Association of methamphetamine use and restrictive interventions in an acute adult inpatient mental health unit: A retrospective cohort study.
The aim of the present study was to describe incidences of restrictive interventions and the association of methamphetamine use at an acute adult inpatient mental health unit in metropolitan Melbourne, Victoria, Australia. A total of 232 consecutive consumer admissions to the inpatient unit across a 3-month period were described for illicit substance use and the use of restrictive interventions (seclusion, mechanical restraint, and physical restraint) prior to and during admission. Of all admissions, 25 (10.8%) involved consumers subjected to a restrictive intervention. Methamphetamine use was either self-reported or detected by saliva test for 71 (30.6%) consumers. Following multivariate analyses, methamphetamine use (odds ratio (OR): 7.83, 95% confidence interval (CI): 2.33-26.31) and restrictive intervention in the emergency department prior to admission (OR: 8.85, 95% CI: 2.83-27.70) were significant independent predictors of the use of restrictive interventions after inpatient admission. Anecdotal observations provided by clinical mental health staff that consumers intoxicated with methamphetamine appear to require restrictive intervention more frequently than other consumers was confirmed with the results of the current study. As the state of Victoria in Australia is on a pathway to the elimination of the use of restrictive interventions in mental health services, clinicians need to develop management strategies that provide specialist mental health care using the least-restrictive interventions. Although 26.8% of methamphetamine users were secluded after admission, restrictive interventions should not be the default management strategy for consumers who present with self-report or positive screen for methamphetamine use.


A nationwide multicenter study of the Cochlin tomo-protein detection test: clinical characteristics of perilymphatic fistula cases.
To investigate the positive rate for the Cochlin tomo-protein (CTP: an inner ear-specific protein) detection test among patients with inner ear-related clinical manifestations and evaluate the clinical characteristics of definite perilymphatic fistula (PLF). We have performed an ELISA-based CTP detection test using middle ear lavage (MEL) samples from 497 cases of suspected PLF enrolled from 70 clinical centers nationwide between 2014 and 2015. In addition to the CTP-positive rate, audio-vestibular symptoms were compared between CTP-positive and -negative cases. 8-50% of patients in category 1 (trauma, middle and inner ear disease cases), and about 20% of those in categories 2, 3 and 4 (external origin antecedent events, internal origin antecedent events, and without antecedent event, respectively) were positive for CTP. In category 1 cases, the earlier tested samples showed a higher CTP-positive rate, whereas no differences were observed in categories 2, 3 or 4. The characteristic clinical features in the earlier tested cases were nystagmus and fistula sign in CTP test-positive cases in category 1, and streaming water-like tinnitus in those in categories 2, 3 and 4. The present study clarified that CTP detection test-positive patients exist at considerable rates among patients with inner ear-related manifestations.


Community and gene composition of a human dental plaque microbiota obtained by metagenomic sequencing.
Human dental plaque is a complex microbial community containing an estimated 700 to 19,000 species/phylotypes. Despite numerous studies analysing species richness in healthy and diseased human subjects, the true genomic composition of the human dental plaque microbiota remains unknown. Here we report a metagenomic analysis of a healthy human plaque sample using a combination of second-generation sequencing platforms. A total of 860 million base pairs of non-human sequences were generated. Various analysis tools revealed the presence of 12 well-characterized phyla, members of the TM-7 and BRC1 clade, and sequences that could not be classified. Both pathogens and opportunistic pathogens were identified, supporting the ecological plaque hypothesis for oral diseases. Mapping the metagenomic reads to sequenced reference genomes demonstrated that 4% of the reads could be assigned to the sequenced species. Preliminary annotation identified genes belonging to all known functional categories. Interestingly, although 73% of the total assembled contig sequences were predicted to code for proteins, only 51% of them could be assigned a functional role. Furthermore, ~2.8% of the total predicted genes coded for proteins involved in resistance to antibiotics and toxic compounds, suggesting that the oral cavity is an important reservoir for antimicrobial resistance.


Association of bilateral salpingo-oophorectomy with all cause and cause specific mortality: population based cohort study.
To determine if bilateral salpingo-oophorectomy, compared with ovarian conservation, is associated with all cause or cause specific death in women undergoing hysterectomy for non-malignant disease, and to determine how this association varies with age at surgery. Population based cohort study. Ontario, Canada from 1 January 1996 to 31 December 2015, and follow-up to 31 December 2017. 200 549 women (aged 30-70 years) undergoing non-malignant hysterectomy, stratified into premenopausal (<45 years), menopausal transition (45-49 years), early menopausal (50-54 years), and late menopausal (≥55 years) groups according to age at surgery; median follow-up was 12 years (interquartile range 7-17). Bilateral salpingo-oophorectomy versus ovarian conservation. The primary outcome was all cause death. Secondary outcomes were non-cancer and cancer death. Within each age group, overlap propensity score weighted survival models were used to examine the association between bilateral salpingo-oophorectomy and mortality outcomes, while adjusting for demographic characteristics, gynaecological conditions, and comorbidities. To account for comparisons in four age groups, P<0.0125 was considered statistically significant. Bilateral salpingo-oophorectomy was performed in 19%, 41%, 69%, and 81% of women aged <45, 45-49, 50-54, and ≥55 years, respectively. The procedure was associated with increased rates of all cause death in women aged <45 years (hazard ratio 1.31, 95% confidence interval 1.18 to 1.45, P<0.001; number needed to harm 71 at 20 years) and 45-49 years (1.16, 1.04 to 1.30, P=0.007; 152 at 20 years), but not in women aged 50-54 years (0.83, 0.72 to 0.97, P=0.018) or ≥55 years (0.92, 0.82 to 1.03, P=0.16). Findings in women aged <50 years were driven largely by increased non-cancer death. In secondary analyses identifying a possible change in the association between bilateral salpingo-oophorectomy and all cause death with advancing age at surgery, the hazard ratio gradually decreased during the menopausal transition and remained around 1 at all ages thereafter. In this observational study, bilateral salpingo-oophorectomy at non-malignant hysterectomy appeared to be associated with increased all cause mortality in women aged <50 years, but not in those aged ≥50 years. While caution is warranted when considering bilateral salpingo-oophorectomy in premenopausal women without indication, this strategy for ovarian cancer risk reduction does not appear to be detrimental to survival in postmenopausal women.


Analysis of Drosophila segmentation network identifies a JNK pathway factor overexpressed in kidney cancer.
We constructed a large-scale functional network model in Drosophila melanogaster built around two key transcription factors involved in the process of embryonic segmentation. Analysis of the model allowed the identification of a new role for the ubiquitin E3 ligase complex factor SPOP. In Drosophila, the gene encoding SPOP is a target of segmentation transcription factors. Drosophila SPOP mediates degradation of the Jun kinase phosphatase Puckered, thereby inducing tumor necrosis factor (TNF)/Eiger-dependent apoptosis. In humans, we found that SPOP plays a conserved role in TNF-mediated JNK signaling and was highly expressed in 99% of clear cell renal cell carcinomas (RCCs), the most prevalent form of kidney cancer. SPOP expression distinguished histological subtypes of RCC and facilitated identification of clear cell RCC as the primary tumor for metastatic lesions.


Effect of Ramadan fasting on tear proteins.
Muslims abstain from eating, drinking and smoking from dawn to sunset during the holy month of Ramadan. Prolonged fasting is thought to be among risk factors for many diseases, e.g., cardiovascular, gastrointestinal and various infectious diseases. It could also play a part in several eye diseases, including dry eye syndrome, glaucoma, and cataract. Toxic and oxidative effects due to increased concentrations of some biochemicals as a result of reduction in tear volume thought to play an important role in damaging ocular tissue. Human tear is an important biological fluid similar to blood in many aspects. Tear film is composed of three basic layers i.e. lipid, aqueous and mucin. The tear film covering the ocular surface presents a mechanical and antimicrobial barrier, and endures an optical refractive surface. The aim of this study was to analyze and compare tear protein of volunteers during fasting. Using two reliable analytical methods, i.e. electrophoresis and high performance liquid chromatography (HPLC), we compared tear protein content of sixty volunteers (35 males and 25 females, 23-27 years old) during fasting in holly month of Ramadan (FAST: n = 62) and one month before Ramadan (CTRL: n = 60). The results showed that some identified tear proteins decreased during fasting. On the other hand, the activity of some enzymes such as lysozyme, lactoferrin and alpha amylase also decreased in fasting samples. Electrophoresis results showed that tear protein patterns in FAST (P < 0.05) were different from those of CTRL. There were a few more protein peaks in the FAST group (P < 0.005) than in CTRL.


Inter-observer agreement according to malaria parasite density.
Recent developments in diagnostic techniques for malaria, particularly DNA probes and sero-immunology, have raised questions as to how these techniques might be used to facilitate malaria diagnosis at the most peripheral levels of the primary health care system. At present, malaria diagnosis is based on the standard microscopic examination of blood films in most field epidemiologic studies and is likely to remain so in the immediate future in Africa. The objective of this study was to assess inter-observer agreement for the examination of Giemsa-stained slides for Plasmodium falciparum parasites. Children aged 0 to 10 years were enrolled yearly in Bancoumana village (West Africa), mainly during the transmission season (June to October). The blood smears obtained from the persistently negative children in June 1996, August 1996, October 1996 and March 1997 were systematically re-examined. A stratified random sample (10%) proportional to the following parasite density classes 1-100, 101-5000, and 5001 and over was taken from the slides collected. The kappa statistics and the intra-class correlation were used as measures of agreement the first and the second slide examinations. The weighted kappa statistic, widely used as a chance-corrected measure for nominal agreement, showed excellent inter-observer agreement (κ(w)=0.7926; 95% CI [0.7588, 0.8263]; p=0.01). The intra-class correlation co-efficient had the same value of 0.7926 confirming the appropriateness of the weighted kappa statistic. Inter-observer agreement for slides read as negative by one observer, or as containing more than 100 parasites per μl, was excellent: 97% (493/506) and 92% (145/158), respectively. In contrast, the inter-observer agreement for slides read by one observer as containing 1-100 parasites/μl was poor, 36% (96/268). In field conditions in Mali, there was a high reproducibility for slides reported as negative or as having more than 100 parasites per μl. However, smears with readings of 1-100 parasites per μl were less reproducible and should be re-examined carefully.


High-frequency ultrasound for diagnosing skin cancer in adults.
Early, accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high-risk skin cancers with the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised, with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Ultrasound is a non-invasive imaging technique that relies on the measurement of sound wave reflections from the tissues of the body. At lower frequencies, the deeper structures of the body such as the internal organs can be visualised, while high-frequency ultrasound (HFUS) with transducer frequencies of 20 MHz or more has a much lower depth of tissue penetration but produces a higher resolution image of tissues and structures closer to the skin surface. Used in conjunction with clinical and/or dermoscopic examination of suspected skin cancer, HFUS may offer additional diagnostic information compared to other technologies. To assess the diagnostic accuracy of HFUS to assist in the diagnosis of a) cutaneous invasive melanoma and atypical intraepidermal melanocytic variants, b) cutaneous squamous cell carcinoma (cSCC), and c) basal cell carcinoma (BCC) in adults. We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists as well as published systematic review articles. Studies evaluating HFUS (20 MHz or more) in adults with lesions suspicious for melanoma, cSCC or BCC versus a reference standard of histological confirmation or clinical follow-up. Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Due to scarcity of data and the poor quality of studies, we did not undertake a meta-analysis for this review. For illustrative purposes, we plot estimates of sensitivity and specificity on coupled forest plots. We included six studies, providing 29 datasets: 20 for diagnosis of melanoma (1125 lesions and 242 melanomas) and 9 for diagnosis of BCC (993 lesions and 119 BCCs). We did not identify any data relating to the diagnosis of cSCC.Studies were generally poorly reported, limiting judgements of methodological quality. Half the studies did not set out to establish test accuracy, and all should be considered preliminary evaluations of the potential usefulness of HFUS. There were particularly high concerns for applicability of findings due to selective study populations and data-driven thresholds for test positivity. Studies reporting qualitative assessments of HFUS images excluded up to 22% of lesions (including some melanomas) due to lack of visualisation in the test.Derived sensitivities for qualitative HFUS characteristics were at least 83% (95% CI 75% to 90%) for the detection of melanoma; the combination of three features (lesions appearing hypoechoic, homogenous and well defined) demonstrating 100% sensitivity in two studies (lower limits of the 95% CIs were 94% and 82%), with variable corresponding specificities of 33% (95% CI 20% to 48%) and 73% (95% CI 57% to 85%), respectively. Quantitative measurement of HFUS outputs in two studies enabled decision thresholds to be set to achieve 100% sensitivity; specificities were 93% (95% CI 77% to 99%) and 65% (95% CI 51% to 76%). It was not possible to make summary statements regarding HFUS accuracy for the diagnosis of BCC due to highly variable sensitivities and specificities. Insufficient data are available on the potential value of HFUS in the diagnosis of melanoma or BCC. Given the between-study heterogeneity, unclear to low methodological quality and limited volume of evidence, we cannot draw any implications for practice. The main value of the preliminary studies included may be in providing guidance on the possible components of new diagnostic rules for diagnosis of melanoma or BCC using HFUS that will require future evaluation. A prospective evaluation of HFUS added to visual inspection and dermoscopy alone in a standard healthcare setting, with a clearly defined and representative population of participants, would be required for a full and proper evaluation of accuracy.


Circumferential Labral Reconstruction Using the Knotless Pull-Through Technique-Surgical Technique.
Arthroscopic labral reconstruction is an alternative procedure for an irreparable hip labrum in the nonarthritic hip population. Although labral reconstruction is a relatively new procedure, data in the literature show favorable outcomes. Patients have shown beneficial outcomes from labral reconstructive surgery as well as when compared with labral repair and debridement patients. However, one of the challenges in performing labral reconstruction has been correctly measuring the graft to perfectly fit the area of labral deficiency. We propose a labral reconstruction technique that will eliminate inaccuracies in graft measurement while incorporating beneficial characteristics of the knotless suture. The advantages of this technique will increase procedural accuracy and brevity.


Amplifying the benefits of agroecology by using the right cultivars.
Tropical soils are particularly vulnerable to fertility losses due to their low capacity to retain organic matter and mineral nutrients. This urges the development of new agricultural practices to manage mineral nutrients and organic matter in a more sustainable way while relying less on fertilizer inputs. Two methods pertaining to ecological engineering and agroecology have been tested with some success: (1) the addition of biochar to the soil, and (2) the maintenance of higher earthworm densities. However, modern crop varieties have been selected to be adapted to agricultural practices and to the soil conditions they lead to and common cultivars might not be adapted to new practices. Using rice as a model plant, we compared the responsiveness to biochar and earthworms of five rice cultivars with contrasted selection histories. These cultivars had contrasted responsivenesses to earthworms, biochar, and the combination of both. The mean relative increase in grain biomass, among all treatments and cultivars, was 94% and 32%, respectively, with and without fertilization. Choosing the best combination of cultivar and treatment led to a more than fourfold increase in this mean benefit (a 437% and a 353% relative increase in grain biomass, respectively, with and without fertilization). Besides, the more rustic cultivar, a local landrace adapted to diverse and difficult conditions, responded the best to earthworms in terms of total biomass, while a modern common cultivar responded the best in term of grain biomass. This suggests that cultivars could be selected to amplify the benefit of biochar- and earthworm-based practices. Overall, selecting new cultivars interacting more closely with soil organisms and soil heterogeneity could increase agriculture sustainability, fostering the positive feedback loop between soils and plants that has evolved in natural ecosystems.


The preference for potential.
When people seek to impress others, they often do so by highlighting individual achievements. Despite the intuitive appeal of this strategy, we demonstrate that people often prefer potential rather than achievement when evaluating others. Indeed, compared with references to achievement (e.g., "this person has won an award for his work"), references to potential (e.g., "this person could win an award for his work") appear to stimulate greater interest and processing, which can translate into more favorable reactions. This tendency creates a phenomenon whereby the potential to be good at something can be preferred over actually being good at that very same thing. We document this preference for potential in laboratory and field experiments, using targets ranging from athletes to comedians to graduate school applicants and measures ranging from salary allocations to online ad clicks to admission decisions.


Biomimetic Bacterial Identification Platform Based on Thermal Wave Transport Analysis (TWTA) through Surface-Imprinted Polymers.
This paper introduces a novel bacterial identification assay based on thermal wave analysis through surface-imprinted polymers (SIPs). Aluminum chips are coated with SIPs, serving as synthetic cell receptors that have been combined previously with the heat-transfer method (HTM) for the selective detection of bacteria. In this work, the concept of bacterial identification is extended toward the detection of nine different bacterial species. In addition, a novel sensing approach, thermal wave transport analysis (TWTA), is introduced, which analyzes the propagation of a thermal wave through a functional interface. The results presented here demonstrate that bacterial rebinding to the SIP layer resulted in a measurable phase shift in the propagated wave, which is most pronounced at a frequency of 0.03 Hz. In this way, the sensor is able to selectively distinguish between the different bacterial species used in this study. Furthermore, a dose-response curve was constructed to determine a limit of detection of 1 × 104 CFU mL-1, indicating that TWTA is advantageous over HTM in terms of sensitivity and response time. Additionally, the limit of selectivity of the sensor was tested in a mixed bacterial solution, containing the target species in the presence of a 99-fold excess of competitor species. Finally, a first application for the sensor in terms of infection diagnosis is presented, revealing that the platform is able to detect bacteria in clinically relevant concentrations as low as 3 × 104 CFU mL-1 in spiked urine samples.


Grain size--dependent alteration and the magnetization of oceanic basalts.
Unblocking temperatures of natural remanent magnetization were found to extend well above the dominant Curie points in samples of oceanic basalts from the axis of the East Pacific Rise. This phenomenon is attributed to the natural presence in the basalts of three related magnetic phases: an abundant fine-grained and preferentially oxidized titanomagnetite that carries most of the natural remanent magnetism, a few coarser and less oxidized grains of titanomagnetite that account for most of the high-field magnetic properties, and a small contribution to both the natural remanent magnetism and high-field magnetic properties from magnetite that may be due to the disproportionation of the oxidized titanomagnetite under sea-floor conditions. This model is consistent with evidence from the Central Anomaly magnetic high that the original magnetization acquired by oceanic basalts upon cooling is rapidly altered and accounts for the lack of sensitivity of bulk rock magnetic parameters to the degree of alteration of the remanence carrier in oceanic basalts.


A novel method of estimating dose responses for polymer gels using texture analysis of scanning electron microscopy images.
Polymer gels are regarded as a potential dosimeter for independent validation of absorbed doses in clinical radiotherapy. Several imaging modalities have been used to convert radiation-induced polymerization to absorbed doses from a macro-scale viewpoint. This study developed a novel dose conversion mechanism by texture analysis of scanning electron microscopy (SEM) images. The modified N-isopropyl-acrylamide (NIPAM) gels were prepared under normoxic conditions, and were administered radiation doses from 5 to 20 Gy. After freeze drying, the gel samples were sliced for SEM scanning with 50×, 500×, and 3500× magnifications. Four texture indices were calculated based on the gray level co-occurrence matrix (GLCM). The results showed that entropy and homogeneity were more suitable than contrast and energy as dose indices for higher linearity and sensitivity of the dose response curves. After parameter optimization, an R (2) value of 0.993 can be achieved for homogeneity using 500× magnified SEM images with 27 pixel offsets and no outlier exclusion. For dose verification, the percentage errors between the prescribed dose and the measured dose for 5, 10, 15, and 20 Gy were -7.60%, 5.80%, 2.53%, and -0.95%, respectively. We conclude that texture analysis can be applied to the SEM images of gel dosimeters to accurately convert micro-scale structural features to absorbed doses. The proposed method may extend the feasibility of applying gel dosimeters in the fields of diagnostic radiology and radiation protection.


Thin-cap fibroatheroma rupture is associated with a fine interplay of shear and wall stress.
In this review, we summarized the effect of mechanical factors (shear and wall stress) on thin-cap fibroatheroma formation and rupture. To make this review understandable for a biology-oriented audience, we start with detailed definitions of relevant mechanical metrics. We then describe how biomechanics has supported histopathologic efforts to understand the basis of plaque rupture. In addition to plaque rupture, biomechanics also contributes toward the progression of thin-cap fibroatheroma through a multitude of reported mechanobiological mechanisms. We thus propose a new mechanism whereby both shear stress and wall stress interact to create thin-cap fibroatheromas. Specifically, when regions of certain blood flow and wall mechanical stimuli coincide, they synergistically create inflammation within the cellular environment that can lead to thin-cap fibroatheroma rupture. A consequence of this postulate is that local shear stress is not sufficient to cause rupture, but it must coincide with regions of local tissue stiffening and stress concentrations that can occur during plaque progression. Because such changes to the wall mechanics occur over a micrometer scale, high spatial resolution imaging techniques will be necessary to evaluate this hypothesis and ultimately predict plaque rupture in a clinical environment.


Current cigarette smoking among adults - United States, 2011.
Tobacco use remains the single largest preventable cause of death and disease in the United States. According to the 2010 U.S. Surgeon General's report, approximately 443,000 U.S. adults die from smoking-related illnesses each year. In addition, smoking has been estimated to cost the United States $96 billion in direct medical expenses and $97 billion in lost productivity annually. To assess progress toward the Healthy People 2020 (HP2020) objective to reduce cigarette smoking by adults (objective TU-1.1),* CDC's Office on Smoking and Health used data from the 2011 National Health Interview Survey (NHIS) to estimate current national cigarette smoking prevalence. The findings indicate that 19.0% of adults smoked cigarettes in 2011 and no statistically significant change in current adult smoking prevalence occurred from 2010 (19.3%) to 2011 (19.0%). Among daily smokers, the proportion who smoked ≥30 cigarettes per day (CPD) declined significantly, from 12.6% in 2005 to 9.1% in 2011, whereas the proportion of those who smoked 1-9 CPD increased significantly, from 16.4% to 22.0%. To help reduce the national prevalence of cigarette smoking among adults to the HP2020 target of 12%, population-based prevention strategies (e.g., increasing prices of tobacco products, antitobacco media campaigns featuring graphic personal stories on the adverse health impact of smoking, smoke-free laws for workplaces and public places, and barrier-free access to help quitting) will need to be implemented more extensively. Such evidence-based tobacco control interventions can help adults quit and prevent the initiation of tobacco use.


Sense of agency is related to gamma band coupling in an inferior parietal-preSMA circuitry.
In the present study we tested whether sense of agency (SoA) is reflected by changes in coupling between right medio-frontal/supplementary motor area (SMA) and inferior parietal cortex (IPC). Twelve healthy adult volunteers participated in the study. They performed a variation of a line-drawing task (Nielsen, 1963; Fourneret and Jeannerod, 1998), in which they moved a cursor on a digital tablet with their right hand without seeing the hand. Visual feedback displayed on a computer monitor was either in correspondence with or deviated from the actual movement. This made participants uncertain as to the agent of the movement and they reported SoA in approximately 50% of trials when the movement was computer-generated. We tested whether IPC-preSMA coupling was associated with SoA, using dynamic causal modeling (DCM) for induced responses (Chen et al., 2008; Herz et al., 2012). Nine different DCMs were constructed for the early and late phases of the task, respectively. All models included two regions: a superior medial gyrus (preSMA) region and a right supramarginal gyrus (IPC) region. Bayesian models selection (Stephan et al., 2009) favored a model with input to IPC and modulation of the forward connection to SMA in the late task phase, and a model with input to preSMA and modulation of the backward connection was favored for the early task phase. The analysis shows that IPC source activity in the 50-60 Hz range modulated preSMA source activity in the 40-70 Hz range in the presence of SoA compared with no SoA in the late task phase, but the test of the early task phase did not reveal any differences between presence and absence of SoA. We show that SoA is associated with a directionally specific between frequencies coupling from IPC to preSMA in the higher gamma (ɣ) band in the late task phase. This suggests that SoA is a retrospective perception, which is highly dependent on interpretation of the outcome of the performed action.


Sequential BMP7/TGF-β1 signaling and microbiota instruct mucosal Langerhans cell differentiation.
Mucosal Langerhans cells (LCs) originate from pre-dendritic cells and monocytes. However, the mechanisms involved in their in situ development remain unclear. Here, we demonstrate that the differentiation of murine mucosal LCs is a two-step process. In the lamina propria, signaling via BMP7-ALK3 promotes translocation of LC precursors to the epithelium. Within the epithelium, TGF-β1 finalizes LC differentiation, and ALK5 is crucial to this process. Moreover, the local microbiota has a major impact on the development of mucosal LCs, whereas LCs in turn maintain mucosal homeostasis and prevent tissue destruction. These results reveal the differential and sequential role of TGF-β1 and BMP7 in LC differentiation and highlight the intimate interplay of LCs with the microbiota.


Visual noise selectively degrades vision in migraine.
Purpose. Migraine is a disabling condition with underlying neuronal mechanisms that remain elusive. Migraineurs experience hyperresponsivity to visual stimuli and frequently experience visual disturbances. In the present study, the equivalent input noise approach was used to reveal abnormalities of visual processing and to isolate factors responsible for any such deficits. This approach partitions visual sensitivity into components that represent the efficiency of using the available stimulus information, the background internal noise due to irregular neuronal fluctuations, and the neuronal noise induced by the external stimulation. Methods. Ten migraine with aura, ten migraine without aura, and ten age-matched headache-free subjects participated. Performance in detecting luminance targets embedded in visual noise, resembling grainy photographs, was measured at various noise levels. Results. Contrast thresholds of the three subject groups were similar in the absence of noise, but both migraine groups performed worse in the presence of high noise levels, with performance of migraineurs with aura significantly poorer (P < 0.05) than that of control subjects. Data were fitted with a perceptual template model that showed that the model parameter determining the internal (neuronal) noise triggered by the external (stimulus) noise was significantly higher (P < 0.001) in both migraine groups than in the non-migraineur group. Migraineurs without aura also showed a significant (P < 0.05) though weak reduction of sampling efficiency (0.12 +/- 0.02) compared with control subjects (0.17 +/- 0.02). Conclusions. The results revealed substantial external noise-exclusion deficits in migraine with aura and a minor impairment of noise exclusion in migraine without aura. Migraineurs appeared prone to abnormally high variability of neuronal activity. This result provides a promising explanation of observed visual deficits in migraine.


Peptidomics-based phylogeny and biogeography of Mantophasmatodea (Hexapoda).
The insect order Mantophasmatodea was described in 2002. Prior to that time, several generations of entomologists had assumed that all major insect taxa were known; thus, its description was a sensation for zoologists. Since then, a surprising abundance and species diversity of this taxon have been found, particularly in the winter rainfall region of South Africa. To learn more about the evolutionary lineages, speciation, and biogeography of Mantophasmatodea, we applied an unusual peptidomics approach. We collected specimens of almost all known and novel taxa of these insects, developed methods for immediate sample preparation in the field, introduced peptide mass fingerprints for the unambiguous identification of taxa, and subsequently analyzed the most extensive data set on peptide hormones ever compiled for insect taxa. To account for intraspecific variation, we analyzed several individuals per putative species. Increased taxon sampling was preferred over a further increase in the number of characters to optimize the accuracy of phylogenetic analyses. The large data set made it possible to test the validity of using neuropeptide sequences, which coevolve with their respective receptors, to analyze phylogenetic relationships among closely related taxa. Altogether, the data from 71 populations of Mantophasmatodea were sufficient to clearly separate the major clades of Mantophasmatodea, including previously undescribed taxa such as Pachyphasma, Striatophasma, and Austrophasmatidae gen. et sp. nov. "RV." The data confirm the monophyly of Austrophasmatidae and show a relatively recent and extensive radiation in the winter rainfall region of South Africa but also suggest that the species-level diversification of Namibian Mantophasma is less marked than previously thought. We discuss the biogeographical and ecological factors that may have resulted in different regional patterns of endemism and species diversity in Mantophasmatodea. The unique development of the neuroendocrine capa-neurons in the ventral nervous system is described as synapomorphy of Mantophasmatodea + Grylloblattodea and is a further argument for a close relationship between these insect taxa.


Applicability of Vapor-Deposited Thermoresponsive Hydrogel Thin Films in Ultrafast Humidity Sensors/Actuators.
Thermoresponsive polymers reversibly react to changes in temperature and water content of their environment (i.e., relative humidity, RH). In the present contribution, the thermoresponsiveness of poly(N-vinylcaprolactam) thin films cross-linked by di(ethylene glycol) divinyl ether deposited by initiated chemical vapor deposition are investigated to assess their applicability to sensor and actuator setups. A lower critical solution temperature (LCST) is observed at around 16 °C in aqueous environment, associated with a dramatic change in film thickness (e.g., 200% increase at low temperatures) and refractive index, while only thermal expansion of the polymeric system is found, when ramping the temperature in dry atmosphere. In humid environment, we observed a significant response occurring in low RH (already below 5% RH), with the moisture swelling the thin film (up to 4%), but mainly replacing air in the polymeric structure up to ∼40% RH. Non-temperature-dependent swelling is observed up to 80% RH. Above that, thermoresponsive behavior is also demonstrated to be present in humid environment for the first time, whereas toward 100% RH, film thickness and index appear to approach the values obtained in water at the respective temperatures. The response times are similar in a large range of RH and are faster than the ones of the reference humidity sensor used (i.e., seconds). A sensor/actuator hygromorphic device was built by coating a thin flower-shaped poly(dimethylsiloxane) (PDMS) substrate with the thermoresponsive polymer. The large swelling due to water uptake upon exposure to humid environment at temperatures below the LCST caused the petals to bend, mimicking the capability of plants to respond to environmental stimuli via reversible mechanical motion.


Experience with endoscopy and endoscopy-assisted management of pediatric surgical problems: results and lessons.
Minimally invasive surgical techniques are becoming increasingly popular within the pediatric population. Flexible endoscopy may enhance or replace existing techniques in the future. Many of the reported benefits of laparoscopy and thoracoscopy may apply to endoscopy and endoscopy-assisted procedures; however, no reports exist as to the application, results, and outcomes for these procedures in children. It was hypothesized that endoscopy is a useful and safe adjunct for pediatric surgical patients. Retrospective review of medical records for patients who underwent endoscopy or endoscopy-assisted operations at two children's hospitals over 3 years (August 31, 2007-August 31, 2010) was completed. During this time period, 30 procedures were performed on 28 patients. Indications for procedure, age, operative technique, operative times, surgical outcomes, complications, and length of stay for each patient were reviewed. Patient age ranged from 3 days to 20 years. Indications for operation included esophageal pathology (13), gastroduodenal pathology (14), pancreatic pseudocyst (2), and displaced sigmoid Chait® (Cook, Inc., Bloomington, IN, USA) tube. Although endoscopy was intended only as an adjunct in all cases, the planned procedure was satisfactorily completed with a purely endoscopic approach in six cases. There were no intraoperative complications, and minor postoperative complications including one stricture requiring dilation, postoperative stridor, and esophageal leak, were each successfully managed conservatively. Endoscopy offers a promising adjunct to more traditional minimally invasive techniques in children. In some cases, endoscopy may offer an alternative to more invasive procedures or eliminate the need for tube thoracostomy or post-procedural contrast studies in some esophageal cases.


Correlative Gene Expression to Protective Seroconversion in Rift Valley Fever Vaccinates.
Rift Valley fever Virus (RVFV), a negative-stranded RNA virus, is the etiological agent of the vector-borne zoonotic disease, Rift Valley fever (RVF). In both humans and livestock, protective immunity can be achieved through vaccination. Earlier and more recent vaccine trials in cattle and sheep demonstrated a strong neutralizing antibody and total IgG response induced by the RVF vaccine, authentic recombinant MP-12 (arMP-12). From previous work, protective immunity in sheep and cattle vaccinates normally occurs from 7 to 21 days after inoculation with arMP-12. While the serology and protective response induced by arMP-12 has been studied, little attention has been paid to the underlying molecular and genetic events occurring prior to the serologic immune response. To address this, we isolated RNA from whole blood of vaccinated calves over a time course of 21 days before and after vaccination with arMP-12. The time course RNAs were sequenced by RNASeq and bioinformatically analyzed. Our results revealed time-dependent activation or repression of numerous gene ontologies and pathways related to the vaccine induced immune response and its regulation. Additional bioinformatic analyses identified a correlative relationship between specific host immune response genes and protective immunity prior to the detection of protective serum neutralizing antibody responses. These results contribute an important proof of concept for identifying molecular and genetic components underlying the immune response to RVF vaccination and protection prior to serologic detection.


Cutaneous metastasis as an initial presentation of lung adenocarcinoma with KRAS mutation: a case report and literature review.
Cutaneous metastasis as an initial presentation occurs in 0.8% of patients with internal malignancies, and is poorly understood in its molecular pathogenesis. We reported a case in which a 61-year-old male patient initially presented with rapidly growing skin nodule on his left chest wall, then developed dyspnea and loss of weight. Echocardiogram showed a large pericardial effusion with right ventricular collapse. PET/CT revealed moderate pleural effusion and multiple lymphadenopathies with hypermetabolic concentration of radiotracer in the lymph nodes as well as in the chest wall skin mass. Biopsy of the skin mass and pericardial/pleural fluids revealed metastatic adenocarcinoma consistent with lung primary with KRAS mutation. Palliative chemotherapy was administered without resulting in any improvement. This is the first case report to show that KRAS-mutant lung adenocarcinoma can be associated with cutaneous metastasis.


Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain's control energy landscape.
Psychedelics including lysergic acid diethylamide (LSD) and psilocybin temporarily alter subjective experience through their neurochemical effects. Serotonin 2a (5-HT2a) receptor agonism by these compounds is associated with more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain's control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states. Using brain states derived from existing functional magnetic resonance imaging (fMRI) datasets, we show that LSD and psilocybin reduce control energy required for brain state transitions compared to placebo. Furthermore, across individuals, reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors (obtained from publicly available positron emission tomography (PET) data under non-drug conditions), we demonstrate an association between the 5-HT2a receptor and reduced control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, we demonstrate that receptor-informed network control theory can model the impact of neuropharmacological manipulation on brain activity dynamics.


Oral versus vaginal combined hormonal contraceptives' effect on coagulation and inflammatory biomarkers among young adult women.
In order to compare the effect of combined oral contraceptive (COC) and combined vaginal contraceptive (CVC) methods on the inflammation and procoagulation, we recruited female participants in 3 groups: control participants, COC users, and CVC users. We measured different blood biomarkers. The users of both COC and CVC had higher levels of C-reactive protein (P < .0001) and factor VII (P < .0001). However, CD40 ligand was only higher for COC users (P < .0001) and not the CVC users. Even though the levels of thrombin/antithrombin III were not higher for COC and CVC users, as compared to the controls, CVC users had higher levels as compared to COC users (P = .0327). As compared to the control group, we observed higher levels von Willebrand factor among CVC users but not the COC users. Longitudinal studies with larger sample size are needed to better assess the inflammatory and procoagulation response due to CVC use.


Mechanisms Underlying the Skin-Gut Cross Talk in the Development of IgE-Mediated Food Allergy.
Immune-globulin E (IgE)-mediated food allergy is characterized by a variety of clinical entities within the gastrointestinal tract, skin and lungs, and systemically as anaphylaxis. The default response to food antigens, which is antigen specific immune tolerance, requires exposure to the antigen and is already initiated during pregnancy. After birth, tolerance is mostly acquired in the gut after oral ingestion of dietary proteins, whilst exposure to these same proteins via the skin, especially when it is inflamed and has a disrupted barrier, can lead to allergic sensitization. The crosstalk between the skin and the gut, which is involved in the induction of food allergy, is still incompletely understood. In this review, we will focus on mechanisms underlying allergic sensitization (to food antigens) via the skin, leading to gastrointestinal inflammation, and the development of IgE-mediated food allergy. Better understanding of these processes will eventually help to develop new preventive and therapeutic strategies in children.


Sequence variation at the human ABO locus.
The ABO blood group is the most important blood group system in transfusion medicine. Since the ABO gene was cloned and the molecular basis of the three major alleles delineated about 10 years ago, the gene has increasingly been examined by a variety of DNA-based genotyping methods and analysed in detail by DNA sequencing. A few coherent observations emerge from these studies. First, there is extensive sequence heterogeneity underlying the major ABO alleles that produce normal blood groups A, B, AB and O when in correct combination with other alleles. Second, there is also extensive heterogeneity underlying the molecular basis of various alleles producing ABO subgroups such as A2, Ax and B3. There are over 70 ABO alleles reported to date and these alleles highlight the extensive sequence variation in the coding region of the gene. A unifying system of nomenclature is proposed to name these alleles. Third, extensive sequence variation is also found in the non-coding region of the gene, including variation in minisatellite repeats in the 5' untranslated region (UTR), 21 single nucleotide polymorphisms (SNPs) in intron 6 and one SNP in the 3' UTR. The haplotypes of these variations reveal a specific relationship with the major ABO alleles. Fourth, excluding the common alleles, about half of the remaining alleles are due to new mutations and the other half can better be explained by intragenic recombination (both crossover and gene conversion) between common alleles. In particular, the recombination sites in hybrid alleles can be quite precisely defined through haplotype analysis of the SNPs in intron 6. This indicates that recombination is equally as important as point mutations in generating the genetic diversity of the ABO locus. Finally, a large number of ABO genotyping methods are available and are based on restriction analysis, allele specific amplification, mutation screening techniques or their combinations.


Paclitaxel nanoparticle awakens immune system to fight against cancer.
A high concentration of paclitaxel (PTX) is used as an anti-tumor chemotherapy but is toxic to immune cells. At lower concentrations, PTX was found able to stimulate the anti-tumor potentials of immune cells. Thus, decreasing the cytotoxicity of PTX at high concentration while maintaining its anti-tumor stimulation to immune cells remains challenging. Herein, by employing a click condensation reaction, we rationally designed a PTX derivative, Cys(StBu)-Arg-Arg-Arg-Lys(PTX)-CBT (1), for the facile preparation of its nanoparticle 1-NP. In vitro assays indicated that, at high PTX concentrations, 1-NP showed significantly lower cytotoxicity to macrophages than did PTX, and could be efficiently phagocytosed by macrophages and consequently polarize the cells into an anti-tumor state in a dose-dependent manner. In vivo experiments further confirmed that 1-NP had a higher anti-tumor efficacy than did free PTX but lower cytotoxicity to immune cells in both immune organs and tumor sites. Our results suggest that, by using different doses of 1-NP, patients can precisely regulate the activation of the immune system for an effective anti-tumor and balanced autoimmune responses. We also envision that our strategy could lead to a combined use of immunotherapy and chemotherapy for a more efficient anti-tumor treatment in the future.


Insulin Induces Microtubule Stabilization and Regulates the Microtubule Plus-end Tracking Protein Network in Adipocytes.
Insulin-stimulated glucose uptake is known to involve microtubules, although the function of microtubules and the microtubule-regulating proteins involved in insulin action are poorly understood. CLASP2, a plus-end tracking microtubule-associated protein (+TIP) that controls microtubule dynamics, was recently implicated as the first +TIP associated with insulin-regulated glucose uptake. Here, using protein-specific targeted quantitative phosphoproteomics within 3T3-L1 adipocytes, we discovered that insulin regulates phosphorylation of the CLASP2 network members G2L1, MARK2, CLIP2, AGAP3, and CKAP5 as well as EB1, revealing the existence of a previously unknown microtubule-associated protein system that responds to insulin. To further investigate, G2L1 interactome studies within 3T3-L1 adipocytes revealed that G2L1 coimmunoprecipitates CLASP2 and CLIP2 as well as the master integrators of +TIP assembly, the end binding (EB) proteins. Live-cell total internal reflection fluorescence microscopy in adipocytes revealed G2L1 and CLASP2 colocalize on microtubule plus-ends. We found that although insulin increases the number of CLASP2-containing plus-ends, insulin treatment simultaneously decreases CLASP2-containing plus-end velocity. In addition, we discovered that insulin stimulates redistribution of CLASP2 and G2L1 from exclusive plus-end tracking to "trailing" behind the growing tip of the microtubule. Insulin treatment increases α-tubulin Lysine 40 acetylation, a mechanism that was observed to be regulated by a counterbalance between GSK3 and mTOR, and led to microtubule stabilization. Our studies introduce insulin-stimulated microtubule stabilization and plus-end trailing of +TIPs as new modes of insulin action and reveal the likelihood that a network of microtubule-associated proteins synergize to coordinate insulin-regulated microtubule dynamics.


Identification of novel microtubule inhibitors effective in fission yeast and human cells and their effects on breast cancer cell lines.
Microtubules are critical for a variety of cellular processes such as chromosome segregation, intracellular transport and cell shape. Drugs against microtubules have been widely used in cancer chemotherapies, though the acquisition of drug resistance has been a significant issue for their use. To identify novel small molecules that inhibit microtubule organization, we conducted sequential phenotypic screening of fission yeast and human cells. From a library of diverse 10 371 chemicals, we identified 11 compounds that inhibit proper mitotic progression both in fission yeast and in HeLa cells. An in vitro assay revealed that five of these compounds are strong inhibitors of tubulin polymerization. These compounds directly bind tubulin and destabilize the structures of tubulin dimers. We showed that one of the compounds, L1, binds to the colchicine-binding site of microtubules and exhibits a preferential potency against a panel of human breast cancer cell lines compared with a control non-cancer cell line. In addition, L1 overcomes cellular drug resistance mediated by βIII tubulin overexpression and has a strong synergistic effect when combined with the Plk1 inhibitor BI2536. Thus, we have established an economically effective drug screening strategy to target mitosis and microtubules, and have identified a candidate compound for cancer chemotherapy.


Assessing faculty integration of adult learning needs in second-degree nursing education.
The limited research data available on effective teaching strategies for accelerated baccalaureate nursing programs has generated interest in identifying and assessing successful teaching tools and strategies in current programs. Most data have been anecdotal and have not emphasized the effectiveness of accelerated programs. This study used a qualitative research design to determine the effectiveness of an integrative learning model in improving nursing student outcomes of second-degree students. Overall data from focus groups in the beginning and end of the study indicated that the use focus groups enhanced the learning process and outcomes.


The distribution of lung cancer across sectors of society in the United Kingdom: a study using national primary care data.
There is pressing need to diagnose lung cancer earlier in the United Kingdom (UK) and it is likely that research using computerised general practice records will help this process. Linkage of these records to area-level geo-demographic classifications may also facilitate case ascertainment for public health programmes, however, there have as yet been no extensive studies of data validity for such purposes. To first address the need for validation, we assessed the completeness and representativeness of lung cancer data from The Health Improvement Network (THIN) national primary care database by comparing incidence and survival between 2000 and 2009 with the UK National Cancer Registry and the National Lung Cancer Audit Database. Secondly, we explored the potential of a geo-demographic social marketing tool to facilitate disease ascertainment by using Experian's Mosaic Public Sector ™ classification, to identify detailed profiles of the sectors of society where lung cancer incidence was highest. Overall incidence of lung cancer (41.4/100, 000 person-years, 95% confidence interval 40.6-42.1) and median survival (232 days) were similar to other national data; The incidence rate in THIN from 2003-2006 was found to be just over 93% of the national cancer registry rate. Incidence increased considerably with area-level deprivation measured by the Townsend Index and was highest in the North-West of England (65.1/100, 000 person-years). Wider variations in incidence were however identified using Mosaic classifications with the highest incidence in Mosaic Public Sector ™types 'Cared-for pensioners, ' 'Old people in flats' and 'Dignified dependency' (191.7, 174.2 and 117.1 per 100, 000 person-years respectively). Routine electronic data in THIN are a valid source of lung cancer information. Mosaic ™ identified greater incidence differentials than standard area-level measures and as such could be used as a tool for public health programmes to ascertain future cases more effectively.


Interleukin-6 Promotes Proliferation but Inhibits Tenogenic Differentiation via the Janus Kinase/Signal Transducers and Activators of Transcription 3 (JAK/STAT3) Pathway in Tendon-Derived Stem Cells.
BACKGROUND Previous studies demonstrated that tendon-derived stem cells (TDSCs) were vital healing cells and that mRNA expression of anti-inflammatory cytokine IL-6 was significantly upregulated in injured tendons. The aim of the present study was to investigate the effects of IL-6 on the TDSCs in vitro. MATERIAL AND METHODS TDSCs isolated from the Achilles tendons in SD rats were co-cultured with various concentrations of IL-6. Cell proliferation, cell cycle analysis, quantitative real-time PCR, western blotting analysis, and statistical analysis were used in the study. RESULTS The result showed that IL-6 strongly increased proliferation capability, and induced cell cycle activation and transition into G2/M phase from G1 phase in TDSCs. However, IL-6 treatment strongly inhibited gene expression of Scleraxis, Collagen 1, Tenomodulin, Collagen 3, Early Growth Response Protein 1, Decorin, Lumican, Biglycan and Fibromodulin in TDSCs. It also strongly inhibited protein expression of tendon cell markers like scleraxis, collagen 1, collagen 3, and tenomodulin. IL-6 treatment strongly activated the JAK/Stat3 signaling pathway in TDSCs. Furthermore, WP1066, a JAK/Stat3 signaling pathway inhibitor, abrogated the effects of IL-6 on TDSCs. CONCLUSIONS These findings indicated that IL-6 might exert dual effects on TDSCs in vitro: strongly enhancing their proliferation but inhibiting their tenogenic differentiation via the JAK/Stat3 pathway.


Development of guidance on the timeliness in response to acute kidney injury warning stage test results for adults in primary care: an appropriateness ratings evaluation.
Tackling the harm associated with acute kidney injury (AKI) is a global priority. In England, a national computerised AKI algorithm is being introduced across the National Health Service (NHS) to drive this change. The study sought to maximise its clinical utility and minimise the potential for burden on clinicians and patients in primary care. An appropriateness ratings evaluation using the RAND/UCLA Appropriateness Method. Clinical scenarios were developed to test the timeliness in (1) communication of AKI warning stage test results from clinical pathology services to primary care, and (2) primary care clinician response to an AKI warning stage test result. A 10-person panel was purposively sampled with representation from clinical biochemistry, acute and emergency medicine and general practice. General practitioners (GPs) represented typical practice in relation to rural and urban practice, out of hours care, GP commissioning and those interested in reducing the impact of medicalisation and 'overdiagnosis'. There was agreement that delivery of AKI warning stage test results through interruptive methods of communication (ie, telephone) from laboratories to primary care was the appropriate next step for patients with an AKI warning stage 3 test result. In the context of acute illness, waiting up to 72 hours to respond to an AKI warning stage test result was deemed an inappropriate action in 62 out of the 65 (94.5%) cases. There was agreement that a clinician response was required within 6 hours, or less, in 39 out of 40 (97.5%) clinical cases relating AKI warning stage test results in the presence of moderate hyperkalaemia. The study has informed national guidance to support a timely and calibrated response to AKI warning stage test results for adults in primary care. Further research is needed to support effective implementation, with a view to examine the effect on health outcomes and costs.


Genomic analysis of 16 Colorado human NL63 coronaviruses identifies a new genotype, high sequence diversity in the N-terminal domain of the spike gene and evidence of recombination.
This study compared the complete genome sequences of 16 NL63 strain human coronaviruses (hCoVs) from respiratory specimens of paediatric patients with respiratory disease in Colorado, USA, and characterized the epidemiology and clinical characteristics associated with circulating NL63 viruses over a 3-year period. From 1 January 2009 to 31 December 2011, 92 of 9380 respiratory specimens were found to be positive for NL63 RNA by PCR, an overall prevalence of 1 %. NL63 viruses were circulating during all 3 years, but there was considerable yearly variation in prevalence and the month of peak incidence. Phylogenetic analysis comparing the genome sequences of the 16 Colorado NL63 viruses with those of the prototypical hCoV-NL63 and three other NL63 viruses from the Netherlands demonstrated that there were three genotypes (A, B and C) circulating in Colorado from 2005 to 2010, and evidence of recombination between virus strains was found. Genotypes B and C co-circulated in Colorado in 2005, 2009 and 2010, but genotype A circulated only in 2005 when it was the predominant NL63 strain. Genotype C represents a new lineage that has not been described previously. The greatest variability in the NL63 virus genomes was found in the N-terminal domain (NTD) of the spike gene (nt 1-600, aa 1-200). Ten different amino acid sequences were found in the NTD of the spike protein among these NL63 strains and the 75 partial published sequences of NTDs from strains found at different times throughout the world.


Direct Observation of Electrically Conductive Pili Emanating from Geobacter sulfurreducens.
Geobacter sulfurreducens is a model microbe for elucidating the mechanisms for extracellular electron transfer in several biogeochemical cycles, bioelectrochemical applications, and microbial metal corrosion. Multiple lines of evidence previously suggested that electrically conductive pili (e-pili) are an essential conduit for long-range extracellular electron transport in G. sulfurreducens. However, it has recently been reported that G. sulfurreducens does not express e-pili and that filaments comprised of multi-heme c-type cytochromes are responsible for long-range electron transport. This possibility was directly investigated by examining cells, rather than filament preparations, with atomic force microscopy. Approximately 90% of the filaments emanating from wild-type cells had a diameter (3 nm) and conductance consistent with previous reports of e-pili harvested from G. sulfurreducens or heterologously expressed in Escherichia coli from the G. sulfurreducens pilin gene. The remaining 10% of filaments had a morphology consistent with filaments comprised of the c-type cytochrome OmcS. A strain expressing a modified pilin gene designed to yield poorly conductive pili expressed 90% filaments with a 3-nm diameter, but greatly reduced conductance, further indicating that the 3-nm diameter conductive filaments in the wild-type strain were e-pili. A strain in which genes for five of the most abundant outer-surface c-type cytochromes, including OmcS, were deleted yielded only 3-nm-diameter filaments with the same conductance as in the wild type. These results demonstrate that e-pili are the most abundant conductive filaments expressed by G. sulfurreducens, consistent with previous functional studies demonstrating the need for e-pili for long-range extracellular electron transfer. IMPORTANCE Electroactive microbes have significant environmental impacts, as well as applications in bioenergy and bioremediation. The composition, function, and even existence of electrically conductive pili (e-pili) has been one of the most contentious areas of investigation in electromicrobiology, in part because e-pili offer a mechanism for long-range electron transport that does not involve the metal cofactors common in much of biological electron transport. This study demonstrates that e-pili are abundant filaments emanating from Geobacter sulfurreducens, which serves as a model for long-range extracellular electron transfer in direct interspecies electron transfer, dissimilatory metal reduction, microbe-electrode exchange, and corrosion caused by direct electron uptake from Fe(0). The methods described in this study provide a simple strategy for evaluating the distribution of conductive filaments throughout the microbial world with an approach that avoids artifactual production and/or enrichment of filaments that may not be physiologically relevant.


Is Urinary Cadmium a Biomarker of Long-term Exposure in Humans? A Review.
Cadmium is a naturally-occurring element, and humans are exposed from cigarettes, food, and industrial sources. Following exposure, cadmium accumulates in the kidney and is slowly released into the urine, usually proportionally to the levels found in the kidneys. Cadmium levels in a single spot urine sample have been considered indicative of long-term exposure to cadmium; however, such a potentially exceptional biomarker requires careful scrutiny. In this review, we report good to excellent temporal stability of urinary cadmium (intraclass correlation coefficient 0.66-0.81) regardless of spot urine or first morning void sampling. Factors such as changes in smoking habits and diseases characterized by increased excretion of proteins may produce short-term changes in urinary cadmium levels. We recommend that epidemiologists use this powerful biomarker in prospective studies stratified by smoking status, along with thoughtful consideration of additional factors that can influence renal physiology and cadmium excretion.


Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy.
To reconstruct the mechanisms for the vasoobliteration that transforms diabetic retinopathy into an ischemic retinopathy, we compared the occurrence of cell death in situ in retinal microvessels of diabetic and nondiabetic individuals. Trypsin digests and sections prepared from the retinas of seven patients (age 67 +/- 7 yr) with .9 +/- 4 yr of diabetes and eight age- and sex-matched nondiabetic controls were studied with the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction which detects preferentially apoptotic DNA fragmentation. The count of total TUNEL+ nuclei was significantly greater in the microvessels of diabetic (13 +/- 12 per one-sixth of retina) than control subjects (1.3 +/- 1.4, P = 0.0016), as were the counts of TUNEL+ pericytes and endothelial cells (P < 0.006). The neural retinas from both diabetic and nondiabetic subjects were uniformly TUNEL-. Retinal microvessels of rats with short duration of experimental diabetes or galactosemia and absent or minimal morphological changes of retinopathy, showed TUNEL+ pericytes and endothelial cells, which were absent in control rats. These findings indicate that (a) diabetes and galactosemia lead to accelerated death in situ of both retinal pericytes and endothelial cells; (b) the event is specific for vascular cells; (c) it precedes histological evidence of retinopathy; and (d) it can be induced by isolated hyperhexosemia. A cycle of accelerated death and renewal of endothelial cells may contribute to vascular architectural changes and, upon exhaustion of replicative life span, to capillary obliteration.


Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients.
Matrix degradation in emphysema has long been attributed to the action of neutrophil elastase (NE). More recently a role for other proteases, particularly the matrix metalloproteinases (MMPs), in the pathogenesis of this disease has been proposed. To date, however, the presence of MMPs in the lungs of patients with emphysema has not been demonstrated. Samples of bronchoalveolar lavage (BAL) fluid from 10 patients with emphysema and from control subjects matched for sex and current smoking status were assessed for collagenase, gelatinase, and NE activity. Pulmonary function tests and computed tomographic (CT) scans were carried out on all study subjects. Collagenase activity was detected in BAL fluid samples from all emphysematous patients but in only one smoking control (p < 0.001). Gelatinase B was present in six patients and in two smoking controls (p < 0.03). The concomitant presence of gelatinase B in complex with lipocalin (NGAL) in the gelatinase positive samples suggests that the neutrophil is a significant source of the gelatinase B observed. NE was detected in six of the 10 patients with emphysema and in two smoking controls (p < 0.01), indicating that collagenase was more useful in discriminating between disease and control groups than either NE or gelatinase B. No relationship was observed between any of the enzymes measured and pulmonary function or CT density score. This study demonstrates, for the first time, the presence of increased levels of matrix metalloproteinases in the lungs of patients with emphysema and suggests that, in BAL fluid, collagenase activity may be a better indicator of the presence of emphysema than elastase.


Effects of prostaglandins on motility of gallbladders removed from patients with gallstones.
Prostaglandins (PGs) affect smooth-muscle contractility and are also involved in the inflammatory reaction. They may therefore affect gallbladder motility in cholecystitis. The contractile effects of PGs were recorded in organ baths on strips from 63 fresh, surgically removed human gallbladders. Spontaneous rhythmic contractions were reduced or abolished by indomethacin, which inhibits endogenous PG synthesis. In strips with chronic cholecystitis, concentration-dependent contractions were produced by PGF2, PGB2 and PGD2; the responses to PGE1 and PGE2 were sometimes variable but there were concentration-dependent contractions after treatment of the strips with indomethacin. The majority of strips with acute cholecystitis responded poorly to PGs even after pretreatment with indomethacin. We concluded from this preliminary study that PGs could affect gallbladder motility and that indomethacin probably reduces the endogenous production of PGs in the gallbladder.


A duplicate gene rooting of seed plants and the phylogenetic position of flowering plants.
Flowering plants represent the most significant branch in the tree of land plants, with respect to the number of extant species, their impact on the shaping of modern ecosystems and their economic importance. However, unlike so many persistent phylogenetic problems that have yielded to insights from DNA sequence data, the mystery surrounding the origin of angiosperms has deepened with the advent and advance of molecular systematics. Strong statistical support for competing hypotheses and recent novel trees from molecular data suggest that the accuracy of current molecular trees requires further testing. Analyses of phytochrome amino acids using a duplicate gene-rooting approach yield trees that unite cycads and angiosperms in a clade that is sister to a clade in which Gingko and Cupressophyta are successive sister taxa to gnetophytes plus Pinaceae. Application of a cycads + angiosperms backbone constraint in analyses of a morphological dataset yields better resolved trees than do analyses in which extant gymnosperms are forced to be monophyletic. The results have implications both for our assessment of uncertainty in trees from sequence data and for our use of molecular constraints as a way to integrate insights from morphological and molecular evidence.


Evaluation of an adjustable epidemiologic information system.
In order to facilitate public health response and to achieve early control of infectious disease epidemics, an adjustable epidemiologic information system (AEIS) was established in the Taiwan public health network in February 2006. The performance of AEIS for the period 2006 through 2008 was evaluated based on a number of response times (RT) and the public health impact. After implementation of the system, the apparent overall shortened RT was mainly due to the shortening of personnel response time (PRT) and the time needed to draft a new questionnaire that incurred as personnel-system interface (PSI); PRT dropped from a fluctuating range of 9.8 ∼28.8 days in the first four months to <10 days in the following months and remained low till 2008 (0.88±1.52 days). The PSIs for newly emerged infectious diseases were 2.6 and 3.4 person-hours for H5N1 in 2007 and chikungunya in 2008, respectively, a much improvement from 1142.5 person-hours for SARS in 2003. The duration of each rubella epidemic cluster was evaluated as public health impact and showed a shortening trend (p = 0.019) that concurred with the shortening of PRT from 64.8±47.3 to 25.2±38.2 hours per cluster (p<0.0001). The first evaluation of the novel instrument AEIS that had been used to assist Taiwan's multi-level government for infectious diseases control demonstrated that it was well integrated into the existing public health infrastructure. It provided flexible tools and computer algorithms with friendly interface for timely data collection, integration, and analysis; as a result, it shortened RTs, filled in gaps of personnel lacking sufficient experiences, created a more efficient flow of response, and identified asymptomatic/mild cases early to minimize further spreading. With further development, AEIS is anticipated to be useful in the application of other acute public health events needing immediate orchestrated data collection and public health actions.


The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells.
Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention.


Behavior change interventions and policies influencing primary healthcare professionals' practice-an overview of reviews.
There is a plethora of interventions and policies aimed at changing practice habits of primary healthcare professionals, but it is unclear which are the most appropriate, sustainable, and effective. We aimed to evaluate the evidence on behavior change interventions and policies directed at healthcare professionals working in primary healthcare centers. Study design: overview of reviews. MEDLINE (Ovid), Embase (Ovid), The Cochrane Library (Wiley), CINAHL (EbscoHost), and grey literature (January 2005 to July 2015). two reviewers independently, and in duplicate, identified systematic reviews, overviews of reviews, scoping reviews, rapid reviews, and relevant health technology reports published in full-text in the English language. two reviewers extracted data pertaining to the types of reviews, study designs, number of studies, demographics of the professionals enrolled, interventions, outcomes, and authors' conclusions for the included studies. We evaluated the methodological quality of the included studies using the AMSTAR scale. For the comparative evaluation, we classified interventions according to the behavior change wheel (Michie et al.). Of 2771 citations retrieved, we included 138 reviews representing 3502 individual studies. The majority of systematic reviews (91%) investigated behavior and practice changes among family physicians. Interactive and multifaceted continuous medical education programs, training with audit and feedback, and clinical decision support systems were found to be beneficial in improving knowledge, optimizing screening rate and prescriptions, enhancing patient outcomes, and reducing adverse events. Collaborative team-based policies involving primarily family physicians, nurses, and pharmacists were found to be most effective. Available evidence on environmental restructuring and modeling was found to be effective in improving collaboration and adherence to treatment guidelines. Limited evidence on nurse-led care approaches were found to be as effective as general practitioners in patient satisfaction in settings like asthma, cardiovascular, and diabetes clinics, although this needs further evaluation. Evidence does not support the use of financial incentives to family physicians, especially for long-term behavior change. Behavior change interventions including education, training, and enablement in the context of collaborative team-based approaches are effective to change practice of primary healthcare professionals. Environmental restructuring approaches including nurse-led care and modeling need further evaluation. Financial incentives to family physicians do not influence long-term practice change.


Use of pathway information in molecular epidemiology.
Candidate gene studies are generally motivated by some form of pathway reasoning in the selection of genes to be studied, but seldom has the logic of the approach been carried through to the analysis. Marginal effects of polymorphisms in the selected genes, and occasionally pairwise gene–gene or gene–environment interactions,are often presented, but a unified approach to modelling the entire pathway has been lacking. In this review, a variety of approaches to this problem is considered, focusing on hypothesis-driven rather than purely exploratory methods. Empirical modelling strategies are based on hierarchical models that allow prior knowledge about the structure of the pathway and the various reactions to be included as 'prior covariates'. By contrast, mechanistic models aim to describe the reactions through a system of differential equations with rate parameters that can vary between individuals, based on their genotypes. Some ways of combining the two approaches are suggested and Bayesian model averaging methods for dealing with uncertainty about the true model form in either framework is discussed. Biomarker measurements can be incorporated into such analyses, and two-phase sampling designs stratified on some combination of disease, genes and exposures can be an efficient way of obtaining data that would be too expensive or difficult to obtain on a full candidate gene sample. The review concludes with some thoughts about potential uses of pathways in genome-wide association studies.


CADRE: the Central Aspergillus Data REpository.
CADRE is a public resource for housing and analysing genomic data extracted from species of Aspergillus. It arose to enable maintenance of the complete annotated genomic sequence of Aspergillus fumigatus and to provide tools for searching, analysing and visualizing features of fungal genomes. By implementing CADRE using Ensembl, a framework is in place for storing and comparing several genomes: the resource will thus expand by including other Aspergillus genomes (such as Aspergillus nidulans) as they become available. CADRE is accessible at http://www.cadre. man.ac.uk.


Imaging across the life span: innovations in imaging and therapy for gynecologic cancer.
The focus of this article is radiation therapy for gynecologic cancers, with emphasis on imaging-based treatment planning and delivery. For the various gynecologic cancers, radiation oncologists rely on essential clinical information to triage treatment options, and various imaging studies are performed for treatment planning and radiation therapy delivery. A practical approach is provided to help radiologists tailor their reports for the needs of their radiation oncology and gynecologic oncology colleagues, to optimize multidisciplinary care for patients with gynecologic cancer. Template radiology reports are proposed to address the specific information needs of oncologists at each phase-before, during, and after treatment. Fueled by the rapid progress in engineering and computer sciences during the past 2 decades, remarkable advances have been made in anatomic, functional, and molecular imaging and in radiation treatment planning and delivery in patients with gynecologic cancer. Radiation therapy has evolved from a nontargeted approach to a precisely targeted, highly conformal treatment modality, to further improve treatment outcomes and reduce morbidity. High-quality imaging has become essential for staging of the disease, delineation of tumor extent for treatment planning and delivery, and monitoring therapy response. Anatomic and functional imaging has also been shown to provide prognostic information that allows clinicians to tailor therapy on the basis of personalized patient information. This field is an area of active research, and future clinical trials are warranted to validate preliminary results in the field.


Generation of human autologous melanoma-specific cytotoxic T-cells using HLA-A2-matched allogeneic melanomas.
Autologous tumor-specific cytotoxic T-lymphocytes (CTLs), generated by repeated stimulation with autologous melanoma and expanded in interleukin 2, are major histocompatibility complex restricted. These CTLs recognize a common tumor-associated antigen in the presence of HLA class I determinants, suggesting that allogeneic melanomas which express the restricting HLA-A region antigen could substitute for the autologous tumor in the generation of CTLs. This was investigated in the HLA-A2 system. Four T-cell lines were established by stimulation of lymphocytes with either autologous tumor or an HLA-A2-matched allogeneic melanoma. Allogeneic stimulated CTLs specifically lysed the autologous tumor and demonstrated an identical pattern of HLA-A2 restriction, when compared to the autologous stimulated CTLs. Lysis by the allogeneic stimulated CTLs was blocked by a monoclonal antibody to HLA class I antigens; lysis was also inhibited by both autologous tumor or HLA-A2 allogeneic melanomas when evaluated in cold target competition studies. The allogeneic stimulated CTLs proliferated in response to both autologous tumor and HLA-A2 melanomas, but not in response to HLA-A2 nonmelanomas. By phenotypic analysis these CTLs were CD3+ and predominantly CD8+ cells. We conclude that autologous tumor-specific CTLs can be generated using HLA-A region-matched allogeneic melanomas for stimulation. Since established, HLA-typed melanoma tumor lines can be used in the absence of autologous tumor; this procedure can be applied clinically to a broad patient population and may prove useful in the adoptive immunotherapy of melanoma.


Effect of anodal high-definition transcranial direct current stimulation on the pain sensitivity in a healthy population: a double-blind, sham-controlled study.
High-definition transcranial direct current stimulation (HD-tDCS) of brain areas related to pain processing may provide analgesic effects evident in the sensory detection and pain thresholds. The somatosensory sensitivity was assessed after HD-tDCS targeting the primary motor cortex (M1) and/or the dorsolateral prefrontal cortex (DLPFC). Eighty-one (40 females) subjects were randomly assigned to 1 of 4 anodal HD-tDCS protocols (20 minutes) applied on 3 consecutive days: Sham-tDCS, DLPFC-tDCS, M1-tDCS, and DLPFC&M1-tDCS (simultaneous transcranial direct current stimulation [tDCS] of DLPFC and M1). Subjects and experimenter were blinded to the tDCS protocols. The somatosensory sensitivity were assessed each day, before and after each tDCS by detection and pain thresholds to thermal and mechanical skin stimulation, vibration detection thresholds, and pressure pain thresholds. Subjects were effectively blinded to the protocol, with no significant difference in rates of whether they received real or placebo tDCS between the 4 groups. Compared with the Sham-tDCS, none of the active HD-tDCS protocols caused significant changes in detection or pain thresholds. Independent of tDCS protocols, pain and detection thresholds except vibration detection were increased immediately after the first tDCS protocol compared with baseline (P < 0.05). Overall, the active stimulation protocols were not able to induce significant modulation of the somatosensory thresholds in this healthy population compared with sham-tDCS. Unrelated to the HD-tDCS protocol, a decreased sensitivity was found after the first intervention, indicating a placebo effect or possible habituation to the quantitative sensory testing assessments. These findings add to the increasing literature of null findings in the modulatory effects of HD-tDCS on the healthy somatosensory system.


High-throughput tracking of pluripotent human embryonic stem cells with dual fluorescence resonance energy transfer molecular beacons.
Pluripotent human embryonic stem cells (hESCs) provide an unprecedented opportunity for the study of human tissue development, and the development of cell-based therapies for human disease. To realize these potential advances, however, methods for monitoring expression of intracellular proteins in live hESCs without altering cellular properties are needed. Molecular beacons are single-stranded oligonucleotides that have been employed to assay gene expression. To test their potential for high-throughput isolation of hESCs, we developed a dual fluorescence resonance energy transfer (FRET) molecular beacon system using fluorescence-activated cell sorting (FACS) with Oct4 as a target. We demonstrate that Oct4 can be detected by FRET using confocal microscopy, that this can be applied in a high-throughput manner to the identification and isolation of Oct4-expressing hESCs by FACS, that FRET-positive hESCs demonstrate pluripotency in culture and in vivo, and that hESCs transfected with molecular beacons demonstrate normal growth rates and oligonucleotide extinction over time. These studies demonstrate that FRET-based FACS using molecular beacons provides a useful tool for isolating Oct4-expressing pluripotent hESCs, and may also be adapted to selecting differentiating hESCs at specific developmental time points determined by transcription factor expression without functional or genomic alteration. As such, it provides an important new method for high-throughput isolation of hESC-derived tissue-specific precursors for analytic and therapeutic purposes.


Levels of health literacy in a community-dwelling population of Chinese older adults.
Lower levels of health literacy have been associated with adverse health outcomes, especially for older adults. However, limited research has been conducted to understand health literacy levels among Chinese American older adults. The PINE study is an epidemiological cohort of 3,159 community-dwelling Chinese older adults, 95% of whom do not speak or read English. Chinese older adults' health literacy levels were examined using the Chinese version of the Rapid Estimate of Adult Literacy in Medicine, Revised (REALM-R) test. Kruskal-Wallis test and chi-square statistics were used to identify significant differences by sociodemographic and self-reported health characteristics. Pearson and Spearman correlation coefficients were used to examine correlations between personal characteristics and health literacy level. The mean age among this sample of Chinese older adults was 72.8 years (SD = 8.3, range = 60-105) and the mean REALM-R test score was 6.9 [SD = 2.3, range (0-8)]. Health literacy was positively associated with education, marriage status, and number of people living with. Older age, being female, greater number of children, years in the United States, and preference for speaking Cantonese or Taishanese were negatively associated with health literacy. Health literary was not associated with self-reported health status or quality of life. In this Chicago Chinese population, older adults had reasonable levels of health literacy in Chinese. Future longitudinal research is needed to understand risk/protective factors associated with health literacy level in Chinese older adults.


Chemoprevention of cervical cancer with folic acid: a phase III Southwest Oncology Group Intergroup study.
Several epidemiological reports and experimental investigations have suggested a preventive role for folic acid in the etiology of cervical cancer. The effect of p.o. folic acid supplementation on the natural history of cervical intraepithelial neoplasia (CIN) was evaluated in a multiinstitutional prospective, randomized, double-blind, placebo-controlled trial. Three hundred thirty-one women with biopsy-proven koilocytic atypia, mild CIN, or moderate CIN were randomized to receive oral folic acid (5 mg) or a similar-appearing placebo daily for 6 months following a 1-month run-in placebo period. Colposcopy, Papanicolaou smear, and serum vitamin levels (folate, retinol, alpha-tocopherol, beta-carotene, and retinyl palmitate) were monitored every 3 months. Demographic, medical, dietary, and sexual history data were obtained from personal interviews. The primary end point of the study was improvement in both Papanicolaou smear and colposcopic picture after 3 and 6 months of treatment as compared to the start of treatment. After 6 months of treatment there was no significant difference between the two study groups in the percentage of patients improved. Median serum folate levels in the treatment arm at 3 and 6 months (29.0 and 20.0 micrograms/dl) were significantly higher than those in the placebo arm (7.8 and 7.1 micrograms/dl, respectively). Mean serum levels of retinol, retinyl palmitate, alpha-tocopherol, and beta-carotene did not differ significantly between the two treatment arms. Our data support the conclusion that supplementation with folic acid (5 mg/day) does not enhance the regression of early epithelial abnormalities of the cervix.(ABSTRACT TRUNCATED AT 250 WORDS)


Homo-dimerization and ligand binding by the leucine-rich repeat domain at RHG1/RFS2 underlying resistance to two soybean pathogens.
The protein encoded by GmRLK18-1 (Glyma_18_02680 on chromosome 18) was a receptor like kinase (RLK) encoded within the soybean (Glycine max L. Merr.) Rhg1/Rfs2 locus. The locus underlies resistance to the soybean cyst nematode (SCN) Heterodera glycines (I.) and causal agent of sudden death syndrome (SDS) Fusarium virguliforme (Aoki). Previously the leucine rich repeat (LRR) domain was expressed in Escherichia coli. The aims here were to evaluate the LRRs ability to; homo-dimerize; bind larger proteins; and bind to small peptides. Western analysis suggested homo-dimers could form after protein extraction from roots. The purified LRR domain, from residue 131-485, was seen to form a mixture of monomers and homo-dimers in vitro. Cross-linking experiments in vitro showed the H274N region was close (<11.1 A) to the highly conserved cysteine residue C196 on the second homo-dimer subunit. Binding constants of 20-142 nM for peptides found in plant and nematode secretions were found. Effects on plant phenotypes including wilting, stem bending and resistance to infection by SCN were observed when roots were treated with 50 pM of the peptides. Far-Western analyses followed by MS showed methionine synthase and cyclophilin bound strongly to the LRR domain. A second LRR from GmRLK08-1 (Glyma_08_g11350) did not show these strong interactions. The LRR domain of the GmRLK18-1 protein formed both a monomer and a homo-dimer. The LRR domain bound avidly to 4 different CLE peptides, a cyclophilin and a methionine synthase. The CLE peptides GmTGIF, GmCLE34, GmCLE3 and HgCLE were previously reported to be involved in root growth inhibition but here GmTGIF and HgCLE were shown to alter stem morphology and resistance to SCN. One of several models from homology and ab-initio modeling was partially validated by cross-linking. The effect of the 3 amino acid replacements present among RLK allotypes, A87V, Q115K and H274N were predicted to alter domain stability and function. Therefore, the LRR domain of GmRLK18-1 might underlie both root development and disease resistance in soybean and provide an avenue to develop new variants and ligands that might promote reduced losses to SCN.


Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury.
Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n=22), moderate (moTBI; n=14) or mild TBI (mTBI; n=108) according to Glasgow Coma Scale. The control group (n=28) comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n=23), moTBI (n=7), mTBI (n=37) patients and controls (n=27). We show that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC=0.84 in validation cohort). Addition of the metabolites to the established clinical model (CRASH), comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified 'TBI metabotype' in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new avenue for the development of diagnostic and prognostic markers of broad spectrum of TBIs.


Molecular screening reveals non-uniform malaria transmission in western Kenya and absence of Rickettsia africae and selected arboviruses in hospital patients.
In sub-Saharan Africa, malaria is the common diagnosis for febrile illness and related clinical features, resulting in the under-diagnosis of other aetiologies, such as arboviruses and Rickettsia. While these may not be significant causes of mortality in malaria-endemic areas, they affect the daily life and performance of affected individuals. It is, therefore, important to have a clear picture of these other aetiologies to institute correct diagnoses at hospitals and improve patient outcomes. Blood samples were collected from patients with fever and other clinical features associated with febrile illness at selected hospitals in the malaria-endemic counties of Busia, Bungoma, and Kakamega, and screened for Crimean-Congo haemorrhagic fever, Sindbis, dengue and chikungunya viruses, Rickettsia africae, and Plasmodium spp. using high-throughput real-time PCR techniques. A logistic regression was performed on the results to explore the effect of demographic and socio-economic independent variables on malaria infection. A total of 336 blood samples collected from hospital patients between January 2018 and February 2019 were screened, of which 17.6% (59/336) were positive for Plasmodium falciparum and 1.5% (5/336) for Plasmodium malariae. Two patients had dual P. falciparum/P. malariae infections. The most common clinical features reported by the patients who tested positive for malaria were fever and headache. None of the patients were positive for the arboviruses of interest or R. africae. Patients living in Busia (OR 5.2; 95% CI 2.46-11.79; p < 0.001) and Bungoma counties (OR 2.7; 95% CI 1.27-6.16; p = 0.013) had higher odds of being infected with malaria, compared to those living in Kakamega County. The reported malaria prevalence is in line with previous studies. The absence of arboviral and R. africae cases in this study may have been due to the limited number of samples screened, low-level circulation of arboviruses during inter-epidemic periods, and/or the use of PCR alone as a detection method. Other sero-surveys confirming their circulation in the area indicate that further investigations are warranted.


Understanding the binary interactions of noble metal and semiconductor nanoparticles.
Molecular dynamics simulations are used to study the solvation and effective pair interactions of Au (1.2 nm) and CdSe (2.2 nm) nanoparticles passivated with alkanethiol and alkylamine ligands, respectively, for two different chain lengths in vacuum and n-hexane at 300 K. The solvation studies focus on quantifying the ligand and solvent shell structures, which are used to rationalize the interactions of nanoparticles in solution. To investigate the effective pair interactions, we compute the isotropic potential of mean forces (PMFs) between two nanoparticles and also analyze the anisotropy in the interactions that arises as a result of ligand shell fluctuations. Both isotropic and anisotropic contributions to the effective pair interactions between the two classes of nanoparticles are compared as a function of the ligand chain length and the solvent quality. It is demonstrated that the inclusion of the anisotropic aspect in the interparticle interactions is essential to properly describe the self-assembly thermodynamics of passivated nanoparticles. The implications of the coarse-grained modeling of the formation of binary nanocrystal superlattices (BNSLs) are considered.