in the hierarchy of visual areas. Notably, the response latencies of LOC neurons were long, the shape selectivity was spatially clustered, LOC receptive fields (RFs) were large and bilateral, and a number of LOC neurons exhibited three-dimensional (3D)-structure selectivity (a preference for convex or concave stimuli), which are all properties typical of end-stage ventral stream areas. Thus, our results challenge prevailing ideas about the position of the more posterior subsector of LOC in the hierarchy of visual areas.


MicroRNA-guided prioritization of genome-wide association signals reveals the importance of microRNA-target gene networks for complex traits in cattle.
MicroRNAs (miRNA) are key modulators of gene expression and so act as putative fine-tuners of complex phenotypes. Here, we hypothesized that causal variants of complex traits are enriched in miRNAs and miRNA-target networks. First, we conducted a genome-wide association study (GWAS) for seven functional and milk production traits using imputed sequence variants (13~15 million) and >10,000 animals from three dairy cattle breeds, i.e., Holstein (HOL), Nordic red cattle (RDC) and Jersey (JER). Second, we analyzed for enrichments of association signals in miRNAs and their miRNA-target networks. Our results demonstrated that genomic regions harboring miRNA genes were significantly (P < 0.05) enriched with GWAS signals for milk production traits and mastitis, and that enrichments within miRNA-target gene networks were significantly higher than in random gene-sets for the majority of traits. Furthermore, most between-trait and across-breed correlations of enrichments with miRNA-target networks were significantly greater than with random gene-sets, suggesting pleiotropic effects of miRNAs. Intriguingly, genes that were differentially expressed in response to mammary gland infections were significantly enriched in the miRNA-target networks associated with mastitis. All these findings were consistent across three breeds. Collectively, our observations demonstrate the importance of miRNAs and their targets for the expression of complex traits.


A high-frequency ultrasonic nebulizer system for radioaerosol delivery.
A prototype high-frequency ultrasonic nebulizer, coupled with a nebulization chamber, has been designed specifically to overcome the problem of inefficient and unpredictable radioaerosol delivery. The objective was to reduce mean particle size, increase aerosol concentration, and minimize dead space. Thirty-nine patients were studied, including 15 patients in significant respiratory distress. Delivery of the radioaerosol proved to be rapid, efficient, and reproducible, and excellent alveolar distribution patterns were obtained in all 39 patients. Minimal nonpathologic tracheal deposition occurred in five patients, but this did not interfere with the interpretability or diagnostic validity of the study. All other instances of airway aerosol deposition correlated with documented airway disease. The images obtained with this system are a reliable measure of ventilatory distribution and airway tubulence.


Mortality among women with ductal carcinoma in situ of the breast in the population-based surveillance, epidemiology and end results program.
Over 14% of breast cancers diagnosed in the United States annually are ductal carcinomas in situ (DCIS). There are no published population-based reports of the likelihood of breast cancer death among US women with DCIS. We used data from the Surveillance, Epidemiology and End Results program to determine the likelihood of breast cancer death at 5 and 10 years among US women aged 40 and older diagnosed with DCIS from 1978 to 1983 (before screening mammography was common; n = 1525) and from 1984 to 1989 (when screening mammography became common; n = 5547). We also calculated standardized mortality ratios (SMRs) to compare observed deaths from breast cancer, cardiovascular disease, and all causes combined among women with DCIS with deaths expected based on general population mortality rates. Among women diagnosed with DCIS from 1978 to 1983, 1.5% died of breast cancer within 5 years and 3.4% within 10 years. Among women diagnosed from 1984 to 1989, 0.7% died of breast cancer within 5 years and 1.9% within 10 years. Relative to the general population, risk of breast cancer death was greater for women diagnosed from 1978 to 1983 (SMR, 3.4; 95% confidence interval [CI], 2.5-4.5) than for women diagnosed from 1984 to 1989 (10-year SMR, 1.9; 95% CI, 1.5-2.3). Women diagnosed from 1984 to 1989 were significantly less likely than women in the general population to have died of cardiovascular diseases (10-year SMR, 0.6; 95% CI, 0.5-0.7) or of all causes combined (SMR, 0.8; 95% CI, 0.7-0.8). Among women diagnosed with DCIS, risk of death from breast cancer was low, at least within the 10 years following diagnosis. This may reflect the effectiveness of treatment for DCIS, the "benign" nature of DCIS, or both. At 10 years, women diagnosed from 1984 to 1989 were less likely than women diagnosed from 1978 to 1983 to have died of breast cancer, and their risk of dying of all causes combined was lower than that in the general population.


Secondary mitral regurgitation: percutaneous edge-to-edge repair on the cutting edge?
Secondary mitral regurgitation commonly complicates heart failure. Although the evidence for its management is most robust for treating the underlying cardiomyopathy, treatment aimed at additionally reducing the severity of mitral regurgitation with a percutaneous edge-to-edge device, MitraClip, has recently emerged. Despite the use of contemporary evidence-based heart failure therapies, patients with secondary mitral regurgitation and heart failure continue to remain at high risk for adverse clinical events; in both the MITRA-FR and COAPT trials, an extremely high event rate was evident in the medically managed arms over the respective 12-24-month follow-up. Data supporting the use of MitraClip to mitigate adverse outcomes in secondary mitral regurgitation is, however, conflicting. In MITRA-FR no difference was noted between MitraClip compared with the medically managed arm for the composite of all-cause death or heart failure hospitalization at 12 months. However, in COAPT, a significant reduction in the rate of heart failure re-hospitalization over 2 years was evident with MitraClip compared with medical therapy alone. Recommendations exist for the use of MitraClip in patients with primary mitral regurgitation and prohibitive surgical risk. However, with the divergent results of two recent high-quality randomized trials, its role in patients with secondary mitral regurgitation remains controversial.


Cancer vaccines: Where are we going?
Abstract The discovery that the immune system can distinguish molecular targets on cancer cells has led to efforts to develop cancer immunotherapeutics that can improve the recognition and effective elimination of tumor cells. Several types of tumor antigens are recognized by T lymphocytes, which are classified according to patterns of gene expression or protein distribution. Of particular interest is the group of molecules known as cancer-germline or cancer-testis antigens. As the relationship between the immune system and cancer has become clearer, so too have the challenges in designing effective cancer immunotherapeutics: (i) antigens need to be specifically selected based on ideal characteristics, such as tissue distribution that is restricted to tumors; (ii) selected antigens need to be combined with adjuvant agents that enhance their immunogenicity and yield robust responses; (iii) vaccination should be timed to pre-empt the development of regulatory suppressive immune mechanisms; and (iv) if suppressive regulatory mechanisms do arise, specific antagonists may be needed to enhance pro-immune outcomes. These challenges are shaping current and future research in this area.


Reduced hepatitis B virus (HBV)-specific CD4+ T-cell responses in human immunodeficiency virus type 1-HBV-coinfected individuals receiving HBV-active antiretroviral therapy.
Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in individuals chronically infected with HBV compared to individuals with self-limiting HBV infection or those on anti-HBV therapy. In individuals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with diverse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins. The magnitude and breadth of CD4(+) and CD8(+) T-cell responses to HBV in peripheral blood were examined by flow cytometry to detect gamma interferon production following stimulation with HBV peptide pools. Chronic HBV carriers (n = 34) were studied, including individuals never treated for HBV infection (n = 7), HBV-infected individuals receiving anti-HBV therapy (n = 13), and HIV-1-HBV-coinfected individuals receiving anti-HBV therapy (n = 14). CD4(+) and CD8(+) HBV-specific T-cell responses were more frequently detected and the CD8(+) T-cell responses were of greater magnitude and breadth in subjects on anti-HBV treatment than in untreated chronic HBV carriers. There was a significant inverse correlation between detection of a HBV-specific T-cell response and HBV viral load. HBV-specific CD4(+) and CD8(+) T-cell responses were significantly (fivefold) reduced compared with HIV-specific responses. Although, the frequency and breadth of HBV-specific CD8(+) T-cell responses were comparable in the monoinfected and HIV-1-HBV-coinfected groups, HBV-specific CD4(+) T-cell responses were significantly reduced in HIV-1-HBV-coinfected individuals. Therefore, HIV-1 infection has a significant and specific effect on HBV-specific T-cell immunity.


Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis.
The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis. Cish-deficient mice were highly resistant to methylcholanthrene-induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged in Cish-deficient mice. The combination of Cish deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy.


Local computation of angular velocity in rotational visual motion.
Retinal images evolve continuously over time owing to self-motions and to movements in the world. Such an evolving image, also known as optic flow, if arising from natural scenes can be locally decomposed in a Bayesian manner into several elementary components, including translation, expansion, and rotation. To take advantage of this decomposition, the brain has neurons tuned to these types of motions. However, these neurons typically have large receptive fields, often spanning tens of degrees of visual angle. Can neurons such as these compute elementary optic-flow components sufficiently locally to achieve a reasonable decomposition? We show that human discrimination of angular velocity is local. Local discrimination of angular velocity requires an accurate estimation of the center of rotation within the optic-flow field. Inaccuracies in estimating the center of rotation result in a predictable systematic error when one is estimating local angular velocity. Our results show that humans make the predicted errors. We discuss how the brain might estimate the elementary components of the optic flow locally by using large receptive fields.


Proopiomelanocortin-related peptides in feto-placental structures throughout pregnancy.
This study evaluates the presence of proopiomelanocortin (POMC)-related peptides in four embryos and eight fetal pituitaries starting from 5 to 25 weeks of pregnancy. Moreover, fetal membranes (amnion and chorion) were also investigated. Freshly collected samples were boiled in acetic acid to destroy enzymes, homogenized and submitted to high performance liquid chromatography (linear gradient from 25 to 40% acetonitrile in 0.01 M HCI, in 15', 1.5 ml/min). The collected fractions were tested for the presence of beta-lipotrophin (beta-LPH), beta-endorphin(beta-EP), gamma-endorphin(gamma-EP) through RIAs. beta-EP and beta-LPH were detected from 7 weeks of pregnancy while gamma-EP appeared later. Only the cephalic portion of the embryos contained the peptides where beta-LPH predominates while no immunoreactivity was detected in the rostral one. In the fetal pituitary there is a progressive increase of gamma-EP according to the gestational age and both beta-EP and beta-LPH showed a trend toward constancy in the 15-25 week range. Amnion and chorion contain a significant amount of the three peptides. Their ontogenesis starts earlier than in the embryo; beta-LPH or beta-EP were detected at 5 weeks of pregnancy. In both tissues beta-EP was higher in the first than in the second trimester. These data demonstrate a different pattern of POMC ontogeny and processing between the conceptus and his environment. This suggests that the POMC-related opiod system of the fetus and of fetal adnexes are independent of each other, possibly subserving to different functions.


MPI Phantom Study with A High-Performing Multicore Tracer Made by Coprecipitation.
Magnetic particle imaging (MPI) is a new imaging technique that detects the spatial distribution of magnetic nanoparticles (MNP) with the option of high temporal resolution. MPI relies on particular MNP as tracers with tailored characteristics for improvement of sensitivity and image resolution. For this reason, we developed optimized multicore particles (MCP 3) made by coprecipitation via synthesis of green rust and subsequent oxidation to iron oxide cores consisting of a magnetite/maghemite mixed phase. MCP 3 shows high saturation magnetization close to that of bulk maghemite and provides excellent magnetic particle spectroscopy properties which are superior to Resovist® and any other up to now published MPI tracers made by coprecipitation. To evaluate the MPI characteristics of MCP 3 two kinds of tube phantoms were prepared and investigated to assess sensitivity, spatial resolution, artifact severity, and selectivity. Resovist® was used as standard of comparison. For image reconstruction, the regularization factor was optimized, and the resulting images were investigated in terms of quantifying of volumes and iron content. Our results demonstrate the superiority of MCP 3 over Resovist® for all investigated MPI characteristics and suggest that MCP 3 is promising for future experimental in vivo studies.


Effects of developmental conditions on growth, stress and telomeres in black-legged kittiwake chicks.
Early-life conditions can drive ageing patterns and life history strategies throughout the lifespan. Certain social, genetic and nutritional developmental conditions are more likely to produce high-quality offspring: those with good likelihood of recruitment and productivity. Here, we call such conditions "favoured states" and explore their relationship with physiological variables during development in a long-lived seabird, the black-legged kittiwake (Rissa tridactyla). Two favoured states were experimentally generated by manipulation of food availability and brood size, while hatching order and sex were also explored as naturally generating favoured states. Thus, the favoured states we explored were high food availability, lower levels of sibling competition, hatching first and male sex. We tested the effects of favoured developmental conditions on growth, stress, telomere length (a molecular marker associated with lifespan) and nestling survival. Generation of favoured states through manipulation of both the nutritional and social environments furthered our understanding of their relative contributions to development and phenotype: increased food availability led to larger body size, reduced stress and higher antioxidant status, while lower sibling competition (social environment) led to lower telomere loss and longer telomere lengths in fledglings. Telomere length predicted nestling survival, and wing growth was also positively correlated with telomere length, supporting the idea that telomeres may indicate individual quality, mediated by favoured states.


Negeviruses Reduce Replication of Alphaviruses during Coinfection.
Negeviruses are a group of insect-specific viruses (ISVs) that have been found in many arthropods. Their presence in important vector species led us to examine their interactions with arboviruses during coinfections. Wild-type negeviruses reduced the replication of several alphaviruses during coinfections in mosquito cells. Negev virus (NEGV) isolates were also used to express green fluorescent protein (GFP) and anti-chikungunya virus (CHIKV) antibody fragments during coinfections with CHIKV. NEGV expressing anti-CHIKV antibody fragments was able to further reduce replication of CHIKV during coinfections, while reductions of CHIKV with NEGV expressing GFP were similar to titers with wild-type NEGV alone. These results are the first to show that negeviruses induce superinfection exclusion of arboviruses and to demonstrate a novel approach to deliver antiviral antibody fragments with paratransgenic ISVs. The ability to inhibit arbovirus replication and express exogenous proteins in mosquito cells makes negeviruses a promising platform for control of arthropod-borne pathogens. IMPORTANCE Negeviruses are a group of insect-specific viruses (ISVs), viruses known to infect only insects. They have been discovered over a wide geographical and species range. Their ability to infect mosquito species that transmit dangerous arboviruses makes negeviruses a candidate for a pathogen control platform. Coinfections of mosquito cells with a negevirus and an alphavirus demonstrated that negeviruses can inhibit the replication of alphaviruses. Additionally, modifying Negev virus (NEGV) to express a fragment of an anti-CHIKV antibody further reduced the replication of CHIKV in coinfected cells. This is the first evidence to demonstrate that negeviruses can inhibit the replication of important arboviruses in mosquito cells. The ability of a modified NEGV to drive the expression of antiviral proteins also highlights a method for negeviruses to target specific pathogens and limit the incidence of vector-borne diseases.


JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells.
It has been recently shown that cannabinoids, the active components of marijuana and their derivatives, inhibit cell cycle progression of human breast cancer cells. Here we studied the mechanism of Delta(9)-tetrahydrocannabinol (THC) antiproliferative action in these cells, and show that it involves the modulation of JunD, a member of the AP-1 transcription factor family. THC activates JunD both by upregulating gene expression and by translocating the protein to the nuclear compartment, and these events are accompanied by a decrease in cell proliferation. Of interest, neither JunD activation nor proliferation inhibition was observed in human non-tumour mammary epithelial cells exposed to THC. We confirmed the importance of JunD in THC action by RNA interference and genetic ablation. Thus, in both JunD-silenced human breast cancer cells and JunD knockout mice-derived immortalized fibroblasts, the antiproliferative effect exerted by THC was significantly diminished. Gene array and siRNA experiments support that the cyclin-dependent kinase inhibitor p27 and the tumour suppressor gene testin are candidate JunD targets in cannabinoid action. In addition, our data suggest that the stress-regulated protein p8 participates in THC antiproliferative action in a JunD-independent manner. In summary, this is the first report showing not only that cannabinoids regulate JunD but, more generally, that JunD activation reduces the proliferation of cancer cells, which points to a new target to inhibit breast cancer progression.


Limiting amino acids in an 11% crude protein corn-soybean meal diet for growing pigs.
Three experiments were conducted to test the hypothesis that methionine, isoleucine, valine or nitrogen either singly or in combination are limiting in an 11% crude protein, lysine-tryptophan-threonine-supplemented, corn-soybean meal diet for growing pigs. A 16% crude protein diet was used as a positive control in each experiment and all amino acid additions were made, at a minimum, to equal requirements. Average initial weights were 21.3 kg, 23.0 kg and 19.1 kg in Exp. 1, 2 and 3, respectively. The experiments averaged 4 wk in duration. In Exp. 1 and 2, neither the addition of glutamic acid as a source of nitrogen, nor methionine to the 11% diet resulted in any improvement (P greater than .20) in rate or efficiency of growth. Addition of the combination of isoleucine and valine to the 11% diet resulted in an increase (P less than .05) in both growth rate and feed efficiency to a level not different (P greater than .20) from that of the pigs consuming the positive control diet. The addition of valine to the 11% crude protein diet with supplemental lysine, tryptophan and threonine (Exp. 3) caused an improvement in daily gain (P less than .05) but not feed efficiency (P greater than .10). Isoleucine addition tended to reduce pig performance. The results of these experiments suggest that an 11% crude protein, corn-soybean meal diet fortified with lysine, tryptophan and threonine is not limiting in sulfur amino acids or nitrogen. Valine may be the only limiting amino acid.


DNA damage response, a double-edged sword for vascular aging.
Vascular aging is a major risk factor for age-related cardiovascular diseases, which have high rates of morbidity and mortality. It is characterized by changes in the blood vessels, such as macroscopically increased vascular diameter and intima-medial thickness, chronic inflammation, vascular calcification, arterial stiffening, and atherosclerosis. DNA damage and the subsequent various DNA damage response (DDR) pathways are important causative factors of vascular aging. Deficient DDR, which may result in the accumulation of unrepaired damaged DNA or mutations, can lead to vascular aging. On the other hand, over-activation of some DDR proteins, such as poly (ADP ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM), also can enhance the process of vascular aging, suggesting that DDR can have both positive and negative effects on vascular aging. Despite the evidence reviewed in this paper, the role of DDR in vascular aging and potential therapeutic targets remain poorly understood and require further investigation.


Zinn's zonule.
The Zonule of Zinn, or ciliary zonule, is the elaborate system of extracellular fibers that centers the lens in the eye. In humans, the fibers transmit forces that flatten the lens during the process of disaccommodation, thereby bringing distant objects into focus. Zonular fibers are composed almost entirely of 10-12 nm-wide microfibrils, of which polymerized fibrillin is the most abundant component. The thickest fibers have a fascicular organization, where hundreds or thousands of microfibrils are gathered into micrometer-wide bundles. Many such bundles are aggregated to form a fiber. Dozens of proteins comprise the zonule. Most are derived from cells of the non-pigmented ciliary epithelium in the pars plana region, although some are probably contributed by the lens and perhaps other tissues of the anterior segment. Zonular fibers are viscoelastic cables but their component microfibrils are rather stiff structures. Thus, the elastic properties of the fibers likely stem from lateral interactions between microfibrils. Rupture of zonular fibers and subsequent lens dislocation (ectopia lentis) can result from blunt force trauma or be a sequela of other eye diseases, notably exfoliation syndrome. Ectopia lentis is also a feature of syndromic conditions caused typically by mutations in microfibril-associated genes. The resulting ocular phenotypes raise the possibility that the zonule regulates lens size and shape, globe size, and even corneal topology, in addition to its well-recognized role in accommodation.


Effects of exogenous glycinebetaine and trehalose on lead accumulation in an aquatic plant (Lemna gibba L.).
This study was aimed at investigating and comparing the effects of exogenous glycinebetaine (GB) and trehalose (TR) on lead (Pb) accumulation in Lemna gibba. Two-way ANOVA showed that both GB and TR had significant effects on Pb accumulation. However, TR seemed to be more effective than GB. It was determined that 5 mM GB application decreased Pb accumulation whereas 0.5 mM TR increased and 2 and 5 mM decreased Pb accumulation. The results obtained from this study will be useful for examining the phytoremediation of polluted water using aquatic plants.


Management of displaced ankle fractures.
Ankle fractures excluding pilon fractures, account for approximately 9% of all fractures with the majority being OTA type B injuries. Although surgeons generally treat undisplaced or minimally displaced injuries nonoperatively and displaced fractures operatively, opinions diverge regarding the management of those displaced fractures with acceptable closed reduction. There is also debate about the use of biodegradable implants in operatively managed ankle fractures, the type and technique of fixation for operatively treated syndesmotic injuries as well as the approach to postoperative rehabilitation. We aimed to review the highest level of available evidence on the operative management of ankle fractures. We focused specifically on studies comparing (1) nonoperative versus operative management of displaced ankle fractures, (2) biodegradable versus metal implants, (3) syndesmotic fixation, and (4) postoperative rehabilitation protocols.


Seasonal Variation in Vitamin D in Association with Age, Inflammatory Cytokines, Anthropometric Parameters, and Lifestyle Factors in Older Adults.
Vitamin D deficiency is present even in sunny regions. Ageing decreases pre-vitamin D production in the skin and is associated with altered cytokine profile. We performed a multivariate analysis considering lifestyle factors, anthropometric, and inflammatory markers according to seasonal variation in Mexican healthy older adults. The same cohort was followed during 12 months. Vitamin D deficiency/insufficiency was found in 91.3% of the subjects despite living in appropriate latitude (25°40'0″N). 25(OH)D levels remained below <30 ng/mL through all seasons. Vitamin D deficiency did not correlate to sun exposure or dietary intake. Gender was the strongest associated factor, explaining a variance of 20%. Waist circumference (WC) greater than 88 cm was a risk factor for vitamin D deficiency. Age (>74 years) combined with WC (>88 cm) and BMI (>32.7) showed a high probability (90%) of vitamin D deficiency. Remarkably, an increase in one centimeter in WC decreased 25(OH)D by 0.176 ng/mL, while an increase in one point BMI decreased 25(OH)D by 0.534 ng/mL. A cutoff point of 74 years of age determined probability of vitamin D hipovitaminosis. Vitamin D deficiency was correlated with TNF-α serum levels, possibly increasing the susceptibility of older adults to a proinflammatory state and its related diseases.


A Review on Strategies to Manage Physician Burnout.
Physician burnout is an emerging condition that can adversely affect the performance of modern-day medicine. Its three domains are emotional exhaustion, depersonalization, and a sense of reduced accomplishment among physicians, with the Maslach Burnout Inventory (MBI) being the gold standard questionnaire used to scale physician burnout. This concern not only impacts physicians but the entire healthcare system in general. There is growing awareness regarding the mental health of physicians and the consequences faced by the healthcare system as a result of burnout. According to a recent study, more than 50% of physicians reported suffering from at least one burnout symptom. In this review article, we aim to identify the causes leading to burnout, its impact on physicians, and hospital management as well as interventions to reduce this work-related syndrome. Some contributing factors leading to burnout are poor working conditions with long work shifts, stressful on-call duties, lack of appreciation, and poor social interactions. Burnout can lead to adverse consequences, such as depression, substance use, and suicidal ideation in physicians and residents. This can result in poor patient care increasing total length of stay, re-admissions, and major medical errors. Due to increased scrutiny of patient and healthcare costs, along with increased lawsuits as a result of major medical errors, it is crucial for both the hospital management and physicians to recognize and address burnout among physicians. Comprehensive professional training such as Cognitive behavioral therapy (CBT), stress-reducing activities such as mindfulness and group activities, and strict implementation of work-hour limitations recommended by Accreditation Council for Graduate Medical Education (ACGME) for residents are a few methods that may help to manage burnout and increase productivity in hospitals.


Oocyte quality in adult polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in women. Folliculogenesis in the PCOS ovary is often disrupted, leading to suboptimal oocyte competence for fertilization. This alteration in oocyte development is likely due to intrinsic molecular defects in the oocyte along with the state of androgen excess in PCOS patients. Many therapeutic options are available to infertile couples with PCOS, including controlled ovarian hyperstimulation and in vitro fertilization. However, because of immature oocytes, many patients are not able to conceive using standard infertility treatments. The advent of in vitro maturation may allow patients an alternative option by which to achieve conception. This review is intended to describe the mechanisms of aberrant folliculogenesis and their impact on fertility in the PCOS patient.


Reconstituted coronavirus TGEV virosomes lose the virus ability to induce porcine interferon-alpha production.
The transmissible gastroenteritis virus (TGEV) is a coronavirus which induces a strong interferon-alpha (IFN-alpha) production in vivo and in vitro. Previous studies have shown that the TGEV external protein M plays a major role in IFN-alpha induction by a non-infectious virus, whereas protein S is not involved. The present study extended these results by showing that monoclonal antibodies (MAbs) directed at the external viral protein sM could not block IFN-alpha induction, which argues against a direct role for this protein. In the same type of blocking experiment, MAbs to the TGEV receptor aminopeptidase N did not inhibit IFN-alpha induction, which strongly indicates that viral replication or entry through the receptor is not needed for TGEV induction of IFN-alpha in leukocytes. In an attempt to isolate functional envelope proteins, TGEV virions were detergent-solubilized and reconstituted in virosomes. Although BIAcore antigenic analysis revealed that the three external viral proteins were present on the virosomes, these proteins were unable to induce IFN-alpha in porcine leukocytes, and seemed to compete with the native virus for IFN-alpha induction. These data indicated that IFN-alpha inducing interactions between TGEV external proteins and leukocytes required a complex native envelope protein structure which has been lost in the virosomes.


An improved method using adaptive smoothing for GNSS tomographic imaging of ionosphere.
Global navigation satellite system (GNSS) is a well-established sensors in the recent ionosphere research. By comparing with classical meteorological equipments, the GNSS application can obtain more reliable and precious ionospheric total electron content (TEC) result. However, the most used GNSS ionospheric tomography technique is sensitive to a priori information due to the sparse and non-uniform distribution of GNSS stations. In this paper, we propose an improved method based on adaptive Laplacian smoothing and algebraic reconstruction technique (ALS-ART). Compared with traditional constant constraints, this method is less dependent on a priori information and adaptive smoothing constraints is closer to the actual situation. Tomography experiments using simulated data show that reconstruction accuracy of ionospheric electron density using ALS-ART method is significantly improved. We also use the method to do the analysis of real observation data and compare the tomography results with ionosonde observation data. The results demonstrate the superiority and reliability of the proposed method compared to traditional constant constraints method which will further improve the capability of obtaining precious ionosphere TEC by using GNSS.


The Yersinia enterocolitica GsrA stress protein, involved in intracellular survival, is induced by macrophage phagocytosis.
The Yersinia enterocolitica gsrA gene is a stress protein gene which was originally identified as essential for protecting cells under both extracellular environmental stress and intracellular stress in macrophages due to phagocytosis. The gsrA gene was shown to be a member of the htrA class of genes and to possess a sequence homologous to that of the promoter recognized by a stress-induced sigma factor, sigmaE. In order to study the induction of the potentially sigmaE-controlled gsrA gene in Y. enterocolitica after phagocytosis by macrophages, we identified GsrA by overproducing the protein using a T7 promoter-gsrA fusion. We found that it is translated as an unstable 49,500-Da protein which is processed by removal of an amino acid fragment consisting of 27 residues, resulting in a stable 46,800-Da protein. By radiolabeling proteins specific to bacteria in the J774-1 macrophage-like cell line, we found that the production of GsrA protein is indeed enhanced in bacterial cells growing within macrophage phagosomes. Transcriptional activation of the gsrA gene was determined by using the gsrA promoter-lacZ fusion system. This work provides the first piece of evidence that the sigmaE regulon responds to the stressful environment found in macrophages.


[Local cambial zones in the brain of mammals in the postnatal period].
On the basis of both the authors' and published data, the structure and morphogenetic functions are analyzed for two zones of mammal brain during postnatal period: fascia dentata of hippocampus and cerebellar cortex. A conclusion is drawn that the local cambial zones arise in those brain regions which acquire in the process of morphogenesis a high degree of spatial separation from the ventricular zone. The main function of the cambial zones in question is the formation of a large number of microneurons during postnatal period.


Cost data in implementation science: categories and approaches to costing.
A lack of cost information has been cited as a barrier to implementation and a limitation of implementation research. This paper explains how implementation researchers might optimize their measurement and inclusion of costs, building on traditional economic evaluations comparing costs and effectiveness of health interventions. The objective of all economic evaluation is to inform decision-making for resource allocation and to measure costs that reflect opportunity costs-the value of resource inputs in their next best alternative use, which generally vary by decision-maker perspective(s) and time horizon(s). Analyses that examine different perspectives or time horizons must consider cost estimation accuracy, because over longer time horizons, all costs are variable; however, with shorter time horizons and narrower perspectives, one must differentiate the fixed and variable costs, with fixed costs generally excluded from the evaluation. This paper defines relevant costs, identifies sources of cost data, and discusses cost relevance to potential decision-makers contemplating or implementing evidence-based interventions. Costs may come from the healthcare sector, informal healthcare sector, patient, participant or caregiver, and other sectors such as housing, criminal justice, social services, and education. Finally, we define and consider the relevance of costs by phase of implementation and time horizon, including pre-implementation and planning, implementation, intervention, downstream, and adaptation, and through replication, sustainment, de-implementation, or spread.


Troponin T3 expression in skeletal and smooth muscle is required for growth and postnatal survival: characterization of Tnnt3(tm2a(KOMP)Wtsi) mice.
The troponin complex, which consists of three regulatory proteins (troponin C, troponin I, and troponin T), is known to regulate muscle contraction in skeletal and cardiac muscle, but its role in smooth muscle remains controversial. Troponin T3 (TnnT3) is a fast skeletal muscle troponin believed to be expressed only in skeletal muscle cells. To determine the in vivo function and tissue-specific expression of Tnnt3, we obtained the heterozygous Tnnt3+/flox/lacZ mice from Knockout Mouse Project (KOMP) Repository. Tnnt3(lacZ/+) mice are smaller than their WT littermates throughout development but do not display any gross phenotypes. Tnnt3(lacZ/lacZ) embryos are smaller than heterozygotes and die shortly after birth. Histology revealed hemorrhagic tissue in Tnnt3(lacZ/lacZ) liver and kidney, which was not present in Tnnt3(lacZ/+) or WT, but no other gross tissue abnormalities. X-gal staining for Tnnt3 promoter-driven lacZ transgene expression revealed positive staining in skeletal muscle and diaphragm and smooth muscle cells located in the aorta, bladder, and bronchus. Collectively, these findings suggest that troponins are expressed in smooth muscle and are required for normal growth and breathing for postnatal survival. Moreover, future studies with this mouse model can explore TnnT3 function in adult muscle function using the conditional-inducible gene deletion approach


Pancreatic enzymes in chronic renal failure.
Serum was obtained from 55 patients, including 43 with stable chronic renal failure (CRF) (28 receiving chronic hemodialysis [CHD] and 15 receiving chronic ambulatory peritoneal dialysis [CAPD]), nine with peritonitis receiving CAPD, and three with pancreatitis receiving CAPD. Total serum amylase activity, lipase activity, isoamylase fractionation, and lipase concentration were used to measure pancreatic enzymes. Amylase activity was increased in 35 of 43 patients with CRF but was greater than threefold elevated in only three. Pancreatic isoamylase activity was greater than 80% in only one patient with CRF but was greater than 80% in all three patients with pancreatitis receiving CAPD. Lipase activity was increased in 26 patients and lipase concentration was elevated in 27. Peritoneal fluid from three patients with pancreatitis receiving CAPD contained high levels of amylase. Serum amylase and lipase are frequently elevated in patients with CRF in the absence of clinical pancreatitis. However, serum amylase activity greater than threefold elevated or the presence of pancreatic enzymes in the peritoneal fluid may suggest coexistent pancreatitis.


Distinct Neural Correlates Underlie Inhibitory Mechanisms of Motor Inhibition and Motor Imagery Restraint.
There is evidence to suggest that motor execution and motor imagery both involve planning and execution of the same motor plan, however, in the latter the output is inhibited. Currently, little is known about the underlying neural mechanisms of motor output inhibition during motor imagery. Uncovering the distinctive characteristics of motor imagery may help us better understand how we abstract complex thoughts and acquire new motor skills. The current study aimed to dissociate the cognitive processes involved in two distinct inhibitory mechanisms of motor inhibition and motor imagery restraint. Eleven healthy participants engaged in an imagined GO/NO-GO task during a 7 Tesla fMRI experiment. Participants planned a specific type of motor imagery, then, imagined the movements during the GO condition and restrained from making a response during the NO-GO condition. The results revealed that specific sub-regions of the supplementary motor cortex (SMC) and the primary motor cortex (M1) were recruited during the imagination of specific movements and information flowed from the SMC to the M1. Such condition-specific recruitment was not observed when motor imagery was restrained. Instead, general recruitment of the posterior parietal cortex (PPC) was observed, while the BOLD activity in the SMC and the M1 decreased below the baseline at the same time. Information flowed from the PPC to the SMC, and recurrently between the M1 and the SMC, and the M1 and the PPC. These results suggest that motor imagery involves task-specific motor output inhibition partly imposed by the SMC to the M1, while the PPC globally inhibits motor plans before they are passed on for execution during the restraint of responses.