Locked chromophore analogs reveal that photoactive yellow protein regulates biofilm formation in the deep sea bacterium Idiomarina loihiensis.
Idiomarina loihiensis is a heterotrophic deep sea bacterium with no known photobiology. We show that light suppresses biofilm formation in this organism. The genome of I. loihiensis encodes a single photoreceptor protein: a homologue of photoactive yellow protein (PYP), a blue light receptor with photochemistry based on trans to cis isomerization of its p-coumaric acid (pCA) chromophore. The addition of trans-locked pCA to I. loihiensis increases biofilm formation, whereas cis-locked pCA decreases it. This demonstrates that the PYP homologue regulates biofilm formation in I. loihiensis, revealing an unexpected functional versatility in the PYP family of photoreceptors. These results imply that I. loihiensis thrives not only in the deep sea but also near the water surface and provide an example of genome-based discovery of photophysiological responses. The use of locked pCA analogs is a novel and generally applicable pharmacochemical tool to study the in vivo role of PYPs irrespective of genetic accessibility. Heterologously produced PYP from I. loihiensis (Il PYP) absorbs maximally at 446 nm and has a pCA pK(a) of 3.4. Photoexcitation triggers the formation of a pB signaling state that decays with a time constant of 0.3 s. FTIR difference signals at 1726 and 1497 cm(-1) reveal that active-site proton transfer during the photocycle is conserved in Il PYP. It has been proposed that a correlation exists between the lifetime of a photoreceptor signaling state and the time scale of the biological response that it regulates. The data presented here provide an example of a protein with a rapid photocycle that regulates a slow biological response.


Single-cycle-PLL detection for real-time FM-AFM applications.
In this paper we present a novel architecture for phase-locked loop (PLL) based high-speed demodulation of frequency-modulated (FM) atomic force microscopy (AFM) signals. In our approach, we use single-sideband (SSB) frequency upconversion to translate the AFM signal from the position sensitive detector to a fixed intermediate frequency (IF) of 10 MHz. In this way, we fully benefit from the excellent noise performance of PLL-based FM demodulators still avoiding the intrinsic bandwidth limitation of such systems. In addition, the upconversion to a fixed IF renders the PLL demodulator independent of the cantilever's resonance frequency, allowing the system to work with a large range of cantilever frequencies. To investigate if the additional noise introduced by the SSB upconverter degrades the system noise figure we present a model of the AM-to-FM noise conversion in PLLs incorporating a phase-frequency detector. Using this model, we can predict an upper corner frequency for the demodulation bandwidth above which the converted noise from the single-sideband upconverter becomes the dominant noise source and therefore begins to deteriorate the overall system performance. The approach is validated by both electrical and AFM measurements obtained with a PCB-based prototype implementing the proposed demodulator architecture.


STAPP: Spatiotemporal analysis of plantar pressure measurements using statistical parametric mapping.
Pedobarography produces large sets of plantar pressure samples that are routinely subsampled (e.g. using regions of interest) or aggregated (e.g. center of pressure trajectories, peak pressure images) in order to simplify statistical analysis and provide intuitive clinical measures. We hypothesize that these data reductions discard gait information that can be used to differentiate between groups or conditions. To test the hypothesis of null information loss, we created an implementation of statistical parametric mapping (SPM) for dynamic plantar pressure datasets (i.e. plantar pressure videos). Our SPM software framework brings all plantar pressure videos into anatomical and temporal correspondence, then performs statistical tests at each sampling location in space and time. Novelly, we introduce non-linear temporal registration into the framework in order to normalize for timing differences within the stance phase. We refer to our software framework as STAPP: spatiotemporal analysis of plantar pressure measurements. Using STAPP, we tested our hypothesis on plantar pressure videos from 33 healthy subjects walking at different speeds. As walking speed increased, STAPP was able to identify significant decreases in plantar pressure at mid-stance from the heel through the lateral forefoot. The extent of these plantar pressure decreases has not previously been observed using existing plantar pressure analysis techniques. We therefore conclude that the subsampling of plantar pressure videos - a task which led to the discarding of gait information in our study - can be avoided using STAPP.


Feasibility study of pre-clinical Thiel embalmed human cadaver for MR-guided focused ultrasound of the spine.
Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) is a non-invasive treatment option based on high acoustic absorption and minimal thermal conductivity of the bone to destroy nerves and reduce pain. There is lack of a preclinical validation tool with correct human anatomy. This work introduces usage of an ex-vivo Thiel embalmed human tissue model for preclinical verification of MRgFUS on intervertebral discs or bone metastases within the spinal body. Thiel embalmed human cadaver was subjected to FUS sonication of the vertebra (with energies 250J, 420J, 600J) and the intervertebral disc (with energies 310J, 610J, 950J) of the lumbar spine for 20s of sonication under MR guidance. For the vertebra, maximum temperatures were recorded as 38 °C, 58.3 °C, 69 °C. The intervertebral disc reached maximum temperatures of 23.7 °C, 54 °C, 83 °C. The temperature measurements showed that the spinal canal and adjacent organs were not heated > 0.1 °C. A heating pattern that can induce thermal ablation was achieved in the vertebral body and the intervertebral disc. Adjacent structures and nerves were not heated in lethal levels. Thus, the Thiel embalmed human cadaver can be a safe and efficient model for preclinical study of application of MRgFUS on the upper lumbar spine.


Our Environment Shapes Us: The Importance of Environment and Sex Differences in Regulation of Autoantibody Production.
Consequential differences exist between the male and female immune systems' ability to respond to pathogens, environmental insults or self-antigens, and subsequent effects on immunoregulation. In general, females when compared with their male counterparts, respond to pathogenic stimuli and vaccines more robustly, with heightened production of antibodies, pro-inflammatory cytokines, and chemokines. While the precise reasons for sex differences in immune response to different stimuli are not yet well understood, females are more resistant to infectious diseases and much more likely to develop autoimmune diseases. Intrinsic (i.e., sex hormones, sex chromosomes, etc.) and extrinsic (microbiome composition, external triggers, and immune modulators) factors appear to impact the overall outcome of immune responses between sexes. Evidence suggests that interactions between environmental contaminants [e.g., endocrine disrupting chemicals (EDCs)] and host leukocytes affect the ability of the immune system to mount a response to exogenous and endogenous insults, and/or return to normal activity following clearance of the threat. Inherently, males and females have differential immune response to external triggers. In this review, we describe how environmental chemicals, including EDCs, may have sex differential influence on the outcome of immune responses through alterations in epigenetic status (such as modulation of microRNA expression, gene methylation, or histone modification status), direct and indirect activation of the estrogen receptors to drive hormonal effects, and differential modulation of microbial sensing and composition of host microbiota. Taken together, an intriguing question develops as to how an individual's environment directly and indirectly contributes to an altered immune response, dysregulation of autoantibody production, and influence autoimmune disease development. Few studies exist utilizing well-controlled cohorts of both sexes to explore the sex differences in response to EDC exposure and the effects on autoimmune disease development. Translational studies incorporating multiple environmental factors in animal models of autoimmune disease are necessary to determine the interrelationships that occur between potential etiopathological factors. The presence or absence of autoantibodies is not a reliable predictor of disease. Therefore, future studies should incorporate all the susceptibility/influencing factors, coupled with individual genomics, epigenomics, and proteomics, to develop a model that better predicts, diagnoses, and treats autoimmune diseases in a personalized-medicine fashion.


The relationship of oral health literacy and self-efficacy with oral health status and dental neglect.
We examined the associations of oral health literacy (OHL) with oral health status (OHS) and dental neglect (DN), and we explored whether self-efficacy mediated or modified these associations. We used interview data collected from 1280 female clients of the Special Supplemental Nutrition Program for Women, Infants and Children from 2007 to 2009 as part of the Carolina Oral Health Literacy Project. We measured OHL with a validated word recognition test (REALD-30), and we measured OHS with the self-reported National Health and Nutrition Examination Survey item. Analyses used descriptive, bivariate, and multivariate methods. Less than one third of participants rated their OHS as very good or excellent. Higher OHL was associated with better OHS (for a 10-unit REALD increase: multivariate prevalence ratio = 1.29; 95% confidence interval = 1.08, 1.54). OHL was not correlated with DN, but self-efficacy showed a strong negative correlation with DN. Self-efficacy remained significantly associated with DN in a fully adjusted model that included OHL. Increased OHL was associated with better OHS but not with DN. Self-efficacy was a strong correlate of DN and may mediate the effects of literacy on OHS.


Floral phenylpropanoid cocktail and architecture of Bulbophyllum vinaceum orchid in attracting fruit flies for pollination.
It is widely believed that most orchid flowers attract insects by using deception or chemical rewards in the form of nectar. Flowers of Bulbophyllum vinaceum produce a large array of phenylpropanoids that lure tephritid fruit fly males and also act as floral reward, which the flies subsequently convert to pheromone components. The major floral volatile components identified are methyl eugenol (ME), trans-coniferyl alcohol (CF), 2-allyl-4,5-dimethoxphenol (DMP), and trans-3,4-dimethoxycinnamyl acetate, whereas the minor components are eugenol, euasarone, trans-3,4-dimethoxy cinnamyl alcohol, and cis-coniferyl alcohol. Among the various floral parts, the lip (which is held in a closed position up against the sexual organs) has the highest concentration of the major compounds. An attracted male fly normally lands on one of the petals before climbing up onto and forcing the "spring loaded" floral lip into the open position, hence exposing the floral sexual organs. The architecture and location of chemical attractants of the lip compel the fly to align itself along the lip's longitudinal axis in a precise manner. As the fly laps up the compounds and moves towards the base of the lip, it passes the point of imbalance causing the lip to spring back to its normal closed position. The fly is catapulted headfirst into the column cavity, and its dorsum strikes the protruding sticky base of the hamulus and adheres to it. The momentum of the fly and the structural morphology of the long stiff hamulus act to pry out the pollinia from its anther cover. Hence, the pollinarium (pollinia + hamulus) is detached from the flower and adhered to the fly's dorsum. In this unique mutualistic association, both species receive direct reproductive benefits--the flower's pollinarium is transported for cross pollination, and the fly is offered a bouquet of phenylpropanoids (synomone) that it consumes, converts, and/or sequesters as sex pheromonal components, thus enhancing sexual attraction and mating success.


Clinical impact of H-Y alloimmunity.
H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H-Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next-generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity.


The Role of Cardiopulmonary Exercise Testing for Decision Making in Patients with Repaired Tetralogy of Fallot.
Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. As a result of the surgical strategies employed at the time of initial repair, chronic pulmonary regurgitation (PR) is prevalent in this population. Despite sustained research efforts, patient selection and timing of pulmonary valve replacement (PVR) to address PR in young asymptomatic patients with repaired tetralogy of Fallot (rToF) remain a fundamental but as yet unanswered question in the field of congenital heart disease. The ability of the heart to compensate for the chronic volume overload imposed by PR is critical in the evaluation of the risks and benefits of PVR. The difficulty in clarifying the functional impact of PR on the cardiovascular capacity may be in part responsible for the uncertainty surrounding the timing of PVR. Cardiopulmonary exercise testing (CPET) may be used to assess abnormal cardiovascular response to increased physiologic demands. However, its use as a tool for risk stratification in asymptomatic adolescents and young adults with rToF is still ill-defined. In this paper, we review the role of CPET as a potentially valuable adjunct to current risk stratification strategies with a focus on asymptomatic rToF adolescents and young adults being considered for PVR. The role of maximal and submaximal exercise measurements to identify young patients with a decreased or borderline low peak VO2 resulting from impaired ventricular function is explored. Current knowledge gaps and research perspectives are highlighted.


Indirect allorecognition of mismatched donor HLA class II peptides in lung transplant recipients with bronchiolitis obliterans syndrome.
A correlation between indirect allorecognition of mismatched donor HLA class I peptides and development of bronchiolitis obliterans syndrome (BOS) after lung transplantation has been previously observed. The aim of this study was to determine whether there was a correlation between indirect allorecognition of mismatched donor HLA class II peptides and development of BOS after lung transplantation. Peripheral blood mononuclear cells from nine BOS+ and nine BOS-lung transplant recipients were cultured with synthetic peptides corresponding to the beta-chain hypervariable region of a mismatched donor HLA-DR molecule. Then, proliferative alloreactivity as well as frequency of alloreactive T cells were determined. In addition, the immunodominant epitopes from the donor HLA-DR molecules were identified in selected patients. T cells from BOS+ patients showed a dose-dependent proliferative alloreactivity against donor HLA-DR peptides that was significantly higher than that observed in BOS- patients (p=0.001). Similarly, the frequency of HLA-DR alloreactive T cells was significantly higher in BOS+ patients than in BOS- patients (p=0.001). This T-cell alloreactivity was directed against a single immunodominant HLA-DR peptide. These results suggest that indirect alloreactivity to donor HLA class II molecules may play a role in the pathogenesis of BOS after lung transplantation.


Macrophage-mediated vascular permeability via VLA4/VCAM1 pathway dictates ascites development in ovarian cancer.
The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development. Previously, we provided evidence that perivascular M2-like macrophages protect the vascular barrier through direct contact with endothelial cells (ECs). Here, we investigated the molecular mechanism and its clinical significance in the ovarian cancer setting. We found that upon direct coculture with the endothelium, M2 macrophages tuned down their VLA4 and reduced the levels of VCAM1 in ECs. On the other hand, ectopically overexpressing VLA4 in macrophages or VCAM1 in ECs induced hyperpermeability. Mechanistically, downregulation of VLA4 or VCAM1 led to reduced levels of RAC1 and ROS, which resulted in decreased phosphorylation of PYK2 (p-PYK2) and VE-cadherin (p-VE-cad), hence enhancing cell adhesion. Furthermore, targeting the VLA4/VCAM1 axis augmented vascular integrity and abrogated ascites formation in vivo. Finally, VLA4 expression on the macrophages isolated from ascites dictated permeability ex vivo. Importantly, VLA4 antibody acted synergistically with bevacizumab to further enhance the vascular barrier. Taking these data together, we reveal here that M2 macrophages regulate the vascular barrier though the VCAM1/RAC1/ROS/p-PYK2/p-VE-cad cascade, which provides specific therapeutic targets for the treatment of malignant ascites.


Immunogenicity of HIV virus-like particles in rhesus macaques by intranasal administration.
Female rhesus macaques were immunized with HIV virus-like particles (HIV-VLPs) or HIV DNA administered as sequential combinations of mucosal (intranasal) and systemic (intramuscular) routes, according to homologous or heterologous prime-boost schedules. The results show that in rhesus macaques only the sequential intranasal and intramuscular administration of HIV-VLPs, and not the intranasal alone, is able to elicit humoral immune response at the systemic as well as the vaginal level.


Healthcare expenditure on Indigenous and non-Indigenous Australians at high risk of cardiovascular disease.
In spite of bearing a heavier burden of death, disease and disability, there is mixed evidence as to whether Indigenous Australians utilise more or less healthcare services than other Australians given their elevated risk level. This study analyses the Medicare expenditure and its predictors in a cohort of Indigenous and non-Indigenous Australians at high risk of cardiovascular disease. The healthcare expenditure of participants of the Kanyini Guidelines Adherence with the Polypill (GAP) pragmatic randomised controlled trial was modelled using linear regression methods. 535 adult (48% Indigenous) participants at high risk of cardiovascular disease (CVD) were recruited through 33 primary healthcare services (including 12 Aboriginal Medical Services) across Australia. There was no significant difference in the expenditure of Indigenous and non-Indigenous participants in non-remote areas following adjustment for individual characteristics. Indigenous individuals living in remote areas had lower MBS expenditure ($932 per year P < 0.001) than other individuals. MBS expenditure was found to increase with being aged over 65 years ($128, p = 0.013), being female ($472, p = 0.003), lower baseline reported quality of life ($102 per 0.1 decrement of utility p = 0.004) and a history of diabetes ($324, p = 0.001), gout ($631, p = 0.022), chronic obstructive pulmonary disease ($469, p = 0.019) and established CVD whether receiving guideline-recommended treatment prior to the trial ($452, p = 0.005) or not ($483, p = 0.04). When controlling for all other characteristics, morbidly obese patients had lower MBS expenditure than other individuals (-$887, p = 0.002). The findings suggest that for the majority of participants, once individuals are engaged with a primary care provider, factors other than whether they are Indigenous determine the level of Medicare expenditure for each person. Australian New Zealand Clinical Trials Registry ACTRN 126080005833347.


Lipid profiling and analytical discrimination of seven cereals using high temperature gas chromatography coupled to high resolution quadrupole time-of-flight mass spectrometry.
Minor lipids in cereals (such as phytosterols and alkylresorcinols) can be important for human nutrition and/or be used as biomarkers for cereal intake. However, the analysis of cereal lipids is very challenging due to the complex lipidome comprising several hundred individual compounds present over a wide range of concentrations. Here we present a method for the profiling of cereal lipids using high temperature gas chromatography coupled to high resolution mass spectrometry (GC/Q-TOF MS). The method was used to investigate the lipid profiles of 77 samples of bread wheat, spelt, einkorn, emmer, barley, rye and oats. Distinct differences in the patterns of alkylresorcinols, free and conjugated sterols and tocopherols between the cereals could be observed. Furthermore, traces of tocomonoenols and diunsaturated and methyl-alkylresorcinols (not previously reported in cereals) could be detected. Finally, the lipid patterns in the cereals could be used to separate the cereals by Principal Component Analysis.


Design and fabrication of an artificial cornea based on a photolithographically patterned hydrogel construct.
We describe the design and fabrication of an artificial cornea based on a photolithographically patterned hydrogel construct, and demonstrate the adhesion of corneal epithelial and fibroblast cells to its central and peripheral components, respectively. The design consists of a central "core" optical component and a peripheral tissue-integrable "skirt." The core is composed of a poly(ethylene glycol)/poly(acrylic acid) (PEG/PAA) double-network with high strength, high water content, and collagen type I tethered to its surface. Interpenetrating the periphery of the core is a microperforated, but resilient poly(hydroxyethyl acrylate) (PHEA) hydrogel skirt that is also surface-modified with collagen type I. The well-defined microperforations in the peripheral component were created by photolithography using a mask with radially arranged chrome discs. Surface modification of both the core and skirt elements was accomplished through the use of a photoreactive, heterobifunctional crosslinker. Primary corneal epithelial cells were cultured onto modified and unmodified PEG/PAA hydrogels to evaluate whether the central optic material could support epithelialization. Primary corneal fibroblasts were seeded onto the PHEA hydrogels to evaluate whether the peripheral skirt material could support the adhesion of corneal stromal cells. Cell growth in both cases was shown to be contingent on the covalent tethering of collagen. Successful demonstration of cell growth on the two engineered components was followed by fabrication of core-skirt constructs in which the central optic and peripheral skirt were synthesized in sequence and joined by an interpenetrating diffusion zone.


Climate-driven build-up of temporal isolation within a recently formed avian hybrid zone.
Divergence in the onset of reproduction can act as an important source of reproductive isolation (i.e., allochronic isolation) between co-occurring young species, but evidence for the evolutionary processes leading to such divergence is often indirect. While advancing spring seasons strongly affect the onset of reproduction in many taxa, it remains largely unexplored whether contemporary spring advancement directly affects allochronic isolation between young species. We examined how increasing spring temperatures affected onset of reproduction and thereby hybridization between pied and collared flycatchers (Ficedula spp.) across habitat types in a young secondary contact zone. We found that both species have advanced their timing of breeding in 14 years. However, selection on pied flycatchers to breed earlier was weaker, resulting in a slower response to advancing springs compared to collared flycatchers and thereby build-up of allochronic isolation between the species. We argue that a preadaptation to a broader niche use (diet) of pied flycatchers explains the slower response to raising spring temperature, but that reduced risk to hybridize may contribute to further divergence in the onset of breeding in the future. Our results show that minor differences in the response to environmental change of co-occurring closely related species can quickly cause allochronic isolation.


The ancestry and affiliations of Kennewick Man.
Kennewick Man, referred to as the Ancient One by Native Americans, is a male human skeleton discovered in Washington state (USA) in 1996 and initially radiocarbon dated to 8,340-9,200 calibrated years before present (BP). His population affinities have been the subject of scientific debate and legal controversy. Based on an initial study of cranial morphology it was asserted that Kennewick Man was neither Native American nor closely related to the claimant Plateau tribes of the Pacific Northwest, who claimed ancestral relationship and requested repatriation under the Native American Graves Protection and Repatriation Act (NAGPRA). The morphological analysis was important to judicial decisions that Kennewick Man was not Native American and that therefore NAGPRA did not apply. Instead of repatriation, additional studies of the remains were permitted. Subsequent craniometric analysis affirmed Kennewick Man to be more closely related to circumpacific groups such as the Ainu and Polynesians than he is to modern Native Americans. In order to resolve Kennewick Man's ancestry and affiliations, we have sequenced his genome to ∼1× coverage and compared it to worldwide genomic data including for the Ainu and Polynesians. We find that Kennewick Man is closer to modern Native Americans than to any other population worldwide. Among the Native American groups for whom genome-wide data are available for comparison, several seem to be descended from a population closely related to that of Kennewick Man, including the Confederated Tribes of the Colville Reservation (Colville), one of the five tribes claiming Kennewick Man. We revisit the cranial analyses and find that, as opposed to genome-wide comparisons, it is not possible on that basis to affiliate Kennewick Man to specific contemporary groups. We therefore conclude based on genetic comparisons that Kennewick Man shows continuity with Native North Americans over at least the last eight millennia.


Prescriber continuity and medication adherence for complex patients.
Medication adherence is a critical aspect of managing cardiometabolic conditions, including diabetes, hypertension, dyslipidemia, and heart failure. Patients who have multiple cardiometabolic conditions and multiple prescribers may be at increased risk for nonadherence. The purpose of this study was to examine the relationship between number of prescribers, number of conditions, and refill adherence to oral medications to treat cardiometabolic conditions. In this retrospective cohort study, 7933 veterans were identified with 1 to 4 cardiometabolic conditions. Refill adherence to oral medications for diabetes, hypertension, and dyslipidemia was measured using an administrative claims-based continuous multiple-interval gap (CMG) that estimates the percentage of days a patient did not possess medication. We dichotomized refill adherence for each condition as a CMG ≤20% for each year of analysis. Condition-specific logistic regression models estimated the relationship between refill adherence and number of cardiometabolic conditions and number of prescribers, controlling for demographic characteristics, other comorbidities, and a count of cardiometabolic drug classes used. Compared with patients with 1 prescriber, antihypertensive refill adherence was lower in patients seeing ≥4 prescribers (odds ratio [OR] = 0.69; 95% CI = 0.59-0.80), but the number of cardiometabolic conditions was not a significant predictor. Antidyslipidemia refill adherence was lower in patients seeing 3 prescribers (OR = 0.80; 95% CI = 0.70-0.92) or ≥4 prescribers (OR = 0.77; 95% CI = 0.64-0.91). Conversely, antidyslipidemia refill adherence improved with the number of cardiometabolic conditions, but differences were only statistically significant for ≥3 conditions (OR = 1.31; 95% CI = 1.09-1.57). In multivariate regression models, the number of conditions and number of prescribers were not significant predictors of refill adherence in the group of patients with diabetes. Effective management of care and medication regimens for complex patients remains an unresolved challenge, but these results suggest that medication refill adherence might be improved by minimizing the number of prescribers involved in a patient's care, at least for hypertension and dyslipidemia.


Dominant interfering alleles define a role for c-Myb in T-cell development.
The transcription activator c-Myb is expressed at high levels in immature thymocytes and during T-cell activation and may be a regulator of T-cell differentiation. To investigate the role of c-Myb in T-cell development, we generated transgenic mice in which two dominant interfering Myb alleles, one a competitive inhibitor of DNA binding, and the other, an active repressor comprising the Myb DNA-binding domain linked to the Drosophila Engrailed transcription repressor domain, were expressed from early times onward in T cells. Both alleles partially blocked thymopoiesis and inhibited proliferation of mature T cells. The Myb-En chimera was the more efficient repressor and might serve as an archetype for the manufacture of other dominant interfering transcription factor alleles.


COMPLEX RETINAL DETACHMENT IN PHAKIC PATIENTS: Previtrectomy Phacoemulsification Versus Combined Phacovitrectomy.
To assess the impact of phacoemulsification performed one week before pars plana vitrectomy versus combined phacovitrectomy on postoperative anterior segment status and final functional and anatomical outcomes in phakic patients affected by complex rhegmatogenous retinal detachment. The authors retrospectively reviewed the records of 59 phakic patients affected by complex rhegmatogenous retinal detachment. Twenty-nine patients underwent cataract surgery 7 days before vitrectomy (preemptive cataract surgery-Group 1), whereas 30 patients underwent combined phacovitrectomy (Group 2). Preoperative, intraoperative, early- and late-postoperative outcomes were measured and compared. Numbers of previous retinal surgical procedures, nuclear sclerosis grade, proliferative vitreoretinopathy grade, eyes with inferior breaks, surgical time, and ratio of silicone oil/gas tamponade were all similar between the two groups. After surgery, there was less extension of posterior synechia in Group 1. There was no significant difference in fibrin, number of patients with posterior synechia, final intraocular pressure, retinal redetachment rate, final retinal status, or final best-corrected visual acuity. Preemptive cataract surgery was associated with less extensive postoperative posterior synechia, however, its final functional and anatomical outcomes were not significantly different from those of phacovitrectomy. Both approaches were efficacious.


'New' direct oral anticoagulants in the perioperative setting.
Out of the anesthetist's perspective, some uncertainties remain with the perioperative management of the so-called NOACs. This review emphasizes on the question of bleeding and thromboembolic risk as well as the management of bleedings and the discontinuing intervals in the context of regional anesthesia. Managing patients with NOAC therapy, an interdisciplinary approach and consent with surgeons and specialist in hemostaseology has to be found. For severe and lifethreatening bleeding there are specific antidotes in development; however, until clinical provement is not yet finished the application of four-factor prothrombin complex concentrate may be the most promising approach. NOACs like dabigatran etexilate, rivaroxaban, apixaban and edoxaban are effective alternatives to warfarin in primary and secondary prophylaxis of thromboembolic conditions. In the perioperative setting, some uncertainties and evidence gaps remain in estimating the bleeding risks associated with surgical procedures, emergency trauma and neuroaxial anesthesia. A discontinuation of NOACs should be at least 1 day before elective operation. Renal and liver impairment, older age, or co-medications could afford longer intervals. As no specific reversal agents are yet available for life-threatening bleeding or emergency surgery; nonspecific prohemostatic therapies are mainly recommended. Oral charcoal, application of tranexamic acid or hemodialysis could bring additional benefit depending on the individual NOAC. Practitioners need to be aware that NOACs can interfere in different pathways with the measurement of common hemostasis parameters. Estimating the bleeding risks and reversal strategies requires careful evaluation also in the light of a potential risk of thromboembolic complications. In difference to warfarin, 'bridging' concepts are not generally recommended for NOACs.


[Dermatoglyphics of the relatives of children with congenital developmental defects].
The localization of an axial triradius and the flexor creases were studied in 173 phenotypically normal mothers and 104 fathers of congenitally malformed children. The most pronounced changes of dermatoglyphics were found in the parents of children with polygenic determined defects, less pronounced ones -- in the parents of children with multiple congenital non-chromosomal defects and with Down's syndrome. The frequency of the pathological features studied was similar both in children with polygenically determined isolated defects and in their parents. In multiple congenital defects and in Down's syndrome the abnormalities of the localization of an axial triradius and of the flexor creases were found in children more frequently than in the parents. It is suggested that the above mentioned peculiarities of parental dermatoglyphics may be useful for the genetic counselling.


Visual outcomes of Boston keratoprosthesis implantation as the primary penetrating corneal procedure.
To report the short-term visual outcomes and complications of keratoprosthesis surgery as the primary penetrating corneal procedure for patients at high risk for conventional corneal transplantation. A retrospective chart review was conducted of 21 eyes of 19 patients who underwent either Boston keratoprosthesis type I or type II as the primary penetrating corneal procedure from February 2007 to March 2011. Nineteen type I (90.5%) and 2 type II (9.5%) Boston keratoprosthesis procedures were performed in 19 patients. Mean follow-up was 14.6 months (range, 6-36.3 mo). Primary indications for surgery included chemical or thermal injury, aniridia, and Stevens-Johnson syndrome. Preoperative best-corrected visual acuity (BCVA) ranged from 20/100 to light perception and was count fingers or worse in 20 eyes (95.2%). At last follow-up for all eyes, 15 eyes (71.4%) achieved BCVA≥20/200 and 4 eyes (19%) improved to BCVA≥20/50. No intraoperative complications occurred. Postoperative complications include retroprosthetic membrane formation (47.6%), cystoid macular edema (33.3%), elevated intraocular pressure (23.8%), glaucoma progression (14.3%), and endophthalmitis (4.8%). The initial keratoprosthesis was retained in 19 eyes (90.5%). The Boston keratoprosthesis, based on early follow-up, is a good alternative as a primary penetrating corneal procedure in a select group of patients with very poor prognosis for penetrating keratoplasty. Although complications can occur and require close monitoring, visual acuity significantly improved in the majority of patients.


Diaqua-bis(4-methyl-benzoato-κO)bis-(nicotinamide-κN)nickel(II).
The title Ni(II) complex, [Ni(C(8)H(7)O(2))(2)(C(6)H(6)N(2)O)(2)(H(2)O)(2)], is centrosymmetric with the Ni atom located on an inversion center. The mol-ecule contains two 4-methyl-benzoate (PMB) and two nicotinamide (NA) ligands and two coordinated water mol-ecules, all ligands being monodentate. The four O atoms in the equatorial plane around the Ni atom form a slightly distorted square-planar arrangement, while the slightly distorted octa-hedral coordination is completed by the two N atoms of the NA ligands in the axial positions. The dihedral angle between the carboxyl-ate group and the adjacent benzene ring is 26.15 (10)°, while the pyridine and benzene rings are oriented at a dihedral angle of 87.81 (4)°. In the crystal structure, inter-molecular O-H⋯O and N-H⋯O hydrogen bonds link the mol-ecules into a three-dimensional network. The π-π contact between the benzene rings [centroid-centroid distance = 3.896 (1) Å] may further stabilize the crystal structure. A weak C-H⋯π inter-action involving the pyridine ring also occurs.


Outcome of symptoms of dizziness in a general practice community sample.
Dizziness is commonly experienced in the community, but little is known about the long-term progression of the condition. We aimed to assess over 18 months the outcome of symptoms of dizziness in a sample of patients identified from London general practices. We followed up at 18 months a cohort of patients who reported symptoms of dizziness with or without anxiety, panic reactions or avoidance of situations that provoked the symptoms. The subjects completed a structured questionnaire both at baseline and at 18 months. At 18 months, 24% (95% CI = 23.5-34.8%) were more handicapped and 20% (95% CI = 15.2-25.2%) had recurrent dizziness, while 20% (95% CI = 14.9-24.8%) had improved. Patients with significant dizziness were more likely to consult their GP (OR = 14.4, 95% CI = 7.0-29.1) and were more likely to receive treatment (OR = 7.8, 95% CI = 3.2-22.4) or be referred to hospital (OR = 8.4, 95% CI = 3.2-22.4). The independent predictors of handicapping dizziness at 18 months were a history of fainting (OR = 2.4, 95% CI = 1.2-4.7), vertigo (OR = 2.6, 95% CI = 1.3-5.0) and avoidance of a situation that provoke dizziness (OR = 4.8, 95% CI = 2.5-9.0). Four per cent of all patients registered with a GP suffer persistent symptoms of dizziness and at least 3% are severely incapacitated by their symptoms. The presence of vertigo, fainting and avoidance in a person with dizziness is predictive of chronic handicapping dizziness. Further research is required on the progressions of symptoms of dizziness in a sample of GP attenders and those in the community.


Role of the cytoplasmic domain in Anabaena sensory rhodopsin photocycling: vectoriality of Schiff base deprotonation.
Light-induced electric signals in intact E. coli cells generated by heterologously expressed full-length and C-terminally truncated versions of Anabaena sensory rhodopsin (ASR) demonstrate that the charge movements within the membrane-embedded part of the molecule are stringently controlled by the cytoplasmic domain. In particular, truncation inverts the direction of proton movement during Schiff base deprotonation from outward to cytoplasmic. Truncation also alters faster charge movements that occur before Schiff base deprotonation. Asp(217) as previously shown by FTIR serves as a proton acceptor in the truncated ASR but not in the full-length version, and its mutation to Asn restores the natural outward direction of proton movement. Introduction of a potential negative charge (Ser(86) to Asp) on the cytoplasmic side favors a cytoplasmic direction of proton release from the Schiff base. In contrast, mutation of the counterion Asp(75) to Glu reverses the photocurrent to the outward direction in the truncated pigment, and in both truncated and full-length versions accelerates Schiff base deprotonation more than 10-fold. The communication between the cytoplasmic domain and the membrane-embedded photoactive site of ASR demonstrated here is likely to derive from the receptor's use of a cytoplasmic protein for signal transduction, as has been suggested previously from binding studies.


Evolutionary history of the cobalamin-independent methionine synthase gene family across the land plants.
Plants are successful paleopolyploids. The wide diversity of land plants is driven strongly by their gene duplicates undergoing distinct evolutionary fates after duplication. We used genomic resources from 35 model plant species to unravel the evolutionary fate of gene copies (paralogs) of the cobalamin-independent methionine synthase (metE) gene family across the land plants. To explore genealogical relationships and characterize positive selection as a driving force in the evolution of metE paralogs within a single species, we carried out complementary analyses on genomic data of 32 genotypes of soybean. The size of the metE gene family remained small across the land plants; most of the studied species possessed 1-6 paralogs. Gene products were either cytosolic or chloroplastic; this dual subcellular distribution arose early during the divergence of the land plants and reached all extant lineages. Biased gene loss and gene retention events took place multiple times; recurrent evolution remodeled redundant metE paralogs to recover and maintain the dual subcellular distribution of MetE. Shared whole-genome duplication events gave rise to the metE paralogs of both soybean and Medicago truncatula. In soybean, the ancestral paralog pair GlymaPP2A encoded a cytosolic isoform of MetE, was under strong purifying selection, and retained high levels of expression across eight RNA-seq expression libraries. The daughters GlymaPP1 and GlymaPP2B showed accelerated rates of evolution, accumulated many sites predicted to be under positive selection, and possessed low levels of expression. Our results suggest that the metE paralogs of soybean follow Ohno's neofunctionalization model of gene duplicate evolution.


The visual word form system in context.
According to the "modular" hypothesis, reading is a serial feedforward process, with part of left ventral occipitotemporal cortex the earliest component tuned to familiar orthographic stimuli. Beyond this region, the model predicts no response to arrays of false font in reading-related neural pathways. An alternative "connectionist" hypothesis proposes that reading depends on interactions between feedforward projections from visual cortex and feedback projections from phonological and semantic systems, with no visual component exclusive to orthographic stimuli. This is compatible with automatic processing of false font throughout visual and heteromodal sensory pathways that support reading, in which responses to words may be greater than, but not exclusive of, responses to false font. This functional imaging study investigated these alternative hypotheses by using narrative texts and equivalent arrays of false font and varying the hemifield of presentation using rapid serial visual presentation. The "null" baseline comprised a decision on visually presented numbers. Preferential activity for narratives relative to false font, insensitive to hemifield of presentation, was distributed along the ventral left temporal lobe and along the extent of both superior temporal sulci. Throughout this system, activity during the false font conditions was significantly greater than during the number task, with activity specific to the number task confined to the intraparietal sulci. Therefore, both words and false font are extensively processed along the same temporal neocortical pathways, separate from the more dorsal pathways that process numbers. These results are incompatible with a serial, feedforward model of reading.


Ebola Virus Disease Complications as Experienced by Survivors in Sierra Leone.
Thousands of people have survived Ebola virus disease (EVD) during the ongoing outbreak. However, data about the frequency and risk factors of long-term post-EVD complications remain scarce. We describe the clinical characteristics of EVD survivors followed in a survivor clinic in Freetown, Sierra Leone. A survivor clinic opened within an Ebola treatment center compound in Freetown, Sierra Leone. At each visit, clinical and psychological assessments were conducted and free treatment was offered. Survivors were referred to a partner's hospitals if their condition could not be managed in the clinic. We used routinely collected data from the clinic to describe long-term complications of EVD and their risk factors. A total of 1001 medical consultations for 166 patients were performed between 3 February and 21 June 2015. The most frequent complaints and diagnoses were arthralgia (n = 129 [77.7%]), fatigue (n = 116 [69.8%]), abdominal pain (n = 90 [54.2%]), headache (n = 87 [52.4%]), anemia (n = 83 [50%]), skin disorders (n = 81 [48.8%]), back pain (n = 54 [32.5%]), and alopecia (n = 53 [31.9%]). Ocular complications were diagnosed in 94 survivors (56.7%); uveitis was the most common (n = 57 [34%]). Survivors were 10 times more likely to develop uveitis post-EVD if they presented with red/injected eyes during the acute phase of their illness. Post-EVD complications among our patients were similar to those described previously and were detected early following the acute phase of disease. Follow-up of survivors should begin immediately after discharge to address sequelae as they arise and reduce the potential for development of long-term disabilities such as blindness.


The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics.
Following our previous description of the serotonin transporter (SERT) acting as a conduit to 5-hydroxytryptamine (5-HT)-mediated apoptosis, specifically in Burkitt's lymphoma, we now detail its expression among a broad spectrum of B cell malignancy, while exploring additional SERT substrates for potential therapeutic activity. SERT was readily detected in derived B cell lines with origins as diverse as B cell precursor acute lymphoblastic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and multiple myeloma. Concentration and timecourse kinetics for the antiproliferative and proapoptotic activities of the amphetamine derivatives fenfluramine (an appetite suppressant) and 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") revealed them as being similar to the endogenous indoleamine. A tricyclic antidepressant, clomipramine, instead mirrored the behavior of the selective serotonin reuptake inhibitor fluoxetine, both being effective in the low micromolar range. A majority of neoplastic clones were sensitive to one or more of the serotonergic compounds. Dysregulated bcl-2 expression, either by t(14;18)(q32;q21) translocation or its introduction as a constitutively active transgene, provided protection from proapoptotic but not antiproliferative outcomes. These data indicate a potential for SERT as a novel anti-tumor target for amphetamine analogs, while evidence is presented that the seemingly more promising antidepressants are likely impacting malignant B cells independently of the transporter itself.


Molecular Insights into Human Serum Albumin as a Receptor of Amyloid-β in the Extracellular Region.
Regulation of amyloid-β (Aβ) aggregation by metal ions and proteins is essential for understanding the pathology of Alzheimer's disease (AD). Human serum albumin (HSA), a regulator of metal and protein transportation, can modulate metal-Aβ interactions and Aβ aggregation in human fluid; however, the molecular mechanisms for such activities remain unclear. Herein, we report the molecular-level complexation between Zn(II), Cu(II), Aβ, and HSA, which is able to alter the aggregation and cytotoxicity of Aβ peptides and induce their cellular transportation. In addition, a single Aβ monomer-bound HSA is observed with the structural change of Aβ from a random coil to an α-helix. Small-angle X-ray scattering (SAXS) studies indicate that Aβ-HSA complexation causes no structural variation of HSA in solution. Conversely, ion mobility mass spectrometry (IM-MS) results present that Aβ prevents the shrinkage of the V-shaped groove of HSA in the gas phase. Consequently, for the first time, HSA is demonstrated to predominantly capture a single Aβ monomer at the groove using the phase transfer of a protein heterodimer from solution to the gas phase. Moreover, HSA sequesters Zn(II) and Cu(II) from Aβ while maintaining Aβ-HSA interaction. Therefore, HSA is capable of controlling metal-free and metal-bound Aβ aggregation and aiding the cellular transportation of Aβ via Aβ-HSA complexation. The overall results and observations regarding HSA, Aβ, and metal ions advance our knowledge of how protein-protein interactions associated with Aβ and metal ions could be linked to AD pathogenesis.


Compound eye systems for nonunity magnification projection.
New compound eye systems for nonunity magnification projection are shown. As all the beams of light on the optical axes of erect or inverted real image systems intersect perpendicular to the object and image planes in these systems, it becomes possible to get rid of any local variation in magnification, which deteriorates the image quality of earlier compound eye systems.


Participation among women living with HIV: a rehabilitation perspective.
The purpose of this phenomenological study was to understand the lived experience of women living with HIV using a rehabilitation lens. Twenty-three women with a mean age of 40.8 years participated in personal interviews regarding barriers and facilitators to participation in society. An open coding analysis revealed the following themes associated with decreased participation: living in poverty, enduring depression and isolation, fearing disclosure and stigma, tolerating the signs and symptoms, experiencing barriers to work and lacking supportive networks. Themes related to women who were participating in their communities included meaning of children, balancing life with HIV, accessing support networks and possessing a strong self-identity. The findings highlight the complexity of the interaction between personal, environmental and health-related factors and the need for supports that incorporate the broader concept of rehabilitation.


Multi-omic molecular profiling of lung cancer in COPD.
Chronic obstructive pulmonary disease (COPD) is a known risk factor for developing lung cancer but the underlying mechanisms remain unknown. We hypothesise that the COPD stroma contains molecular mechanisms supporting tumourigenesis.We conducted an unbiased multi-omic analysis to identify gene expression patterns that distinguish COPD stroma in patients with or without lung cancer. We obtained lung tissue from patients with COPD and lung cancer (tumour and adjacent non-malignant tissue) and those with COPD without lung cancer for profiling of proteomic and mRNA (both cytoplasmic and polyribosomal). We used the Joint and Individual Variation Explained (JIVE) method to integrate and analyse across the three datasets.JIVE identified eight latent patterns that robustly distinguished and separated the three groups of tissue samples (tumour, adjacent and control). Predictive variables that associated with the tumour, compared to adjacent stroma, were mainly represented in the transcriptomic data, whereas predictive variables associated with adjacent tissue, compared to controls, were represented at the translatomic level. Pathway analysis revealed extracellular matrix and phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B signalling pathways as important signals in the tumour adjacent stroma.The multi-omic approach distinguishes tumour adjacent stroma in lung cancer and reveals two stromal expression patterns associated with cancer.


A CD11d monoclonal antibody treatment reduces tissue injury and improves neurological outcome after fluid percussion brain injury in rats.
Traumatic brain injury (TBI) is an international health concern often resulting in chronic neurological abnormalities, including cognitive deficits, emotional disturbances, and motor impairments. An anti-CD11d monoclonal antibody that blocks the CD11d/CD18 integrin and vascular cell adhesion molecule (VCAM)-1 interaction following experimental spinal cord injury improves functional recovery, while reducing the intraspinal number of neutrophils and macrophages, oxidative activity, and tissue damage. Since the mechanisms of secondary injury in the brain and spinal cord are similar, we designed a study to evaluate fully the effects of anti-CD11d treatment after a moderate lateral fluid percussion TBI in the rat. Rats were treated at 2 h after TBI with either the anti-CD11d antibody or an isotype-matched control antibody 1B7, and both short (24- to 72-h) and long (4-week) recovery periods were examined. The anti-CD11d integrin treatment reduced neutrophil and macrophage levels in the injured brain, with concomitant reductions in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss. The reduced neuroinflammation seen in anti-CD11d-treated rats correlated with improved performance on a number of behavioral tests. At 24 h, the anti-CD11d group performed significantly better than the 1B7 controls on several water maze measures of spatial cognition. At 4 weeks post-injury the anti-CD11d-treated rats had better sensorimotor function as assessed by the beam task, and reduced anxiety-like behaviors, as evidenced by elevated-plus maze testing, compared to 1B7 controls. These findings suggest that neuroinflammation is associated with behavioral deficits after TBI, and that anti-CD11d antibody treatment is a viable strategy to improve neurological outcomes after TBI.


A Primary Care Agenda for Brain Health: A Scientific Statement From the American Heart Association.
A healthy brain is critical for living a longer and fuller life. The projected aging of the population, however, raises new challenges in maintaining quality of life. As we age, there is increasing compromise of neuronal activity that affects functions such as cognition, also making the brain vulnerable to disease. Once pathology-induced decline begins, few therapeutic options are available. Prevention is therefore paramount, and primary care can play a critical role. The purpose of this American Heart Association scientific statement is to provide an up-to-date summary for primary care providers in the assessment and modification of risk factors at the individual level that maintain brain health and prevent cognitive impairment. Building on the 2017 American Heart Association/American Stroke Association presidential advisory on defining brain health that included "Life's Simple 7," we describe here modifiable risk factors for cognitive decline, including depression, hypertension, physical inactivity, diabetes, obesity, hyperlipidemia, poor diet, smoking, social isolation, excessive alcohol use, sleep disorders, and hearing loss. These risk factors include behaviors, conditions, and lifestyles that can emerge before adulthood and can be routinely identified and managed by primary care clinicians.


Probing the endosperm gene expression landscape in Brassica napus.
In species with exalbuminous seeds, the endosperm is eventually consumed and its space occupied by the embryo during seed development. However, the main constituent of the early developing seed is the liquid endosperm, and a significant portion of the carbon resources for the ensuing stages of seed development arrive at the embryo through the endosperm. In contrast to the extensive study of species with persistent endosperm, little is known about the global gene expression pattern in the endosperm of exalbuminous seed species such as crucifer oilseeds. We took a multiparallel approach that combines ESTs, protein profiling and microarray analyses to look into the gene expression landscape in the endosperm of the oilseed crop Brassica napus. An EST collection of over 30,000 entries allowed us to detect close to 10,000 unisequences expressed in the endosperm. A protein profile analysis of more than 800 proteins corroborated several signature pathways uncovered by abundant ESTs. Using microarray analyses, we identified genes that are differentially or highly expressed across all developmental stages. These complementary analyses provided insight on several prominent metabolic pathways in the endosperm. We also discovered that a transcription factor LEAFY COTYLEDON (LEC1) was highly expressed in the endosperm and that the regulatory cascade downstream of LEC1 operates in the endosperm. The endosperm EST collection and the microarray dataset provide a basic genomic resource for dissecting metabolic and developmental events important for oilseed improvement. Our findings on the featured metabolic processes and the LEC1 regulatory cascade offer new angles for investigation on the integration of endosperm gene expression with embryo development and storage product deposition in seed development.


Conformational memory in the association of the transmembrane protein phospholamban with the sarcoplasmic reticulum calcium pump SERCA.
The sarcoplasmic reticulum Ca2+-ATPase SERCA promotes muscle relaxation by pumping calcium ions from the cytoplasm into the sarcoplasmic reticulum. SERCA activity is regulated by a variety of small transmembrane peptides, most notably by phospholamban in cardiac muscle and sarcolipin in skeletal muscle. However, how phospholamban and sarcolipin regulate SERCA is not fully understood. In the present study, we evaluated the effects of phospholamban and sarcolipin on calcium translocation and ATP hydrolysis by SERCA under conditions that mimic environments in sarcoplasmic reticulum membranes. For pre-steady-state current measurements, proteoliposomes containing SERCA and phospholamban or sarcolipin were adsorbed to a solid-supported membrane and activated by substrate concentration jumps. We observed that phospholamban altered ATP-dependent calcium translocation by SERCA within the first transport cycle, whereas sarcolipin did not. Using pre-steady-state charge (calcium) translocation and steady-state ATPase activity under substrate conditions (various calcium and/or ATP concentrations) promoting particular conformational states of SERCA, we found that the effect of phospholamban on SERCA depends on substrate preincubation conditions. Our results also indicated that phospholamban can establish an inhibitory interaction with multiple SERCA conformational states with distinct effects on SERCA's kinetic properties. Moreover, we noted multiple modes of interaction between SERCA and phospholamban and observed that once a particular mode of association is engaged it persists throughout the SERCA transport cycle and multiple turnover events. These observations are consistent with conformational memory in the interaction between SERCA and phospholamban, thus providing insights into the physiological role of phospholamban and its regulatory effect on SERCA transport activity.


Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk.
Epidemiological studies have shown that taller people are at increased risk of cancer, but it is unclear if height-associated risks vary by cancer site, or by other factors such as smoking and socioeconomic status. Our aim was to investigate these associations in a large UK prospective cohort with sufficient information on incident cancer to allow direct comparison of height-associated risk across cancer sites and in relation to major potential confounding and modifying factors. Information on height and other factors relevant for cancer was obtained in 1996-2001 for middle-aged women without previous cancer who were followed up for cancer incidence. We used Cox regression models to calculate adjusted relative risks (RRs) per 10 cm increase in measured height for total incident cancer and for 17 specific cancer sites, taking attained age as the underlying time variable. We also did a meta-analysis of published results from prospective studies of total cancer risk in relation to height. 1 297 124 women included in our analysis were followed up for a total of 11·7 million person-years (median 9·4 years per woman, IQR 8·4-10·2), during which time 97 376 incident cancers occurred. The RR for total cancer was of 1·16 (95% CI 1·14-1·17; p<0·0001) for every 10 cm increase in height. Risk increased for 15 of the 17 cancer sites we assessed, and was statistically significant for ten sites: colon (RR per 10 cm increase in height 1·25, 95% CI 1·19-1·30), rectum (1·14, 1·07-1·22), malignant melanoma (1·32, 1·24-1·40), breast (1·17, 1·15-1·19), endometrium (1·19, 1·13-1·24), ovary (1·17, 1·11-1·23), kidney (1·29, 1·19-1·41), CNS (1·20, 1·12-1·29), non-Hodgkin lymphoma (1·21, 1·14-1·29), and leukaemia (1·26, 1·15-1·38). The increase in total cancer RR per 10 cm increase in height did not vary significantly by socioeconomic status or by ten other personal characteristics we assessed, but was significantly lower in current than in never smokers (p<0·0001). In current smokers, smoking-related cancers were not as strongly related to height as were other cancers (RR per 10 cm increase in height 1·05, 95% CI 1·01-1·09, and 1·17, 1·13-1·22, respectively; p=0·0004). In a meta-analysis of our study and ten other prospective studies, height-associated RRs for total cancer showed little variation across Europe, North America, Australasia, and Asia. Cancer incidence increases with increasing adult height for most cancer sites. The relation between height and total cancer RR is similar in different populations. Cancer Research UK and the UK Medical Research Council.


Vitamin D supplementation and its influence on muscle strength and mobility in community-dwelling older persons: a systematic review and meta-analysis.
It has been suggested that vitamin D status or supplementation is important for maintaining or improving muscle strength and mobility in older adults. The study results, however, do not provide consistent results. We therefore aimed to summarise the available evidence systematically, including only studies conducted in community-dwelling older persons. A systematic search of the literature was performed in April of 2016. The systematic review includes studies that used vitamin D with or without calcium supplementation as the exposure variable and various measurements of muscle strength and mobility. The meta-analysis was limited to studies using hand grip strength (HGS) and timed-up-and-go test as the outcome variables. A total of 15 studies out of 2408 articles from the literature search were included in the systematic review, providing 2866 participants above the age of 65 years. In the majority of studies, no improvement in muscle strength and mobility was observed after administration of vitamin D with or without calcium supplements. In the meta-analysis, we observed a nonsignificant change in HGS [+0.2 kg (95% confidence interval = -0.25 to 0.7 kg; seven studies)] and a small, significant increase in the timed-up-and-go test [0.3 s (95% confidence interval = 0.1 to 0.5 s; five studies)] after vitamin D supplementation. The meta-analyses showed a high degree of heterogeneity between the studies. In conclusion, we observed no improvement in muscle strength after the administration of vitamin D with or without calcium supplements. We did find a small but significant deterioration of mobility. However, this is based on a limited number of studies and participants.


Prevalence of intestinal parasitic infections among school children in capital areas of the Democratic Republic of São Tomé and Príncipe, West Africa.
Although the Democratic Republic of Sao Tome and Principe (DRSTP) has undertaken school children-based deworming programs against intestinal parasitic infections (IPIs) using a single dose of mebendazole annually since 2005, it remains unclear as to the outcome to date. The present study intends to investigate the recent IPIs status among school children living in capital areas of the DRSTP. A total of 252 school children (121 boys and 131 girls) of grades 4 and 5 from 4 primary schools located in the capital areas participated in the present study and their fresh fecal specimens were examined for the presence of any parasites using the merthiolate-iodine-formaldehyde concentration method as conducted. The overall prevalence of IPIs was 64.7% (163/ 252). No significant gender difference in prevalence between boys (67.8%) and girls (61.8%) was found (p = 0.3). The majority of school children were infected with a single species of parasite (55.8%). Altogether, 12 different intestinal parasite species were identified in DRSTP school children, of which 9 species were pathogenic and the remaining 3 were non-pathogenic. Improving the detection method, sanitation facilities and personal hygiene as well as utilizing combined drugs are all important measures to greatly reduce IPIs in DRSTP school children.


Hülle Cells of Aspergillus nidulans with Nuclear Storage and Developmental Backup Functions Are Reminiscent of Multipotent Stem Cells.
Some aspergilli are among the most cosmopolitan and ecologically dominant fungal species. One pillar of their success is their complex life cycle, which creates specialized cell types for versatile dispersal and regenesis. One of these cell types is unique to aspergilli-the Hülle cells. Despite being known for over a century, the biological and ecological roles of Hülle cells remain largely speculative. Previously reported data on in vivo Hülle cell formation and localization have been conflicting. Our quantification reveals that Hülle cells can occur at all locations on hyphae and that they show cellular activity similar to that seen with adjacent hyphae, indicating that they develop as intricate parts of hyphal tissue. In addition, we show that during sexual development associated with two parental strains, the typically multinucleate Hülle cells can inherit nuclei from both parents, indicating that they may serve as genetic backups. We provide an easy, reproducible method to study Hülle cell biology and germination with which we investigate the 90-year-old puzzle of whether and how Hülle cells germinate. We present clear evidence for the germination of Hülle cells, and we show that Hülle cells grow hyphae that develop into a spore-producing colony. Finally, we show that Hülle cell-derived colonies produce conidiospores faster than spore-derived colonies, providing evidence for an as-yet-undescribed developmental shortcut program in Aspergillus nidulans We propose that Hülle cells represent a unique cell type as specialized hypha-derived sexual tissue with a nucleus storage function and may act as fungal backup stem cells under highly destructive conditions.IMPORTANCE The in vivo identification of Hülle cells in cases of aspergillosis infections in animals and humans illustrates their biological relevance and suggests that they might be involved in pathogenicity. It is striking that aspergilli have developed and maintained a multinucleate nurse cell that is presumably energy-intensive to produce and is usually found only in higher eukaryotes. Our findings shed light on how the understudied Hülle cells might contribute to the success of aspergilli by acting not only as nurse cells under detrimental conditions (sexual development) but also as fungal backup stem cells with the capacity to produce genetically diverse spores in an accelerated manner, thereby substantially contributing to survival in response to predator attack or under otherwise severely destructive conditions. Our study solved the 90-year-old puzzle of Hülle cell germination and provides easy, reproducible methods that will facilitate future studies on biological and ecological roles of Hülle cells in aspergilli.


Compression garments and cerebral blood flow: Influence on cognitive and exercise performance.
This study aimed to describe the effect of compression garments on middle cerebral artery blood flow velocity (MCAv) in relation to cognitive and exercise performance whilst cycling. In a randomised-controlled-cross-over design, 15 well-trained male cyclists were recruited to participate in three identical trials wearing loose fitting shorts (control), low-grade, or medium-grade compression garments. The protocol involved four 8 min increments of cycling at 30%, 50%, 70%, and 85% maximal power output and a 4 km time-trial. Participants undertook a cognitive Stroop task at baseline and at the midpoint of each increment. MCAv was monitored with Transcranial Doppler Ultrasonography. Mean arterial pressure (MAP) and partial pressure of end-tidal CO2 (PetCO2) were measured throughout. MCAv, MAP, PetCO2, and reaction time of the complex Stroop task were influenced by exercise intensity, but not compression garments. Compression garments significantly affected cognitive accuracy in the complex Stroop task such that low-grade compression appeared to enhance cognitive accuracy in comparison to the control condition at the highest intensity (p = .010). Time-trial performance did not differ between the control (338.0 ± 17.3 s), low-grade (338.7 ± 18.7 s), or medium-grade (342.2 ± 19.3 s) conditions (p = .114). Compression garments did not affect MCAv during exercise or time-trial performance, but compression may be beneficial for improved cognitive accuracy during high-intensity exercise. Further research is required to elucidate the potential impact on cognitive performance.


A cross-sectional study of the radiation dose and image quality of X-ray equipment used in IVR.
There are case reports of injuries caused by the radiation from interventional radiology (IVR) X-ray systems. Therefore, the management of radiation doses in IVR is important. However, no detailed report has evaluated image quality for a large number of IVR X-ray systems. As a result, it is unclear whether the image quality of the X-ray equipment currently used in IVR procedures is optimal. We compared the entrance surface doses and image quality of multiple IVR X-ray systems. This study was conducted in 2014 at 13 medical facilities using 18 IVR X-ray systems. We evaluated image quality and simultaneously measured the radiation dose. Entrance surface doses for fluoroscopy (duration, 1 min) and cineradiography (duration, 10 s) are measured using a 20-cm-thick acrylic plate and skin dose monitor. The image quality (such as spatial resolution and low-contrast detectability) of both fluoroscopy and cineradiography was evaluated using a QC phantom. For fluoroscopy, the average entrance surface dose using the 20-cm-thick acrylic plate was 13.9 (range 2.1-28.2) mGy/min. For cineradiography, the average entrance surface dose was 24.6 (range 5.1-49.3) mGy/10 s. We found positive correlations between radiation doses and image quality scores, in general, especially for fluoroscopy. The differences in surface dose among the 18 IVR X-ray systems were high (max/min, 9.7-fold for cineradiography; 13.4-fold for fluoroscopy). The differences in image quality scores (spatial resolution, low-contrast detectability, and dynamic range) were also very large. In general, there tended to be a correlation between radiation dose and image quality. Periodical measurements of the radiation dose and image quality of the X-ray equipment used for cineradiography and fluoroscopy in IVR are necessary. The need to minimize patient exposure requires that the dose be reduced to the minimum level that will generate an image with an acceptable degree of noise.


Labeling of cells with ferumoxides-protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells.
Two FDA-approved agents, ferumoxides (Feridex), a suspension of superparamagnetic iron oxide (SPIO) nanoparticles and protamine sulfate, a drug used to reverse heparin anticoagulation, can be complexed and used to label cells magnetically ex vivo. Labeling stem cells with ferumoxides-protamine sulfate (FePro) complexes allows for non-invasive monitoring by MRI. However, in order for stem cell trials or therapies to be effective, this labeling technique must not inhibit the ability of cells to differentiate. In this study, we examined the effect of FePro labeling on stem cell differentiation. Viability, phenotypic expression and differential capacity of FePro labeled CD34 + hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) were compared with unlabeled control cells. Colony-forming unit (CFU) assays showed that the capacity to differentiate was equivalent for labeled and unlabeled HSC. Furthermore, labeling did not alter expression of surface phenotypic markers (CD34, CD31, CXCR4, CD20, CD3 and CD14) on HSC, as measured by flow cytometry. SDF-1-induced HSC migration and HSC differentiation to dendritic cells were also unaffected by FePro labeling. Both FePro-labeled and unlabeled MSC were cultured in chondrogenesis-inducing conditions. Alcian blue staining for proteoglycans revealed similar chondrogenic differentiation for both FePro-labeled and unlabeled cells. Furthermore, collagen X proteins, indicators of cartilage formation, were detected at similar levels in both labeled and unlabeled cell pellets. Prussian blue staining confirmed that cells in labeled pellets contained iron oxide, whereas cells in unlabeled pellets did not. It is concluded that FePro labeling does not alter the function or differentiation capacity of HSC and MSC. These data increase confidence that MRI studies of FePro-labeled HSC or MSC will provide an accurate representation of in vivo trafficking of unlabeled cells.


Silica-induced pleural disease: an unusual case mimicking malignant mesothelioma.
A 57-year-old man with a history of exposure to silica for 32 years presented with pleural thickening of the lower lobe of the left lung and a chronic right-sided pleural effusion without any radiographic evidence of parenchymal nodules in either lung. Light microscopic examination of a left visceral pleural biopsy specimen revealed markedly thickened pleura with fibrosis and macrophages containing birefringent silica and silicates. Occasional rounded intrapleural silicotic nodules were present. The underlying lung tissue did not show fibrosis or silicotic nodules. An energy-dispersive x-ray analysis confirmed the presence of silica. In the absence of lung involvement, this case represents a very unusual pathologic reaction caused by silica and silicates and adds to the clinical differential diagnosis of chronic pleuritis and malignant mesothelioma.


An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division.
RNA interference (RNAi) is an evolutionarily conserved defence mechanism whereby genes are specifically silenced through degradation of messenger RNAs; this process is mediated by homologous double-stranded (ds)RNA molecules. In invertebrates, long dsRNAs have been used for genome-wide screens and have provided insights into gene functions. Because long dsRNA triggers a nonspecific interferon response in many vertebrates, short interfering (si)RNA or short hairpin (sh)RNAs must be used for these organisms to ensure specific gene silencing. Here we report the generation of a genome-scale library of endoribonuclease-prepared short interfering (esi)RNAs from a sequence-verified complementary DNA collection representing 15,497 human genes. We used 5,305 esiRNAs from this library to screen for genes required for cell division in HeLa cells. Using a primary high-throughput cell viability screen followed by a secondary high content videomicroscopy assay, we identified 37 genes required for cell division. These include several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. Thus, our study uncovers new aspects of cell division and establishes esiRNA as a versatile approach for genomic RNAi screens in mammalian cells.


Seroprevalence of Entamoeba histolytica infection in HIV-infected patients in China.
Seroprevalence of Entamoeba histolytica infection in HIV-infected individuals from Shanghai city, Anhui province, and Henan province, China, was examined by enzyme-linked immunosorbent assay using crude antigen and a recombinant surface antigen, C-Igl, of the parasite. In 215 HIV-infected individuals, the positive rates for these antigens were 12.1% and 7.9%, respectively; these rates were significantly higher than the rates of 3.1% and 0.5%, respectively, in 191 patients with gastrointestinal symptoms who were not infected with HIV. There was no significant difference in seropositivity to E. histolytica between men and women. Seropositivity in HIV-infected individuals was higher in patients with a CD4(+) T cell count of < 200/microL. This is the first report showing a higher seroprevalence of E. histolytica infection in HIV-infected patients in China. Our results also suggest that HIV infection is a risk factor for infection with E. histolytica.


Biomarkers for malignant pleural mesothelioma: current status.
Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, whose main etiology is exposure to asbestos fibers. The incidence of MPM is anticipated to increase worldwide during the first half of this century. For various reasons, MPM is difficult to diagnose and is notoriously refractory to most treatments. However, recently two active chemotherapy regimens have been demonstrated to significantly increase survival in patients with MPM, and several therapeutic agents and strategies are currently under evaluation.Researchers have actively sought MPM biomarkers for more than 20 years. Biomarkers would be helpful in managing three clinical aspects of MPM: early diagnosis, prognosis, and treatment outcome prediction. The aims of the present review are to summarize the published and recently presented data on MPM biomarkers and to identify the prospects for future translational research projects.Among the 'classical' diagnostic biomarkers measured in biological fluids, such as cytokeratins and cell surface antigens, none discriminate patients with MPM from those with other malignancies and nonmalignant diseases. Osteopontin, soluble mesothelin, and megakaryocyte potentiating factor (MPF) appear to be the most promising of the recent biomarkers, but are still subject to some limitations. Osteopontin lacks specificity for mesothelioma, while both soluble mesothelin and MPF lack sensitivity for detecting non-epithelial subtypes. Panels consisting of a small set of biomarkers do not improve the diagnostic yield, and results from molecular profiling are too preliminary to be brought into daily clinical practice. While a large number of biomarkers have been assessed in biological fluids and tumor tissue for their prognostic value, none have had a widespread impact on clinical practice. In contrast, data concerning predictive biomarkers are very limited, even though they are most interesting from the perspective of clinicians.Additional prospective studies, in large and independent samples of patients, with rigorous statistical methodology and standardized laboratory techniques are now warranted to validate and define the precise value of diagnostic and prognostic MPM biomarkers. Future research efforts should focus on biomarkers predictive of the efficacy and toxicity of standard chemotherapy. Translational research should be systematically incorporated into the design of clinical trials assessing new targeted agents in MPM.


Oatp58Dc contributes to blood-brain barrier function by excluding organic anions from the Drosophila brain.
The blood-brain barrier (BBB) physiologically isolates the brain from the blood and, thus, plays a vital role in brain homeostasis. Ion transporters play a critical role in this process by effectively regulating access of chemicals to the brain. Organic anion-transporting polypeptides (Oatps) transport a wide range of amphipathic substrates and are involved in efflux of chemicals across the vertebrate BBB. The anatomic complexity of the vascularized vertebrate BBB, however, creates challenges for experimental analysis of these processes. The less complex structure of the Drosophila BBB facilitates measurement of solute transport. Here we investigate a physiological function for Oatp58Dc in transporting small organic anions across the BBB. We used genetic manipulation, immunocytochemistry, and molecular techniques to supplement a whole animal approach to study the BBB. For this whole animal approach, the traceable small organic anion fluorescein was injected into the hemolymph. This research shows that Oatp58Dc is involved in maintaining a chemical barrier against fluorescein permeation into the brain. Oatp58Dc expression was found in the perineurial and subperineurial glia, as well as in postmitotic neurons. We specifically targeted knockdown of Oatp58Dc expression in the perineurial and subperineurial glia to reveal that Oatp58Dc expression in the perineurial glia is necessary to maintain the barrier against fluorescein influx into the brain. Our results show that Oatp58Dc contributes to maintenance of a functional barrier against fluorescein influx past the BBB into the brain.


The impact of post-processing on spinal cord diffusion tensor imaging.
Diffusion tensor imaging (DTI) provides information about the microstructure in the brain and spinal cord. While new neuroimaging techniques have significantly advanced the accuracy and sensitivity of DTI of the brain, the quality of spinal cord DTI data has improved less. This is in part due to the small size of the spinal cord (ca. 1cm diameter) and more severe instrumental (e.g. eddy current) and physiological (e.g. cardiac pulsation) artefacts present in spinal cord DTI. So far, the improvements in image quality and resolution have resulted from cardiac gating and new acquisition approaches (e.g. reduced field-of-view techniques). The use of retrospective correction methods is not well established for spinal cord DTI. The aim of this paper is to develop an improved post-processing pipeline tailored for DTI data of the spinal cord with increased quality. For this purpose, we compared two eddy current and motion correction approaches using three-dimensional affine (3D-affine) and slice-wise registrations. We also introduced a new robust-tensor-fitting method that controls for whole-volume outliers. Although in general 3D-affine registration improves data quality, occasionally it can lead to misregistrations and biassed tensor estimates. The proposed robust tensor fitting reduced misregistration-related bias and yielded more reliable tensor estimates. Overall, the combination of slice-wise motion correction, eddy current correction, and robust tensor fitting yielded the best results. It increased the contrast-to-noise ratio (CNR) in FA maps by about 30% and reduced intra-subject variation in fractional anisotropy (FA) maps by 18%. The higher quality of FA maps allows for a better distinction between grey and white matter without increasing scan time and is compatible with any multi-directional DTI acquisition scheme.


Endothelial proteolytic activity and interaction with non-resorbing osteoclasts mediate bone elongation.
Growth plate cartilage contributes to the generation of a large variety of shapes and sizes of skeletal elements in the mammalian system. The removal of cartilage and how this process regulates bone shape are not well understood. Here we identify a non-bone-resorbing osteoclast subtype termed vessel-associated osteoclast (VAO). Endothelial cells at the bone/cartilage interface support VAOs through a RANKL-RANK signalling mechanism. In contrast to classical bone-associated osteoclasts, VAOs are dispensable for cartilage resorption and regulate anastomoses of type H vessels. Remarkably, proteinases including matrix metalloproteinase-9 (Mmp9) released from endothelial cells, not osteoclasts, are essential for resorbing cartilage to lead directional bone growth. Importantly, disrupting the orientation of angiogenic blood vessels by misdirecting them results in contorted bone shape. This study identifies proteolytic functions of endothelial cells in cartilage and provides a framework to explore tissue-lytic features of blood vessels in fracture healing, arthritis and cancer.


Evidence-based nursing care for patients with heart failure.
There is a gap between the evidence that supports treatments used in heart failure and day-to-day patient care. Clinical practice guidelines are evidence-based and suggest best practices; however, healthcare providers, patient and system factors complicate the diagnosis and must be addressed. Performance measures specific to nursing can be derived from the guidelines to guide practice and increase high-quality care. Innovative practice improvement programs, clinical leaders, and system tools are needed to close the gap. Nurses can facilitate processes that advance care planning and promote effective care delivery as part of a multidisciplinary team of healthcare providers.


[Development and structure of proplastids].
In this study the proplastid development in embryonic cells is described for the apical meristem of Elodea canadensis, embryo sacs from Lilies, and Begonia leaf buds. The formation of these cell organelles originates with submicroscopical particles which consist of a homogeneous stroma with a surrounding double membrane. When these proplastids reach an average size of 1 micro, the inner layer of the membrane begins to invaginate into the stroma. This process is comparable to tubuli formation in mitochondria. Under growth conditions with sufficient exposure to light, the development of the grana and stroma lamellae proceeds without interruption. If the plants are kept in the dark, small vesicles are formed which accumulate in the prolamellar body of the proplastids. After illumination these elementary vesicles merge to form membranes which evolve into grana and stroma lamellae. The structural similarity of the early proplastid stages with the mitochondria seems to indicate that there exists some phylogenetic relationship between the two cell organelles.


Discrepancy Between the Clinical and Final Pathological Findings of Lymph Node Metastasis in Superficial Esophageal Cancer.
Recent advances in endoscopic examinations have resulted in the detection of a larger number of early esophageal cancers; however, there have been many cases with clinically negative but pathologically positive lymph node metastasis (LNM). In this study, we aimed to evaluate the discrepancy between the clinical and pathological diagnoses of LNM in patients with cT1a-MM/cT1b N0M0 esophageal cancer, and assess LNM size in these patients to clarify the presence of LNM that cannot be detected with current modalities. This study included 50 patients who underwent surgery for cT1a-MM/cT1b N0M0 thoracic esophageal squamous cell carcinoma between January 2012 and November 2016 at our institution. The maximum size of involved LNs and metastatic nests were measured, and the distribution of LNM was investigated. Of the 50 patients, 13 (26%) had LNM on pathological examination. Lymphatic invasion was significantly more frequent in the LNM-positive group than in the LNM-negative group (p = 0.005). The median sizes of 28 involved LNs and metastatic nests were 3 and 1.6 mm, respectively. Of these LNs, 20 (71%) were classified as micrometastases (≤ 2 mm). The involved nodes were distributed across three fields. There was a discrepancy between the clinical and final pathological findings of LNM in patients with cT1a-MM/cT1b N0M0 esophageal cancer. The detection of involved nodes with current modalities in these patients was difficult because of the small size of LNM. Therefore, continued strong consideration for extended LN dissection is necessary in these patients to ensure appropriate diagnosis and treatment.


Modeling the Impacts of Price of an Over-the-Counter Progestin-Only Pill on Use and Unintended Pregnancy among U.S. Women.
To model the impacts of out-of-pocket cost of an over-the-counter (OTC) progestin-only pill on use and associated unintended pregnancy among U.S. women. Using data from a 2015 nationally representative survey of 2,539 U.S. women aged 15 to 44 assessing interest in using an OTC progestin-only pill, we used discrete survival analysis and a Markov model to analyze women's likelihood of using of an OTC pill at different price points and by sociodemographic characteristics. We modeled the impact of product price on the potential total number of U.S. users and on unintended pregnancies in 1 year among adult women at risk of unintended pregnancy. In a model assuming no out-of-pocket costs, more than 12.5 million adults and 1.75 million teens reported likely use of an OTC progestin-only pill if available. Among adults, this resulted in an estimated 8% decrease in unintended pregnancy in 1 year. Adult and teen women on average were willing to pay $15 and $10, respectively, resulting in 7.1 million adult and 1.3 million teen users and an estimated 5% decrease in unintended pregnancy among adults. At low and no out-of-pocket cost, a large population of women in the United States might likely use an OTC progestin-only pill. A low retail price and insurance coverage are necessary to provide equitable access to this method for low-income populations across the United States, fill current gaps in contraceptive access, and potentially decrease unintended pregnancy.


Statistical shape modelling of hip and lumbar spine morphology and their relationship in the MRC National Survey of Health and Development.
The anatomical shape of bones and joints is important for their proper function but quantifying this, and detecting pathological variations, is difficult to do. Numerical descriptions would also enable correlations between joint shapes to be explored. Statistical shape modelling (SSM) is a method of image analysis employing pattern recognition statistics to describe and quantify such shapes from images; it uses principal components analysis to generate modes of variation describing each image in terms of a set of numerical scores after removing global size variation. We used SSM to quantify the shapes of the hip and the lumbar spine in dual-energy x-ray absorptiometry (DXA) images from 1511 individuals in the MRC National Survey of Health and Development at ages 60-64 years. We compared shapes of both joints in men and women and hypothesised that hip and spine shape would be strongly correlated. We also investigated associations with height, weight, body mass index (BMI) and local (hip or lumber spine) bone mineral density. In the hip, all except one of the first 10 modes differed between men and women. Men had a wider femoral neck, smaller neck-shaft angle, increased presence of osteophytes and a loss of the femoral head/neck curvature compared with women. Women presented with a flattening of the femoral head and greater acetabular coverage of the femoral head. Greater weight was associated with a shorter, wider femoral neck and larger greater and lesser trochanters. Taller height was accompanied by a flattening of the curve between superior head and neck and a larger lesser trochanter. Four of the first eight modes describing lumbar spine shape differed between men and women. Women tended to have a more lordotic spine than men with relatively smaller but caudally increasing anterior-posterior (a-p) vertebral diameters. Men were more likely to have a straighter spine with larger vertebral a-p diameters relative to vertebral height than women, increasing cranially. A weak correlation was found between body weight and a-p vertebral diameter. No correlations were found between shape modes and height in men, whereas in women there was a weak positive correlation between height and evenness of spinal curvature. Linear relationships between hip and spine shapes were weak and inconsistent in both sexes, thereby offering little support for our hypothesis. In conclusion, men and women entering their seventh decade have small but statistically significant differences in the shapes of their hips and their spines. Associations with height, weight, BMI and BMD are small and correspond to subtle variations whose anatomical significance is not yet clear. Correlations between hip and spine shapes are small.


Influence of jasmonic acid as potential activator of induced resistance against Karnal bunt in developing spikes of wheat.
Induction of defense response against Karnal bunt (KB)by suppressing the pathogenesis was observed upon exogenous application of jasmonic acid (JA)as evident from decrease in the coefficient of infection and overall response value in both susceptible and resistant varieties of wheat. The ultra-structural changes during disease progression showed the signs of programmed cell death (PCD). However, JA strengthened the defense barrier by enhancing the lignifications of cell walls as observed in spikes of both varieties by histochemical analysis. Compared to the plants inoculated with pathogen alone, plants of resistant line (RJP) first treated with JA followed by inoculation with pathogen showed more lignifications and extracellular deposition of other metabolites on cells, which is supposed to prevent mycelial invasions. Contrary to this, susceptible (SJP)lines also showed lignifications but the invasion was more compared to resistant line. Induction of protease activity was higher in resistant variety than its corresponding susceptible variety. The protease activity induced during the colonization of the pathogen and its proliferation inside the host system gets inhibited by JA treatment as demonstrated by the quantitative and in-gel protease assay. The results indicate the role of JA signalling in inhibiting the proteases due to expression of certain protease inhibitor genes. SDS-PAGE analysis shows differential gene expression through induction and/or suppression of different proteins in wheat spikes of resistant and susceptible varieties under the influence of JA. Thus, exogenously applied JA provides the conditioning effect prior to the challenge of infection and induces defense against KB probably by maintaining a critical balance between proteases and protease inhibitors and/or coordinating induction of different families of new proteins.


Degeneration of Injured Axons and Dendrites Requires Restraint of a Protective JNK Signaling Pathway by the Transmembrane Protein Raw.
The degeneration of injured axons involves a self-destruction pathway whose components and mechanism are not fully understood. Here, we report a new regulator of axonal resilience. The transmembrane protein Raw is cell autonomously required for the degeneration of injured axons, dendrites, and synapses in Drosophila melanogaster In both male and female raw hypomorphic mutant or knock-down larvae, the degeneration of injured axons, dendrites, and synapses from motoneurons and sensory neurons is strongly inhibited. This protection is insensitive to reduction in the levels of the NAD+ synthesis enzyme Nmnat (nicotinamide mononucleotide adenylyl transferase), but requires the c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase and the transcription factors Fos and Jun (AP-1). Although these factors were previously known to function in axonal injury signaling and regeneration, Raw's function can be genetically separated from other axonal injury responses: Raw does not modulate JNK-dependent axonal injury signaling and regenerative responses, but instead restrains a protective pathway that inhibits the degeneration of axons, dendrites, and synapses. Although protection in raw mutants requires JNK, Fos, and Jun, JNK also promotes axonal degeneration. These findings suggest the existence of multiple independent pathways that share modulation by JNK, Fos, and Jun that influence how axons respond to stress and injury.SIGNIFICANCE STATEMENT Axonal degeneration is a major feature of neuropathies and nerve injuries and occurs via a cell autonomous self-destruction pathway whose mechanism is poorly understood. This study reports the identification of a new regulator of axonal degeneration: the transmembrane protein Raw. Raw regulates a cell autonomous nuclear signaling pathway whose yet unknown downstream effectors protect injured axons, dendrites, and synapses from degenerating. These findings imply that the susceptibility of axons to degeneration is strongly regulated in neurons. Future understanding of the cellular pathway regulated by Raw, which engages the c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase and Fos and Jun transcription factors, may suggest new strategies to increase the resiliency of axons in debilitating neuropathies.