Public safety aspects of pyrethroid insecticides used in West Nile virus-carrying mosquito control.
West Nile virus is becoming increasingly prevalent in the USA, causing fever, encephalitis, meningitis and many fatalities. Spread of the disease is reduced by controlling the mosquito vectors by a variety of means, including the use of pyrethroid insecticides, which are currently under scrutiny for potential carcinogenic effects in humans. Pyrethrins and resmethrin, a pyrethroid, have been shown to cause tumours in rat and mouse models respectively. However, the tumours appear to be caused by liver enzyme induction and hypertrophy rather than genotoxicity, and the results are therefore unlikely to be applicable to humans. Nonetheless, for resmethrin, the US Environmental Protection Agency (EPA) has concluded that there is a likely risk of carcinogenicity in humans, requiring the manufacturers to provide more detailed data to prove that it can be used safely in vector control. Reproductive toxicity of resmethrin in the rat is also discussed.


Large-scale white matter network reorganization in posttraumatic stress disorder.
Recently, graph theoretical approaches applied to neuroimaging data have advanced understanding of the human brain connectome and its abnormalities in psychiatric disorders. However, little is known about the topological organization of brain white matter networks in posttraumatic stress disorder (PTSD). Seventy-six patients with PTSD and 76 age, gender, and years of education-matched trauma-exposed controls were studied after the 2008 Sichuan earthquake using diffusion tensor imaging and graph theoretical approaches. Topological properties of brain networks including global and nodal measurements and modularity were analyzed. At the global level, patients showed lower clustering coefficient (p = .016) and normalized characteristic path length (p = .035) compared with controls. At the nodal level, increased nodal centralities in left middle frontal gyrus, superior and inferior temporal gyrus and right inferior occipital gyrus were observed (p < .05, corrected for false-discovery rate). Modularity analysis revealed that PTSD patients had significantly increased inter-modular connections in the fronto-parietal module, fronto-striato-temporal module, and visual and default mode modules. These findings indicate a PTSD-related shift of white matter network topology toward randomization. This pattern was characterized by an increased global network integration, reflected by increased inter-modular connections with increased nodal centralities involving fronto-temporo-occipital regions. This study suggests that extremely stressful life experiences, when they lead to PTSD, are associated with large-scale brain white matter network topological reconfiguration at global, nodal, and modular levels.


[Determination and treatment of human body total potassium capacity].
The system of determination and treatment of human body total potassium capacity (HBTPC) were based on curves: the values of serum potassium concentration, arterial blood pH and variation of HBTPC. We compared the values of 40 health persons and those of 350 patients who received abdominal operation. The patients with abnormal HBTPC were treated successfully. We consider that this system is better than traditional method.


Incidence and time course of cardiovascular side effects during spinal anesthesia after prophylactic administration of intravenous fluids or vasoconstrictors.
We studied the time course of arterial hypotension and/or bradycardia requiring treatment during spinal anesthesia and compared the efficacy of i.v. fluid or vasoconstrictor administration for the prevention of these side effects. Patients (n = 1066) were randomly allocated to either a volume group (lactated Ringer's solution 15 mL/kg within 15 min before spinal anesthesia), a dihydroergotamine group (10 microg/kg i.m. 15 min before anesthesia), or a placebo group. All patients breathed O2-enriched air during spinal anesthesia (4 mL of plain 0.5% bupivacaine). With the placebo, there were side effects (mean incidence 22.9%) for up to 45 min after the start of anesthesia. Dihydroergotamine reduced the incidence of side effects, preferentially the late ones, more (mean incidence 11.8%) than fluid administration (mean incidence 16.9%), which was effective only during the first 15 min of anesthesia. Both heart rate and arterial pressure decreased within 15 min before the manifestation of symptoms. In a subgroup of patients, the incidence of side effects (8%) was greatly reduced by the intraoperative application of both sedatives and opioids. We conclude that cardiovascular side effects may occur at any time during spinal anesthesia. Fluid administration reduced the incidence of early events, but dihydroergotamine the late events. Cardiovascular side effects requiring treatment occurred at any time during spinal anesthesia in our placebo-controlled study, regardless of the prophylactic regimen (fluid infusions versus dihydroergotamine).


Biology, Ecology, and Control of Lasioderma serricorne (F.) (Coleoptera: Anobiidae): A Review.
The cigarette beetle, Lasioderma serricorne(F.) (Coleoptera: Anobiidae), is an important pest in the food and tobacco industry in many regions of the world. Despite a great deal of research, control of this pest still relies on the use of phosphine fumigation, which is becoming less effective as the insect develops resistance to this compound. In addition, series of other nonchemical methods used to control the insect have given mixed and irregular results. This review summarizes and discusses information on important aspects of the biology and ecology of the cigarette beetle, and its control. The topics covered include a taxonomic discussion of the cigarette beetle, which includes a discussion of other anobiid species of economic importance. The mating behavior of the insect and conditions favorable for pest development were described. The review also includes a discussion of the life stages of the insect, its feeding habit, and economic damage. Important aspects of its chemical ecology and a discussion on the association between this species and its microorganisms, and major natural enemies, were presented. A summary of its flight behavior, including the factors governing flight initiation and temporal and seasonal flight activity were reviewed. Finally, the control methods currently used in the management of the insect were described. The review also identifies potential areas of further research on L. serricorne and gives an analysis of the control methods worthy of further investigation in the search for practical and sustainable methods for the management of this pest.


Community paramedics treat high acuity conditions in the home: a prospective observational study.
As the US population ages and healthcare reimbursement shifts, identifying new patient-centred, cost-effective models to address acute medical needs will become increasingly important. This study examined whether community paramedics can evaluate and treat, under the direction of a credentialed physician, high acuity medical conditions in the home within an advanced illness management (AIM) practice. A prospective observational study of an urban/suburban community paramedicine (CP) programme, with responses initiated based on AIM-practice protocols and triaged prior to dispatch using the Advanced Medical Priority Dispatch System (AMPDS). Primary outcome was association between AMPDS acuity levels and emergency department (ED) transport rates. Secondary outcomes were ED presentations at 24 and 48 hours post-visit, and patient/caregiver survey results. 1159 individuals received 2378 CP responses over 4 years. Average age was 86 years; dementia, heart failure and asthma/chronic obstructive pulmonary disease were prevalent. Using AMPDS, most common reasons for dispatch included 'breathing problems' (28.2%), 'sick person' (26.5%) and 'falls' (13.1%). High acuity responses were most prevalent. 17.9% of all responses and 21.0% of high acuity responses resulted in ED transport. Within 48 hours of the visit, only 5.7% of the high acuity responses not initially transported were transported to the ED. Patient/caregiver satisfaction rates were high. Community paramedics, operating within an AIM programme, can evaluate and treat a range of conditions, including high acuity conditions, in the home that would typically result in ED transport in a conventional 911 system. This model may provide an effective means for avoiding hospital-based care, allowing older adults to age in place.


Influence of an intra-articular lipopolysaccharide challenge on markers of inflammation and cartilage metabolism in young horses.
Nineteen weanling Quarter Horses (225 to 380 kg) were used in a randomized complete block design to investigate the effects of intra-articular lipopolysaccharide (LPS) to induce acute joint inflammation in young horses. Horses were blocked by age, BW, and sex and were randomly assigned to 1 of 3 treatments for a 35-d experiment. Treatments included intra-articular injection of 0.25 ng (n = 7) or 0.50 ng (n = 6) of LPS obtained from Escherichia coli O55:B5 or sterile lactated Ringer's solution (n = 6; control) into the radial carpal joint. Synovial fluid was obtained at preinjection h 0 and 2, 6, 12, 24, 168, and 336 h postinjection and was analyzed for PGE2, carboxypeptide of type II collagen (CPII), and collagenase cleavage neopeptide (C2C) biomarkers via commercial ELISA kits. Rectal temperature (RT), heart rate (HR), respiratory rate (RR), and carpal circumference were recorded before each sample. Lameness scores on a 0 to 5 scale were conducted after arthrocentesis. Data were analyzed using PROC MIXED procedure of SAS. Linear and cubic effects were tested in the form of contrasts. Clinical assessment of HR, RR, and RT were not influenced by treatment (P ≤ 0.16). All horses exhibited increased lameness scores over time (P ≤ 0.01), and horses receiving LPS, regardless of dose, had greater recorded lameness scores at 12 and 24 h postinjection (P ≤ 0.05). Joint circumference increased (P ≤ 0.01) across treatments in response to repeated arthrocentesis. Mean synovial fluid PGE2 concentrations increased linearly with increasing levels of LPS administration (P ≤ 0.01). Additionally, regardless of treatment, PGE2 increased over time and peaked at 12 h postinjection (P ≤ 0.01) and remained elevated above baseline at 336 h postinduction. Synovial concentrations of anabolic CPII increased linearly (P ≤ 0.01) with increasing dosage of LPS and increased (P ≤ 0.01) over 24 h in all horses, beginning at 6 h and peaking at 24 h postinjection. Concentrations of C2C in synovial fluid were not influenced by treatment and decreased from 0 to 6 h and steadily increased to 24 h in all horses (P ≤ 0.01). These results indicate that intra-articular LPS induced intra-articular inflammation and collagen synthesis in young horses and that the response is dose dependent. The use of this model to induce predictable joint inflammation may provide insight to the efficacy of preventative strategies relating to joint disease in the young horse.


Incidence and Mortality of Sarcomas in Shanghai, China, During 2002-2014.
Background: Sarcomas are a heterogeneous group of rare but deadly malignant tumors. The aim of this study was to comprehensively describe the incidence and mortality of sarcomas in Shanghai during 2002-2014. Method: Data were from Shanghai Cancer Registry. All new cases diagnosed with sarcomas and all death records where the cause of death listed as sarcomas were included. The characteristics of sarcomas incidence and mortality were analyzed. Age-standardized rates (ASRs) were adjusted by the world standard population. The trends were assessed by Joinpoint analysis. Results: A total of 9,440 incident cases were identified. The ASR was 3.4/105 for all sarcomas combined. Incidence of sarcomas overall was similar in females (3.5/105) as in males (3.4/105). Except for sarcomas "Not Otherwise Specified" (NOS), the most common histological subtype was gastrointestinal stromal sarcoma (GISS) (14.8%), which was followed by fibrosarcoma (7.2%), lipoblastoma (6.7%), leiomyosarcomas (6.5%), and osteosarcoma (5.3%). Among those incident cases, 87.9% were located in soft tissue sarcomas (STS) and 12.1% in bone and joint (bone sarcomas). The ASRs for STS and bone sarcomas were 2.8/105 and 0.6/105, respectively. Incidence rates for all STS combined rose exponentially with age, while bone sarcomas had the highest incidence at age 0-19. There were 4,279 deaths during 2002-2014 with the ASR of 1.3/105. Age-adjusted mortality due to sarcomas was slightly higher in males (1.5/105) than females (1.2/105). Except for sarcomas NOS, leiomyosarcomas was the most common subtype, comprising 9.9% of deaths due to sarcomas, followed by lipoblastoma (6.4%) and osteosarcoma (6.3%). The ASRs of mortality for STS and bone sarcomas were 1.0/105 and 0.2/105, respectively. For both males and females, the age-standardized incidence for STS and bone sarcomas did not change meaningfully over the study period. In contrast, age-standardized STS mortality in females increased by 2.3% per year (95% CI: 0.3, 4.4%), but was unchanged in males. No meaningful trends in bone sarcomas mortality were observed for either males or females. Conclusion: This population-based study was the first report of epidemiology of sarcomas in Shanghai according to anatomic site and histologic type. The diversity and rarity of sarcomas suggested more detailed data are warranted.


Optical microscopy. 3. Tracking fluorescently labeled neurons in developing brain.
For decades, time-lapse microscopy has been used to track dynamic events associated with biological phenomena. Time-lapse studies of the developing nervous system have been restricted to analysis of dissociated cell cultures or of a series of static images from living organisms. The advent of new fluorescent dyes and video imaging technology has produced novel views of the behavior of neurons in the context of the developing nervous tissue, such as migrations within and away from proliferative zones and navigation of axonal processes to synaptic targets. After fixation of the tissue preparation, time-lapse monitoring can be followed by other analytical techniques and forms of microscopy, e.g., immunocytochemistry or electron microscopy, producing information on the interactions of individual cells whose behavioral histories are known. The power of video time-lapse microscopy of living brain tissue lies in the firsthand documentation of developmental patterning, which in turn can serve as an experimental assay.


Modeling human perception of orientation in altered gravity.
Altered gravity environments, such as those experienced by astronauts, impact spatial orientation perception, and can lead to spatial disorientation and sensorimotor impairment. To more fully understand and quantify the impact of altered gravity on orientation perception, several mathematical models have been proposed. The utricular shear, tangent, and the idiotropic vector models aim to predict static perception of tilt in hyper-gravity. Predictions from these prior models are compared to the available data, but are found to systematically err from the perceptions experimentally observed. Alternatively, we propose a modified utricular shear model for static tilt perception in hyper-gravity. Previous dynamic models of vestibular function and orientation perception are limited to 1 G. Specifically, they fail to predict the characteristic overestimation of roll tilt observed in hyper-gravity environments. To address this, we have proposed a modification to a previous observer-type canal-otolith interaction model based upon the hypothesis that the central nervous system (CNS) treats otolith stimulation in the utricular plane differently than stimulation out of the utricular plane. Here we evaluate our modified utricular shear and modified observer models in four altered gravity motion paradigms: (a) static roll tilt in hyper-gravity, (b) static pitch tilt in hyper-gravity, (c) static roll tilt in hypo-gravity, and (d) static pitch tilt in hypo-gravity. The modified models match available data in each of the conditions considered. Our static modified utricular shear model and dynamic modified observer model may be used to help quantitatively predict astronaut perception of orientation in altered gravity environments.


Personalized machine learning of depressed mood using wearables.
Depression is a multifaceted illness with large interindividual variability in clinical response to treatment. In the era of digital medicine and precision therapeutics, new personalized treatment approaches are warranted for depression. Here, we use a combination of longitudinal ecological momentary assessments of depression, neurocognitive sampling synchronized with electroencephalography, and lifestyle data from wearables to generate individualized predictions of depressed mood over a 1-month time period. This study, thus, develops a systematic pipeline for N-of-1 personalized modeling of depression using multiple modalities of data. In the models, we integrate seven types of supervised machine learning (ML) approaches for each individual, including ensemble learning and regression-based methods. All models were verified using fourfold nested cross-validation. The best-fit as benchmarked by the lowest mean absolute percentage error, was obtained by a different type of ML model for each individual, demonstrating that there is no one-size-fits-all strategy. The voting regressor, which is a composite strategy across ML models, was best performing on-average across subjects. However, the individually selected best-fit models still showed significantly less error than the voting regressor performance across subjects. For each individual's best-fit personalized model, we further extracted top-feature predictors using Shapley statistics. Shapley values revealed distinct feature determinants of depression over time for each person ranging from co-morbid anxiety, to physical exercise, diet, momentary stress and breathing performance, sleep times, and neurocognition. In future, these personalized features can serve as targets for a personalized ML-guided, multimodal treatment strategy for depression.


Evidence for a role of frataxin in pancreatic islets isolated from multi-organ donors with and without type 2 diabetes mellitus.
Frataxin (FXN) is a mitochondrial protein involved in iron metabolism and in the modulation of reactive oxygen and/or nitrogen species production. No information is currently available as for the role of frataxin in isolated human pancreatic islets. We studied islets from pancreases of multi-organ donors with (T2DM) and without (Ctrl) Type 2 diabetes mellitus. In these islets, we determined FXN gene and protein expression by qualitative and quantitative Real-Time RT-PCR, nitrotyrosine concentration, and insulin release in response to glucose stimulation (SI). FXN gene and protein were expressed in human islets, though the level of expression was much lower in T2DM islets. The latter also had lower insulin release and higher concentration of nitrotyrosine. A positive correlation was apparent between SI and FXN gene expression, while a negative correlation was found between nitrotyrosine islet concentration and FXN expression. Transfection of Ctrl islets with siRNA FXN caused reduction of FXN expression, increase of nitrotyrosine concentration, and reduction of insulin release. In conclusion, in human pancreatic islets FXN contributes to regulation of oxidative stress and insulin release in response to glucose. In islets from T2DM patients FXN expression is reduced while oxidative stress is increased and insulin release in response to glucose impaired.


Expression of the murine RanBP1 and Htf9-c genes is regulated from a shared bidirectional promoter during cell cycle progression.
The murine Htf9-a/RanBP1 and Htf9-c genes are divergently transcribed from a bidirectional promoter. The Htf9-a gene encodes the RanBP1 protein, a major partner of the Ran GTPase. The divergently transcribed Htf9-c gene encodes a protein sharing similarity with yeast and bacterial nucleic acid-modifying enzymes. We report here that both mRNA species produced by the Htf9-associated genes are regulated during the cell cycle progression, peak in S phase and decrease during mitosis. Transient expression experiments with reporter constructs showed that cell cycle expression is controlled at the transcriptional level, because the bidirectional Htf9 promoter is down-regulated in growth-arrested cells, is activated at the G1/S transition and reaches maximal activity in S phase, though with a different efficiency for each orientation. We have delimited specific promoter regions controlling S phase activity in one or both orientations: identified elements contain recognition sites for members belonging to both the E2F and Sp1 families of transcription factors. Together, the results suggest that the sharing of the regulatory region supports co-regulation of the Htf9-a/RanBP1 and Htf9-c genes in a common window of the cell cycle.


A High-Throughput Screening Identifies MicroRNA Inhibitors That Influence Neuronal Maintenance and/or Response to Oxidative Stress.
Small non-coding RNAs (sncRNAs), including microRNAs (miRNAs) are important post-transcriptional gene expression regulators relevant in physiological and pathological processes. Here, we combined a high-throughput functional screening (HTFS) platform with a library of antisense oligonucleotides (ASOs) to systematically identify sncRNAs that affect neuronal cell survival in basal conditions and in response to oxidative stress (OS), a major hallmark in neurodegenerative diseases. We considered hits commonly detected by two statistical methods in three biological replicates. Forty-seven ASOs targeting miRNAs (miRNA-ASOs) consistently decreased cell viability under basal conditions. A total of 60 miRNA-ASOs worsened cell viability impairment mediated by OS, with 36.6% commonly affecting cell viability under basal conditions. In addition, 40 miRNA-ASOs significantly protected neuronal cells from OS. In agreement with cell viability impairment, damaging miRNA-ASOs specifically induced increased free radical biogenesis. miRNAs targeted by the detrimental ASOs are enriched in the fraction of miRNAs downregulated by OS, suggesting that the miRNA expression pattern after OS contributes to neuronal damage. The present HTFS highlighted potentially druggable sncRNAs. However, future studies are needed to define the pathways by which the identified ASOs regulate cell survival and OS response and to explore the potential of translating the current findings into clinical applications.


Asymmetrical visual deprivation: a technique to differentially influence lateral hemispheric function.
This article describes a contact-lens method to sustain asymmetry in visual deprivation and the use of this method to test the general hypothesis that asymmetry in input deprivation can shift activation balance in the integrated brain, differentially influencing lateral hemispheric function. Effects of asymmetrical visual deprivation were as predicted on lateral asymmetry of EEG theta, producing more theta over the deprived hemisphere. Cross-modal influence of such visual deprivation was found in the perception of pleasantness of odors. An interaction was found between side of visual deprivation and performance on verbal reasoning and spatial orientation tasks. A line-bisection test of visual attention was not sensitive to the effects. Fatigue as rated on the Profile of Mood States was greatest when the left hemisphere was deprived.


Conformational and electrostatic similarity between polyprotonated and Ca(2+)-bound mu-opioid peptides.
In a previous paper (Zhorov and Ananthanarayanan, J. Biomol, Struct. Dynam. 1995, 13:1-13) we had calculated the minimum-energy conformations of monoprotonated and zwitterionic mu-opioid peptides and demonstrated the remarkable similarity between Ca(2+)-bound morphine on the one hand and the Ca(2+)-bound forms of these peptides on the other. We postulated that the Ca(2+)-bound forms of mu-opioids would activate the mu-receptor. To assess further the involvement of multiple positive charges on some of the mu-opioid ligands in their interaction with the receptor, we have, in this work, studied the geometry of five mu-opioid peptides containing two to four protonated groups and having chemical structures essentially different from the endogenous mu-opioid peptide Met-enkephalin (EK). Conformational space was searched using the Monte Carlo-with-energy-minimization method. Ca(2+)-bound forms of the selected peptides were found to be energetically unfavourable implying that one of the protonated groups plays a role similar to that Ca2+ plays in EK-Ca2+ complex. Bioactive conformations of the polyprotonated peptides were then selected using the criteria formulated earlier for Ca(2+)-bound ligands as well as additional criteria requiring ligands to have an elongated conical overall shape complementary to the interface between the transmembrane segments of mu-receptor. Low-energy conformations meeting these criteria were found in all the peptides considered, the protonated groups being separated from each other by about 8 and 16 A. The possible role of the ligands' cationic groups in mu-receptor activation is discussed.


Disease activity and low physical activity associate with number of hospital admissions and length of hospitalisation in patients with rheumatoid arthritis.
Substantial effort has been devoted for devising effective and safe interventions to reduce preventable hospital admissions in chronic disease patients. In rheumatoid arthritis (RA), identifying risk factors for admission has important health policy implications, but knowledge of which factors cause or prevent hospital admissions is currently lacking. We hypothesised that disease activity/severity and physical activity are major predictors for the need of hospitalisation in patients with RA. A total of 244 RA patients were assessed for: physical activity (International Physical Activity Questionnaire), RA activity (C-reactive protein: CRP; disease activity score: DAS28) and disability (Health Assessment Questionnaire: HAQ). The number of hospital admissions and length of hospitalisation within a year from baseline assessment were collected prospectively. Disease activity and disability as well as levels of overall and vigorous physical activity levels correlated significantly with both the number of admissions and length of hospitalisation (P < 0.05); regression analyses revealed that only disease activity (DAS28) and physical activity were significant independent predictors of numbers of hospital admissions (DAS28: (exp(B) = 1.795, P = 0.002 and physical activity: (exp(B) = 0.999, P = 0.046)) and length of hospitalisation (DAS28: (exp(B) = 1.795, P = 0.002 and physical activity: (exp(B) = 0.999, P = 0.046). Sub-analysis of the data demonstrated that only 19% (n = 49) of patients engaged in recommended levels of physical activity. This study provides evidence that physical activity along with disease activity are important predictors of the number of hospital admissions and length of hospitalisation in RA. The combination of lifestyle changes, particularly increased physical activity along with effective pharmacological therapy may improve multiple health outcomes as well as cost of care for RA patients.


Noise reduction in diffusion MRI using non-local self-similar information in joint x-q space.
Diffusion MRI affords valuable insights into white matter microstructures, but suffers from low signal-to-noise ratio (SNR), especially at high diffusion weighting (i.e., b-value). To avoid time-intensive repeated acquisition, post-processing algorithms are often used to reduce noise. Among existing methods, non-local means (NLM) has been shown to be particularly effective. However, most NLM algorithms for diffusion MRI focus on patch matching in the spatial domain (i.e., x-space) and disregard the fact that the data live in a combined 6D space covering both spatial domain and diffusion wavevector domain (i.e., q-space). This drawback leads to inaccurate patch matching in curved white matter structures and hence the inability to effectively use recurrent information for noise reduction. The goal of this paper is to overcome this limitation by extending NLM to the joint x-q space. Specifically, we define for each point in the x-q space a spherical patch from which we extract rotation-invariant features for patch matching. The ability to perform patch matching across q-samples allows patches from differentially orientated structures to be used for effective noise removal. Extensive experiments on synthetic, repeated-acquisition, and HCP data demonstrate that our method outperforms state-of-the-art methods, both qualitatively and quantitatively.


Hexapleomera urashima sp. nov. (Crustacea: Tanaidacea), a tanaidid epibiotic on loggerhead sea turtles at Yakushima Island, Japan.
We describe Hexapleomera urashima sp. nov. from the carapaces of loggerhead sea turtles (Caretta caretta) on Yakushi-ma Island, southwestern Japan, the primary nesting site for the North Pacific population of this turtle. Hexapleomera urashima closely resembles H. edgari Bamber collected from Australian loggerheads (South Pacific population), sharing a uropod with four articles and maxillipedal endites with distal spiniform setae, but differs in having the maxillipedal coxa with two simple setae, the maxillipedal endite with two tiny dorsosubdistal and two distal spiniform setae, the labial palp fused to the outer lobe of the labium, and the basal article of pleopod 3 without inner setae. Several characters (e.g., size or presence/absence of a dorsal triangular process on the male fixed finger; number of inner setae on the pleopodal endopod), assumed to be diagnostic for species in Hexapleomera, actually vary within H. urashima, indicating that reassessment of species diagnoses is warranted. Hexapleomera urashima showed two COI haplotypes differing by one substitution, but separated from representatives of four other genera by 32.2-48.4% K2P distance. Indices of saturation substitution indicated that COI is not useful for phylogeny reconstruction within Tanaididae.


Impact of insufficient sleep on dysregulated blood glucose control under standardised meal conditions.
Sleep, diet and exercise are fundamental to metabolic homeostasis. In this secondary analysis of a repeated measures, nutritional intervention study, we tested whether an individual's sleep quality, duration and timing impact glycaemic response to a breakfast meal the following morning. Healthy adults' data (N = 953 [41% twins]) were analysed from the PREDICT dietary intervention trial. Participants consumed isoenergetic standardised meals over 2 weeks in the clinic and at home. Actigraphy was used to assess sleep variables (duration, efficiency, timing) and continuous glucose monitors were used to measure glycaemic variation (>8000 meals). Sleep variables were significantly associated with postprandial glycaemic control (2 h incremental AUC), at both between- and within-person levels. Sleep period time interacted with meal type, with a smaller effect of poor sleep on postprandial blood glucose levels when high-carbohydrate (low fat/protein) (pinteraction = 0.02) and high-fat (pinteraction = 0.03) breakfasts were consumed compared with a reference 75 g OGTT. Within-person sleep period time had a similar interaction (high carbohydrate: pinteraction = 0.001, high fat: pinteraction = 0.02). Within- and between-person sleep efficiency were significantly associated with lower postprandial blood glucose levels irrespective of meal type (both p < 0.03). Later sleep midpoint (time deviation from midnight) was found to be significantly associated with higher postprandial glucose, in both between-person and within-person comparisons (p = 0.035 and p = 0.051, respectively). Poor sleep efficiency and later bedtime routines are associated with more pronounced postprandial glycaemic responses to breakfast the following morning. A person's deviation from their usual sleep pattern was also associated with poorer postprandial glycaemic control. These findings underscore sleep as a modifiable, non-pharmacological therapeutic target for the optimal regulation of human metabolic health. Trial registration ClinicalTrials.gov NCT03479866.


Double homozygous waltzer and Ames waltzer mice provide no evidence of retinal degeneration.
To determine whether cadherin 23 and protocadherin 15 can substitute for one another in the maintenance of the retina and other tissues in the mouse. Does homozygosity for both v and av mutant alleles (i.e., a double homozygous mouse) cause retinal degeneration or an obvious retinal histopathology? We generated mice homozygous for both Cdh23(v-6J) and Pcdh15(av-Jfb) alleles. The retinal phenotypes of double heterozygous and double homozygous mutant mice were determined by light microscopy and electroretinography (ERG). Histology on 32 different tissues, scanning electron microscopy of organ of Corti hair cells as well as serum biochemical and hematological examinations were evaluated. ERG waves of double heterozygous and double homozygous mice showed similar shape, growth of the amplitude with intensity, and implicit time for both rod and cone pathway mediated responses. Mice homozygous for both Cdh23(v-6J) and Pcdh15(av-Jfb) mutations showed no sign of retinitis pigmentosa or photoreceptor degeneration but, as expected, were deaf and had disorganized hair cell sensory bundles. The simultaneous presence of homozygous mutant alleles of cadherin 23 and protocadherin 15 results only in deafness, not retinal degeneration or any other additional obvious phenotype of the major organ systems. We conclude that in the mouse cadherin 23 or protocadherin 15 appear not to compensate for one another to maintain the retina.


Passive Exposure to Pollutants from a New Generation of Cigarettes in Real Life Scenarios.
The use of electronic cigarettes (e-cigarettes) and heat-not-burn tobacco (HNBT), as popular nicotine delivery systems (NDS), has increased among adult demographics. This study aims to assess the effects on indoor air quality of traditional tobacco cigarettes (TCs) and new smoking alternatives, to determine the differences between their potential impacts on human health. Measurements of particulate matter (PM1, PM2.5 and PM10), black carbon, carbon monoxide (CO) and carbon dioxide (CO2) were performed in two real life scenarios, in the home and in the car. The results indicated that the particle emissions from the different NDS devices were significantly different. In the home and car, the use of TCs resulted in higher PM10 and ultrafine particle concentrations than when e-cigarettes were smoked, while the lowest concentrations were associated with HNBT. As black carbon and CO are released by combustion processes, the concentrations of these two pollutants were significantly lower for e-cigarettes and HNBT because no combustion occurs when they are smoked. CO2 showed no increase directly associated with the NDS but a trend linked to a higher respiration rate connected with smoking. The results showed that although the levels of pollutants emitted by e-cigarettes and HNBT are substantially lower compared to those from TCs, the new smoking devices are still a source of indoor air pollutants.


A multitask deep learning radiomics model for predicting the macrotrabecular-massive subtype and prognosis of hepatocellular carcinoma after hepatic arterial infusion chemotherapy.
The macrotrabecular-massive (MTM) is a special subtype of hepatocellular carcinoma (HCC), which has commonly a dismal prognosis. This study aimed to develop a multitask deep learning radiomics (MDLR) model for predicting MTM and HCC patients' prognosis after hepatic arterial infusion chemotherapy (HAIC). From June 2018 to March 2020, 158 eligible patients with HCC who underwent surgery were retrospectively enrolled in MTM related cohorts, and 752 HCC patients who underwent HAIC were included in HAIC related cohorts during the same period. DLR features were extracted from dual-phase (arterial phase and venous phase) contrast-enhanced computed tomography (CECT) of the entire liver region. Then, an MDLR model was used for the simultaneous prediction of the MTM subtype and patient prognosis after HAIC. The MDLR model for prognostic risk stratification incorporated DLR signatures, clinical variables and MTM subtype. The predictive performance of the DLR model for the MTM subtype was 0.968 in the training cohort [TC], 0.912 in the internal test cohort [ITC] and 0.773 in the external test cohort [ETC], respectively. Multivariable analysis identified portal vein tumor thrombus (PVTT) (p = 0.012), HAIC response (p < 0.001), HAIC sessions (p < 0.001) and MTM subtype (p < 0.001) as indicators of poor prognosis. After incorporating DLR signatures, the MDLR model yielded the best performance among all models (AUC, 0.855 in the TC, 0.805 in the ITC and 0.792 in the ETC). With these variables, the MDLR model provided two risk strata for overall survival (OS) in the TC: low risk (5-year OS, 44.9%) and high risk (5-year OS, 4.9%). A tool based on MDLR was developed to consider that the MTM is an important prognosis factor for HCC patients. MDLR showed outstanding performance for the prognostic risk stratification of HCC patients who underwent HAIC and may help physicians with therapeutic decision making and surveillance strategy selection in clinical practice.


Online Information About Harmful Tobacco Constituents: A Content Analysis.
Tobacco products and smoke contain more than 7000 chemicals (ie, constituents). Research shows that consumers have poor understanding of tobacco constituents and find communication about them to be confusing. The current content analysis describes how information is communicated about tobacco constituents online in terms of source, target audience, and message. A search was conducted in September 2015 using tobacco constituent and tobacco terms and identified 226 relevant Web sites for coding. Web sites were coded for type, target audience, reading level, constituent information, type of tobacco product, health effects, and emotional valence by two coders who independently coded half of the sample. There was a 20% overlap to assess interrater reliability, which was high (κ = .83, p < .001). The mean reading grade level of information online was 8.2 (SD = 2.8) with 81.7% of Web sites above the sixth grade reading level. Nearly all Web sites presented information in a qualitative narrative format (93%) and almost half (48.2%) presented information in a quantitative format. Nicotine (59.3%) and nitrosamines (28.8%) were the mostly frequently mentioned tobacco constituents. Cancer was the most frequently mentioned health effect (51.3%). Nearly a quarter (23%) of the Web sites did not explicitly state that tobacco constituents or tobacco products are associated with health effects. Large gaps exist in online information about tobacco constituents including incomplete information about tobacco constituent-related health effects and limited information about tobacco products other than cigarettes and smokeless tobacco. This study highlights opportunities to improve the content and presentation of information related to tobacco constituents. The US Food and Drug Administration (FDA) is required to publicly display a list of tobacco constituents in tobacco products and tobacco smoke by brand. However, little is known about tobacco constituent information available to the public. This is the first systematic content analysis of online information about tobacco constituents. The analysis reveals that although information about tobacco constituents is available online, large information gaps exist, including incomplete information about tobacco constituent-related health effects. This study highlights opportunities to improve the content and presentation of public information related to tobacco constituents.


Pregnancy complications in spontaneous and assisted conceptions of women with infertility and subfertility factors. A comprehensive review.
In the literature, there is growing evidence that assisted reproductive techniques increase the risk of pregnancy complications in subfertile couples. Moreover, many concomitant preconception risk factors for subfertility are frequently present in the same subject and increase the risk of pregnancy complications. This review aimed to summarize in a systematic fashion the best current evidence regarding the effects of preconception maternal factors on maternal and neonatal outcomes. A literature search up to March 2016 was performed in IBSS, SocINDEX, Institute for Scientific Information, PubMed, Web of Science and Google Scholar. An evidence-based hierarchy was used to determine which articles to include and analyse. Available data show that the risk of pregnancy complications in spontaneous and assisted conceptions is likely multifactorial, and the magnitude of this risk is probably very different according specific subgroups of patients. Notwithstanding the only moderate level and quality of the available evidence, available data suggest that the presence and the treatment of specific preconception cofactors of subfertility should be always taken into account both in clinical practice and for scientific purposes.


Inherited and noninherited risk factors in rheumatoid arthritis.
Rheumatoid arthritis (RA) is likely the result of a concerted action of several inherited and noninherited factors. Although there is a high suspicion that environmental factors are important, proof is missing. Most information has been collected on genetic risk factors. The inheritance pattern for RA is complex, and there is good evidence that HLA as well as non-HLA genes are involved. Almost all racial-ethnic groups share the association of RA with the HLA-DRB1-encoded sequence motif QKRAA or QRRAA. However, the completeness of the association varies significantly in different ethnic cohorts, as can be expected in a multigene model. The sequence motif translates into a pocket in the antigen-binding site of the HLA-DR molecule. The "rheumatoid pocket" accommodates peptide side chains and has distinct binding characteristics. Epidemiologic evidence points toward a role for non-HLA genes. Candidate genes, such as transporter in antigen processing (TAP) genes are currently explored. Major advances in defining and understanding the contribution of inherited and noninherited factors in RA may come from abandoning the concept of RA as a single entity and accepting a heterogeneity model for RA. Distributions of HLA-DR genes indicate that several subsets of RA patients exist. Seronegative (prognostically good) and seropositive (prognostically worse) patients can be distinguished by the arginine versus lysine substitution at position 71 of the HLA-DRB1 gene. A different dimension of disease, rheumatoid organ disease, appears to be reached in patients with two HLA-DRB1*0401 alleles. Identification of distinct RA subsets may allow us to stratify patients into categories that differ with respect to etiology, disease course, clinical pattern, and treatment response.


Trimetazidine improves recovery during reperfusion in isolated rat hearts after prolonged ischemia.
Trimetazidine (TMZ) is a cellular anti-ischemic agent, which has been studied in clinical and experimental investigations, and was shown to have protective affects against myocardial ischemia and reperfusion injury. The major objective of this study was to investigate the cardio-protective effects of trimetazidine in prolonged global ischemia subjected Langendorff perfused rat hearts. Twenty rats (Male Sprague-Dawley) were divided into two study groups. In Group 2 (n=10) TMZ was given by intra-gastric gavage (3 mg/kg BW twice daily for 5 days) prior to operation and was added to the Krebbs-Henseleit perfusate to create a 10-6 M solution to perfuse the isolated rat hearts. Group 1 (n=10) reserved as control group and received saline at the same time period. All hearts were paced at 300 beats/min. After a 20-minute of stabilization period, hearts in both groups were arrested for 120 minutes with crystalloid cardioplegia. After ischemic period, the hearts were then reperfused for 30 minutes. Hemodynamic measurements from left ventricular latex balloon, coronary flow, and creatine kinase (CK-MB) and troponin T (cTnT) levels determined from the coronary effluent were analyzed at the end of stabilization and at every 10-min intervals during reperfusion, and results were compared between two groups. No significant differences were observed in all entered hemodynamic and biochemical parameters between two groups at the end of the stabilization. However, peak systolic pressure, end diastolic pressure and +dP/dt values reflected improved mechanical myocardial recovery in Group 2 hearts after prolonged ischemia. Besides coronary flow measurements were higher in Group 2 compared with Group 1. CK-MB and cTnT levels indicated to less enzymatic damage in trimetazidine treated hearts during reperfusion. In conclusion, both pre-treatment and treatment protocols with TMZ reduce the myocardial damage caused by global ischemia following reperfusion. We could speculate that this beneficial effect of trimetazidine might be useful in open-heart surgery patients, who were subjected to global myocardial ischemia.


Projecting seismicity induced by complex alterations of underground stresses with applications to geothermal systems.
Seismicity associated with subsurface operations is a major societal concern. It is therefore critical to improve predictions of the induced seismic hazard. Current statistical approaches account for the physics of pore pressure increase only. Here, we present a novel mathematical model that generalises adopted statistics for use in arbitrary injection/production protocols and applies to arbitrary physical processes. In our model, seismicity is driven by a normalised integral over the spatial reservoir volume of induced variations in frictional Coulomb stress, which-combined with the seismogenic index-provides a dimensionless proxy of the induced seismic hazard. Our model incorporates the classical pressure diffusion based and poroelastic seismogenic index models as special cases. Applying our approach to modeling geothermal systems, we find that seismicity rates are sensitive to imposed fluid-pressure rates, temperature variations, and tectonic conditions. We further demonstrate that a controlled injection protocol can decrease the induced seismic risk and that thermo-poroelastic stress transfer results in a larger spatial seismic footprint and in higher-magnitude events than does direct pore pressure impact for the same amount of injected volume and hydraulic energy. Our results, validated against field observations, showcase the relevance of the novel approach to forecast seismic hazards induced by subsurface activities.


Mitochondria and cancer: past, present, and future.
The area of mitochondrial genomics has undergone unprecedented growth over the past several years. With the advent of the age of omics, investigations have reached beyond the nucleus to encompass the close biological communication and finely coordinated interactions between mitochondria and their nuclear cell mate. Application of this holistic approach, to all metabolic interactions within the cell, is providing a more complete understanding of the molecular transformation of the cell from normal to malignant behavior, before histopathological indications are evident. In this review the surging momentum in mitochondrial science, as it relates to cancer, is described in three progressive perspectives: (1) Past: the historical contributions to current directions of research; (2) Present: Contemporary findings, results and approaches to mitochondria and cancer, including the role of next generation sequencing and proteomics; (3) FUTURE: Based on the present body of knowledge, the potential assets and benefits of mitochondrial research are projected into the near future.


[The Journal of Slavonian Physicians (Glasnik druztva Slavonskih Liecnika), the journal of the medical society in Croatia 1877-1878].
If we discuss chronological appearance of medical journals as official gazettes of medical associations in this part of the world and Europe, then Glasnik druztva slavonskih liecnika (Glasnik DSL) is the first and the oldest medical journal of this kind in Croatia, whose first number is dated January 1, 1877, and the last December 1, 1878. It is the gazette of the Slavonian Medical Association in Osiek (DSL in Osiek), a professional medical association founded in 1874, which today marks its activity as the Croatian Medical Association--Osijek Branch (HLZ). Our goal was to investigate the key determinants of its appearance in the context of the role and contribution of Slavonian physicians in the promotion and development of Croatian medical literature, particularly medical periodicals in the 19th century. The conclusions we reached are based on the knowledge acquired during previous investigations on the history of medical associations and development of professional medical periodicals in Croatia and Slavonia in the 19th century, and on the historical material and preserved documentation of DSL in Osiek, HLZ in Zagreb, and Glasnik DSL from the beginning of 1874 through 1878. Basic determinants of the appearance and relatively short duration of the monthly periodical Glasnik DSL are highlighted, with the emphasis on: 1) events preceding its publication, including initiatives of physicians in Slavonia for the development of Croatian medical terminology, professional medical publications, particularly medical journals from the middle of the 19th century through 1876; 2) circumstances accompanying the publication of the journal Glasnik DSL in the period from January 1, 1877 through 1878; 3) events contributing to making decision on discontinuation of its publishing. The results are presented in several separate chapters which offer new scientific knowledge about the history of the medical Journal Glasnik DSL, and about the role of Slavonian physicians and DSL in Osiek in the promotion of Croatian medical terminology and the development of professional medical literature from the middle of the 19th century through 1878. In Glasnik DSL we today recognize our first medical periodical as the oldest scientific and professional gazette of the medical association; the unique source and material for studying the history of Croatian medical journals; history of medical associations; health-related circumstances, conditions of work and striving of physician, and professional and scientific scopes in Croatia in the 19th century. Each number is by itself a value and a bibilographic rarity, all numbers together represent a unique monument to Croatian medical heritage, whose availability for the new generations is facilitated by publishing the reprint issue in 1999.


Enhanced charge collection with ultrathin AlOx electron blocking layer for hole-transporting material-free perovskite solar cell.
An ultrathin AlOx layer has been deposited onto a CH3NH3PbI3 film using atomic layer deposition technology, to construct a metal-insulator-semiconductor (MIS) back contact for the hole-transporting material-free perovskite solar cell. By optimization of the ALD deposition cycles, the average power conversion efficiency (PCE) of the cell has been enhanced from 8.61% to 10.07% with a highest PCE of 11.10%. It is revealed that the improvement in cell performance with this MIS back contact is mainly attributed to the enhancement in charge collection resulting from the electron blocking effect of the AlOx layer.


Bi-allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families.
Exome and genome sequencing were used to identify the genetic etiology of a severe neurodevelopmental disorder in two unrelated Ashkenazi Jewish families with three affected individuals. The clinical findings included a prenatal presentation of microcephaly, polyhydramnios and clenched hands while postnatal findings included microcephaly, severe developmental delay, dysmorphism, neurologic deficits, and death in infancy. A shared rare homozygous, missense variant (c.274A > G; p.Ser92Gly, NM_024516.4) was identified in PAGR1, a gene currently not associated with a Mendelian disease. PAGR1 encodes a component of the histone methyltransferase MLL2/MLL3 complex and may function in the DNA damage response pathway. Complete knockout of the murine Pagr1a is embryonic-lethal. Given the available evidence, PAGR1 is a strong candidate gene for a novel autosomal recessive severe syndromic neurodevelopmental disorder.


Inhibition of GSDMD activation by Z-LLSD-FMK or Z-YVAD-FMK reduces vascular inflammation and atherosclerotic lesion development in ApoE-/- mice.
Pyroptosis is a form of pro-inflammatory cell death that can be mediated by gasdermin D (GSDMD) activation induced by inflammatory caspases such as caspase-1. Emerging evidence suggests that targeting GSDMD activation or pyroptosis may facilitate the reduction of vascular inflammation and atherosclerotic lesion development. The current study investigated the therapeutic effects of inhibition of GSDMD activation by the novel GSDMD inhibitor N-Benzyloxycarbonyl-Leu-Leu-Ser-Asp(OMe)-fluoromethylketone (Z-LLSD-FMK), the specific caspase-1 inhibitor N-Benzyloxycarbonyl-Tyr-Val-Ala-Asp(OMe)-fluoromethylketone (Z-YVAD-FMK), and a combination of both on atherosclerosis in ApoE-/- mice fed a western diet at 5 weeks of age, and further determined the efficacy of these polypeptide inhibitors in bone marrow-derived macrophages (BMDMs). In vivo studies there was plaque formation, GSDMD activation, and caspase-1 activation in aortas, which increased gradually from 6 to 18 weeks of age, and increased markedly at 14 and 18 weeks of age. ApoE-/- mice were administered Z-LLSD-FMK (200 µg/day), Z-YVAD-FMK (200 µg/day), a combination of both, or vehicle control intraperitoneally from 14 to 18 weeks of age. Treatment significantly reduced lesion formation, macrophage infiltration in lesions, protein levels of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, and pyroptosis-related proteins such as activated caspase-1, activated GSDMD, cleaved interleukin(IL)-1β, and high mobility group box 1 in aortas. No overt differences in plasma lipid contents were detected. In vitro treatment with these polypeptide inhibitors dramatically decreased the percentage of propidium iodide-positive BMDMs, the release of lactate dehydrogenase and IL-1β, and protein levels of pyroptosis-related proteins both in supernatants and cell lysates elevated by lipopolysaccharide + nigericin. Notably however, there were no significant differences in the above-mentioned results between the Z-LLSD-FMK group and the Z-YVAD-FMK group, and the combination of both did not yield enhanced effects. These findings indicate that suppression of GSDMD activation by Z-LLSD-FMK or Z-YVAD-FMK reduces vascular inflammation and lesion development in ApoE-/- mice.


Recent Advances on Edible Films Based on Fruits and Vegetables-A Review.
Food packaging materials are traditionally expected to contain foodstuffs and protect them from deteriorating agents. Although petroleum-derived polymers have been widely used for this purpose, the rising concern with their nonrenewable and/or nonbiodegradable nature paves the route for the development of greener alternatives, including polysaccharides and polypeptides. The use of these food-grade biomacromolecules, in addition to fruits and vegetables, provides edible packaging with suitable physical-mechanical properties as well as unique sensory and nutritional characteristics. This text reviews the chronological development pathway of films based on fruit and vegetable purees, pomaces, and extracts. Recent advances are extensively reviewed with an emphasis on the role that each film component plays in the resulting materials, whose production methods are examined from a technical standpoint and essential properties are compiled and contrasted to their conventional, synthetic counterparts. Finally, this comprehensive review discusses advantages and limitations of edible films based on fruits and vegetables.


Paradigms, pragmatism and possibilities: mixed-methods research in speech and language therapy.
After the decades of the so-called 'paradigm wars' in social science research methodology and the controversy about the relative place and value of quantitative and qualitative research methodologies, 'paradigm peace' appears to have now been declared. This has come about as many researchers have begun to take a 'pragmatic' approach in the selection of research methodology, choosing the methodology best suited to answering the research question rather than conforming to a methodological orthodoxy. With the differences in the philosophical underpinnings of the two traditions set to one side, an increasing awareness, and valuing, of the 'mixed-methods' approach to research is now present in the fields of social, educational and health research. To explore what is meant by mixed-methods research and the ways in which quantitative and qualitative methodologies and methods can be combined and integrated, particularly in the broad field of health services research and the narrower one of speech and language therapy. The paper discusses the ways in which methodological approaches have already been combined and integrated in health services research and speech and language therapy, highlighting the suitability of mixed-methods research for answering the typically multifaceted questions arising from the provision of complex interventions. The challenges of combining and integrating quantitative and qualitative methods and the barriers to the adoption of mixed-methods approaches are also considered. The questions about healthcare, as it is being provided in the 21st century, calls for a range of methodological approaches. This is particularly the case for human communication and its disorders, where mixed-methods research offers a wealth of possibilities. In turn, speech and language therapy research should be able to contribute substantively to the future development of mixed-methods research.


Contribution of abnormal central blood pressure to left ventricular filling pressure during exercise in patients with heart failure and preserved ejection fraction.
Hypertension is ubiquitous in patients with heart failure and preserved ejection fraction (HFpEF) and contributes to arterial and ventricular stiffening. Exertional dyspnea may result from diastolic dysfunction with exercise; however, the association of central blood pressure (BP) to left ventricular filling pressure during exercise has not been assessed in this population and was the aim of this study. Fifteen patients with HFpEF and 15 age-matched and sex-matched controls were studied at rest, during submaximal and immediately after maximal exercise. Simultaneous echocardiography and radial tonometry was performed to measure E/e' and central BP, defined by central augmented pressure (C_AP) and augmentation index (AIx). Patients with HFpEF had higher E/e' (P = 0.020) and peripheral and central BP (P < 0.001) at rest, yet similar C_AP and AIx to controls (P > 0.05). There was a large increase in E/e' with exercise in patients (P = 0.012) but no change in C_AP or AIx. Importantly, the change in E/e' from rest to submaximal exercise was significantly and independently associated with ΔC_AP (r = 0.559; P = 0.030) and ΔAIx (r = 0.654; P = 0.008) in patients with HFpEF. In contrast with the controls, E/e', C_AP and AIx decreased with exercise and there were no associations between exercise E/e' and central or peripheral BP (P > 0.05 for all). Indices of central BP are associated with the left ventricular diastolic response to exercise in patients with HFpEF. Arterial function and central hemodynamics may be important targets for treating symptoms associated with raised left ventricular filling pressure with exertion.


Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2.
New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 (2) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 (PfeEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline (2) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency.


Proline hydroxylation by soybean lipoxygenase.
The lipoxygenase-catalyzed hydroxylation of proline was studied in vitro in the presence of linoleic acid. The rate of reaction exhibited dependence on the concentration of proline, linoleic acid and the enzyme. The magnitude of hydroxyproline formed per mg of protein was time-dependent. Nordihydroguaiaretic acid at 0.1 mM concentration completely inhibited this reaction. No proline hydroxylation was detected during peroxidation of linoleic acid by vanadyl(IV). It is suggested that free-radical products of linoleic acid peroxidation may co-oxygenate proline in the presence of lipoxygenase.


Social skills development in children with autism spectrum disorders: a review of the intervention research.
Social reciprocity deficits are a core feature of the autism spectrum disorders (ASD). This review summarizes the state of research in group-based social skills training programs for school-age children and adolescents with ASD. All published studies of group social skills interventions between 1985 and 2006 were reviewed, as well as dissertations examining group-based social skills intervention programs. To assess the state of the science, a template developed by an NIMH work group was applied to 14 identified studies. Based on this review, the empirical support for this approach is incomplete, but promising intervention strategies were identified. Recommendations for the design of future treatment trials to guide clinical practice are offered.


Common genetic control of haemangioblast and cardiac development in zebrafish.
Over the past few years it has become clear that over half of the mammalian heart derives from outside the heart field as originally defined. Such a second heart field, however, has not been described in zebrafish, which could explain its smaller, two-chambered heart. Instead, zebrafish have a population of haemangioblasts, which is absent in mammalian embryos, raising the possibility that these cells represent the evolutionary ancestor of the second heart field. Here, we show for the first time that the genetic programmes of these anterior haemangioblasts and the adjacent heart field are co-regulated, by transcription factors previously associated with heart but not blood or endothelial development. We demonstrate that gata4, gata5 and gata6 are essential for anterior haemangioblast specification, and for subsequent myelopoiesis, acting as early as cloche and upstream of scl. The requirement for gata4, gata5 and gata6 in myeloid, endothelial and cardiac specification is in the mesoderm, but these factors also control, from within the endoderm and the yolk syncytial layer, the migration of the cardiac precursors as they differentiate. This genetic link between the blood/endothelial and cardiac programmes supports the notion that this haemangioblast population in zebrafish is an evolutionary antecedent of the second heart field, and has implications for the differentiation of haemangioblasts and cardiomyocytes from pluripotent cells, and for the origins of stem cells in the adult heart.


Altered von Willebrand factor subunit proteolysis and multimer processing associated with the Cys2362Phe mutation in the B2 domain.
The normal von Willebrand factor (vWF) multimer pattern results from the ADAMTS-13 cleavage of the Tyr 1605-Met 1606 bond in the A2 domain of vWF. We identified a patient with severe von Willebrand disease (vWD) homozygously carrying a Cys to Phe mutation in position 2362 of vWF with markedly altered vWF multimers and an abnormal proteolytic pattern. The proband's phenotype was characterized by a marked drop in plasma vWF antigen and ristocetin cofactor activity, and a less pronounced decrease in FVIII. The vWF multimers lacked any triplet structure, replaced by single bands with an atypical mobility, surrounded by a smear, and abnormally large vWF multimers. Analysis of the plasma vWF subunit's composition revealed the 225 kDa mature form and a single 205 kDa fragment, but not the 176 kDa and 140 kDa fragments resulting from cleavage by ADAMTS-13. The 205 kDa fragment was distinctly visible, along with the normal vWF cleavage products, in the patient's parents who were heterozygous for the Cys2362Phe mutation. Their vWF levels were mildly decreased and vWF multimers were organized in triplets, but also demonstrated abnormally large forms and smearing. Our findings indicate that a proper conformation of the B2 domain, which depends on critical Cys residues, may be required for the normal proteolytic processing of vWF multimers.


Flavonoids induce cell death in Leishmania amazonensis: in vitro characterization by flow cytometry and Raman spectroscopy.
Leishmaniasis comprises a group of infectious diseases with worldwide distribution, of which both the visceral and cutaneous forms are caused by Leishmania parasites. In the absence of vaccines, efficacious chemotherapy remains the basis for leishmaniasis control. The available drugs are expensive and associated with several secondary adverse effects. Due to these limitations, the development of new antileishmanial compounds is imperative, and plants offer various perspectives in this regard. The present study evaluated the in vitro leishmanicidal activity of flavonoids isolated from Solanum paludosum Moric. and investigated the mechanisms of cell death induced by them. These compounds were evaluated in vitro for their antileishmanial activity against Leishmania amazonensis promastigotes and they showed prominent leishmanicidal activity. The EtOAc fraction, gossypetin 3,7,8,4'-tetra-O-methyl ether (1), and kaempferol 3,7-di-O-methyl ether (3) were selected to be used in an in vitro assay against L. amazonensis amastigotes and cell death assays. The flavonoids (1) and (3) presented significant activity against L. amazonensis amastigotes, exhibiting the IC50 values of 23.3 ± 4.5 μM, 34.0 ± 9.6 μM, and 10.5 ± 2.5 μM for the EtOAc fraction, (1), and (3), respectively, without toxic effects to the host cells. Moreover, (1) and (3) induced blocked cell cycle progression at the G1/S transition, ultimately leading to G1/G0 arrest. Flavonoid (3) also induced autophagy. Using Raman spectroscopy in conjunction with principal component analysis, the biochemical changes in the cellular components induced by flavonoids (1) and (3) were presented. The obtained results indicated that the mechanisms of action of (1) and (3) occurred through different routes. The results support that the flavonoids derived from S. paludosum can become lead molecules for the design of antileishmanial prototypes.


Shedding light on an ultra-bright photoluminescent lamellar gold thiolate coordination polymer [Au(p-SPhCO2Me)]n.
The first structure elucidation of a lamellar gold thiolate coordination polymer is described. [Au(p-SPhCO2Me)]n is obtained from the simultaneous esterification of mercaptobenzoic acid and reduction of the Au(iii) precursor. Despite the presence of aurophilic interactions, the intense phosphorescence (QY ∼ 70%) originates from intra-ligand and metal-to-ligand transitions.


Population Pharmacokinetics and Pharmacodynamics of Oral Propranolol in Pediatric Patients With Infantile Hemangioma.
This study aimed to characterize the population pharmacokinetics and exposure-response relationship of propranolol (Hemangiol® Syrup for Pediatric) in infants with infantile hemangioma. Using nonlinear mixed-effects modeling with 63 pooled sets of plasma concentration-time data from 32 Japanese patients aged 35-150 days, we described the disposition of propranolol adequately by a 1-compartment model with first-order absorption. The estimated population mean apparent clearance and apparent central volume of distribution were 9.34 L/h and 146 L, respectively. Body weight and postnatal age influenced the population pharmacokinetic model. The clinical end points-success (complete or nearly complete resolution of the target hemangioma) and failure-at weeks 12 and 24 were characterized by logistic regression using the area under the concentration-time curve (AUC), estimated from the final population pharmacokinetic model, as an exposure predictor. The logistic regression showed that a higher AUC was associated with a higher probability of successful treatment. At each exposure level, probability of successful treatment was correlated with gestational age and treatment duration. Model-predicted probabilities of successful treatment were consistent with actual results in the clinical trial. Simulations using several dosing regimens indicated that oral propranolol at 3 mg/kg per day was effective and would be appropriate for treating Japanese infants. These simulation results can support optimization of dosing regimens, such as selecting amounts, treatment durations, and dosing intervals, for clinical use.


Predictors of adverse outcome in patients with myocardial infarction with non-obstructive coronary artery (MINOCA) disease.
Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCAs) is an increasingly recognized entity. No previous study has evaluated predictors for new major adverse cardiacvascular events (MACEs) and death in patients with MINOCA. We conducted an observational study of MINOCA patients recorded between July 2003 and June 2013 and followed until December 2013 for outcome events. Out of 199,163 MI admissions, 9092 consecutive unique patients with MINOCA were identified. The mean age was 65.5 years and 62% were women. MACE was defined as all-cause mortality, rehospitalization for acute MI, ischemic stroke and heart failure. Hazard ratio and 95% confidence interval (HR; 95% CI) was calculated using Cox-regression. A total of 2147 patients (24%) experienced a new MACE and 1254 patients (14%) died during the mean follow-up of 4.5 years. Independent predictors for MACE after adjustment, were older age (1.05; 1.04-1.06), diabetes (1.44; 1.21-1.70), hypertension (1.25; 1.09-1.43), current smoking (1.38; 1.15-1.66), previous myocardial infarction (1.38; 1.04-2.82), previous stroke (1.69; 1.35-2.11), peripheral vascular disease (1.55; 1.97-2.23), chronic obstructive pulmonary disease (1.63; 1.32-2.00), reduced left ventricular ejection fraction (2.00; 1.54-2.60), lower level of total cholesterol (0.88; 0.83-0.94) and higher level of creatinine (1.01; 1.00-1.03). Independent predictors for all cause death were age, current smoking, diabetes, cancer, chronic obstructive pulmonary disease, previous stroke, reduced left ventricular fraction, lower level of total cholesterol and higher levels of creatinine and CRP. The clinical factors predicting new MACE and death of MINOCA patients seem to be strikingly similar to factors previously shown to predict new cardiovascular events in patients with MI and obstructive coronary artery disease.


Variations in the management of primary care: effect on cost in an HMO network.
To determine the relation to cost of different aspects of the management of primary care among group practices within a health maintenance organization network. A cross-sectional survey study of medical practices conducted with Blue Cross Blue Shield of Minnesota, St Paul. The subjects were group practices accepting financial and administrative responsibility for primary care services in the managed care plans of Blue Cross Blue Shield of Minnesota. One hundred twelve primary care practices and 153397 enrollees were included in this analysis. The principal resource use measure in this study was nonhospital cost per member per year estimated from payments to providers plus subscriber-eligible liability. The medical directors' responses revealed considerable variability in the management of primary care in these 112 practices. Group practice characteristics consistently associated with lower nonhospital cost were patient identification of a primary care physician, cost of care profiling, more frequent physician profiling, more patients per hour in the clinic, a higher proportion of primary care physicians in the specialty of family or general practice, and a greater number of physicians in the group practice. Results of this study demonstrate substantial variation in the management of primary care among group practices participating in a health maintenance organization network. These differences are associated with significant variation in the nonhospital cost of care for enrollees.


Hypoxia regulates PGE(2) release and EP1 receptor expression in osteoblastic cells.
Changes in regional O(2) tension that occur during fracture and skeletal unloading may stimulate local bone cell activity and ultimately regulate bone maintenance and repair. The mechanisms by which bone cells sense and respond to changes in O(2) tension are unclear. In this study we investigated the effects of low O(2) on activation of the hypoxia response element (HRE), prostaglandin E(2) (PGE(2)) production, PGE(2) receptor (EP) expression and proliferation in MC3T3-E1 osteoblastic cells. Cells were cultured for up to 72 h in 2% O(2) (considered hypoxic), 5% O(2) (in the range of normal O(2) tension in vivo) or 21% O(2) (commonly used for cell culture). Cells cultured in 2% O(2) showed activation of the HRE, increased PGE(2) release, increased EP1 expression, and reduced cell proliferation compared to cells grown at 21% O(2). Similarly, cells cultured in 5% O(2) showed increased expression of EP1 and a trend toward a decrease in proliferation, but no activation of the HRE or increase in PGE(2) levels. Expression of EP2, EP3 and EP4 were not affected by O(2) tension. The differences in EP receptor profile observed in cells grown at 5% compared to 21% O(2) suggest that bone cell phenotype may be altered under routine cell culture conditions. Furthermore, our data suggest that hypoxia-dependent PGE(2) production and EP1 expression in bone cells may play a role in bone remodeling and repair in regions of compromised or damaged bone, where O(2) tension is low.


The language of online leadership: gender and youth engagement on the internet.
This study examines the JUNIOR SUMMIT online community, which consisted of 3,062 adolescents representing 139 countries, varying SES, and a range of experience with computers. The online forum culminated in the election of 100 delegates. By analyzing the messages posted before results of the election were announced, we explore whether language use predicts who was elected as a leader, as well as gender differences in leadership style. Results indicate that the young online leaders do not adhere to adult leadership styles of contributing many ideas, sticking to task, and using powerful language. On the contrary, while the young people elected as delegates do contribute more, their linguistic style is likely to keep the goals and needs of the group as central--by referring to the group rather than to themselves, and by synthesizing the posts of others rather than solely contributing their own ideas. Furthermore, both boy and girl leaders follow this pattern of interpersonal language use. These results reassure us that young people can be civically engaged and community minded, while indicating that these concepts themselves may change through contact with the next generation.


Comparison of Machine Learning Models on Performance of Single- and Dual-Type Electrochromic Devices.
This study shows that the model fitting based on machine learning (ML) from experimental data can successfully predict the electrochromic characteristics of single- and dual-type flexible electrochromic devices (ECDs) by using tungsten trioxide (WO3) and WO3/vanadium pentoxide (V2O5), respectively. Seven different regression methods were used for experimental observations, which belong to single and dual ECDs where 80% percent was used as training data and the remaining was taken as testing data. Among the seven different regression methods, K-nearest neighbor (KNN) achieves the best results with higher coefficient of determination (R 2) score and lower root-mean-squared error (RMSE) for the bleaching state of ECDs. Furthermore, higher R 2 score and lower RMSE for the coloration state of ECDs were achieved with Gaussian process regressor. The robustness result of the ML modeling demonstrates the reliability of prediction outcomes. These results can be proposed as promising models for different energy-saving flexible electronic systems.


[Analysis of risk factors of prolonged intensive care unit stay of critically ill obstetric patients: a 5-year retrospective review in 3 hospitals in Beijing].
To identify the risk factors of prolonged intensive care unit (ICU) stay of critically ill obstetric patients. A retrospective analysis of cases of critically ill obstetric patients admitted to the ICUs of Peking University Third Hospital, Capital Medical University Affiliated Beijing Chaoyang Hospital, and PLA 306 Hospital from January 1st 2006 to December 31st 2010 was made. Data included demographics, causes of critical illness or complications that prompted ICU admission, the acute physiology and chronic health evaluation II (APACHEII) scores, the time intervals between onset of acute symptoms and ICU admission, laboratory test results, treatment measures, length of ICU stay and the final maternal mortality. Data were used to identify univariate and multivariate predictors for prolonged ICU stay. During the 5-year period there were 207 obstetric patients [mean age (31.74±2.32) years old, mean gestational age (34.86±4.72) weeks] were transferred to the ICU for critical care (42 ICU admissions per 10 000 deliveries), and among them 4 women died (mortality rate 1.93%). The pathogenesis of the cases could be divided into direct obstetric pathologies (n=138) and indirect or coincidental pathologies (n=69). The most common obstetric causes of admission were massive postpartum haemorrhage (n=42, 20.29%) and pregnancy associated hypertension (n=36, 17.39%), followed by acute fatty liver of pregnancy (AFLP, n=27, 13.04%), obstetric disseminated intravascular coagulation (DIC, n=23, 11.11%). The most common non obstetric causes of admission were acute heart failure (n=26, 12.56%) and acute respiratory failure (n=22, 10.63%), followed by severe acute pancreatitis (SAP, n=11, 5.31%). The incidence of prolonged ICU stay (ICU stay >3 days) was 52.66% (n=109). Univariate predictors of prolonged ICU stay included inadvertent antenatal care, high serum creatinine, abnormal international normalized ratio of prothrombin time (INR), abnormal oxygenation index (PaO(2)/FiO(2)), AFLP, obstetric DIC, SAP, use of mechanical ventilation, indications for inotropic support, and blood purification, and >24 hour interval between onset of acute symptoms and ICU admission. Multivariate modeling identified that inadvertent and irregular antenatal care [odds ratio (OR) 1.68, 95% confidence interval (95%CI) 1.14-2.69, P=0.011], PaO(2)/FiO(2) (OR 4.73, 95%CI 1.46-11.37, P=0.013), AFLP (OR3.21, 95%CI 1.13-4.76, P=0.026), DIC (OR 2.73, 95%CI 1.28-4.02, P=0.018), SAP (OR 4.78, 95%CI 1.83-7.42, P=0.021 ), indications for inotropic support (OR 1.96, 95%CI 1.24-3.15, P=0.001), blood purification (OR 11.02, 95%CI 3.04-58.02, P=0.015) and >24 hour interval between onset of acute symptoms and ICU admission (OR 2.04, 95%CI 1.21-4.25, P<0.001) were the independent predictors for prolonged ICU stay. The incidence of prolonged ICU stay is high for critically ill obstetric patients. Patients with identified multivariate predictors carry a high risk of prolonged ICU stay, they may benefit from enhanced regular antenatal care, prevention of critical obstetric and medical complications, shortening the interval between onset of acute symptoms and ICU admission and strengthening the support of organ function.


The physician healer: ancient magic or modern science?
The therapeutic role of general practitioners (GPs) is one that, over the years, has slowly diminished with the growing fashion for evidence-based medicine. However, it is clear that the art of healing and the strength of the doctor-patient relationship play a vital role in improving the well-being of patients. This is exemplified by the placebo effect, where the attitude of the doctor can make an appreciable difference to the psychological response of the patient who feels the need to be understood and listened to empathically. By maximizing the role of the physician healer, there is considerable scope for bridging the gap left by the impersonality of medical science, while at the same time increasing the GP's effectiveness.


A series of self-measurements by the patient is a reliable alternative to ambulatory blood pressure measurement.
Several studies have reported overdiagnosis and overtreatment of hypertensive patients, especially in borderline hypertensives. To find a blood pressure measurement procedure that reduces the risk of misclassification to an acceptable level. Comparative, prospective study over seven months of primary care patients with elevated initial blood pressures. Blood pressure measurements made by general practitioners (GPs), practice nurses, and patients were compared with ambulatory blood pressure measurements. Ninety-nine patients completed the study. Mean differences (systolic blood pressure) between different measurement procedures and ambulatory measurement ranged from +10 mmHg (doctor) to -1 mmHg (patient), and (diastolic) from +4 mmHg (doctor) to -2 mmHg (patient). Standard deviations of mean differences ranged from 12 mmHg (doctor/systolic) to 10 mmHg (patient/systolic), and from 8 mmHg (doctor/diastolic) to 7 mmHg (patient/diastolic). Self-measurements by the patient appear to be a reliable alternative to ambulatory blood pressure measurement. In diagnosing and managing mild hypertension, we recommend the use of a valid self-measuring device.


Loading-device effects on the protein-unfolding mechanisms using molecular-dynamic simulations.
Experimental force spectroscopy has been effectively utilized for measuring structural characterization of biomolecules and mechanical properties of biomaterials. Specifically, atomic force microscopy (AFM) has been widely used to portray biomolecular characterization in single-molecule experiment by observing the unfolding behavior of the proteins. Not only the experimental techniques enable us to characterize globular protein, but computational methods like molecular dynamics (MD) also gives insight into understanding biomolecular structures. To better comprehend the behavior of biomolecules, conditions such as pulling velocities and loading rates are put to the test, yet there are still limitations in understanding the unfolding behavior of biomolecules with the effect of different loading devices. In this study, we performed an all-atom MD and steered molecular dynamics (SMD) simulations considering different loading device effects such as "soft" and "stiff" to characterize the anisotropic unfolding behavior of ubiquitin protein. We found out the anisotropic unfolding pathways of the protein through the broken number of hydrogen bonds and geometric secondary structures of the biomolecule. Our study provides the importance for usage of various loading-devices on biomolecules when analyzing the structural compositions and the characteristics of globular biomolecules.


Improving treatment plan evaluation with automation.
The goal of this work is to evaluate the effectiveness of Plan-Checker Tool (PCT) which was created to improve first-time plan quality, reduce patient delays, increase the efficiency of our electronic workflow, and standardize and automate the phys-ics plan review in the treatment planning system (TPS). PCT uses an application programming interface to check and compare data from the TPS and treatment management system (TMS). PCT includes a comprehensive checklist of automated and manual checks that are documented when performed by the user as part of a plan readiness check for treatment. Prior to and during PCT development, errors identified during the physics review and causes of patient treatment start delays were tracked to prioritize which checks should be automated. Nineteen of 33checklist items were automated, with data extracted with PCT. There was a 60% reduction in the number of patient delays in the six months after PCT release. PCT was suc-cessfully implemented for use on all external beam treatment plans in our clinic. While the number of errors found during the physics check did not decrease, automation of checks increased visibility of errors during the physics check, which led to decreased patient delays. The methods used here can be applied to any TMS and TPS that allows queries of the database.


Mentoring the next generation of behavioral health scientists to promote health equity.
Health inequities and disparities among various racial/ethnic minority, sexual minority, and rural populations are the focus of increasing national efforts. Three health problems disproportionately affecting these populations-HIV/AIDS, substance abuse, and trauma-deserve particular attention because of their harmful effects on health across the life span. To address these problems, our training program, the UCLA HIV/AIDS, Substance Abuse, and Trauma Training Program (HA-STTP), mentors and trains early career behavioral health scientists to conduct research using scientifically sound, culturally collaborative, and population-centered approaches. HA-STTP has been highly successful in training a diverse, productive, nationwide group of scholars. The program provides 2 years of training and mentorship to 20 (5 per year over 4 years) scholars. It is unique in its attention to traumatic stress as a form of dysregulation, particularly as experienced by underserved populations. Furthermore, our training program embraces a uniquely comprehensive, culturally grounded understanding of traumatic stress and its implications for substance abuse and HIV. HA-STTP advances scholars' knowledge of the interconnections among substance abuse, HIV/AIDS, traumatic stress, and health disparities, particularly in underrepresented populations; provides intensive mentorship to support scholars' research interests and career trajectories; capitalizes on a multidisciplinary, multiracial/ethnic network of expert faculty; and evaluates the program's impact on scholars' knowledge and productivity. By fostering the growth of scholars committed to conducting research with underrepresented populations that are disproportionately affected by HIV/AIDS, substance abuse, and traumatic stress, this program enhances nationwide efforts to diminish the prevalence of these problems and improve health and quality of life. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Glycosylated albumin and serum protein in diabetic dogs.
Glycosylated albumin and glycosylated protein in serum were measured in 4 well-controlled diabetic dogs, 4 poorly controlled diabetic dogs, and 21 nondiabetic dogs. Concentrations of both glycosylated components in the well-controlled dogs were similar to those in nondiabetic dogs. Serum concentrations of glycosylated albumin and protein in the poorly controlled diabetic dogs were higher (P less than 0.001) than those of the nondiabetic and well-controlled diabetic dogs. Because of the essentially irreversible nature of the glycosylation reaction and the relatively short turnover time of albumin and other serum proteins, measurements of glycosylated serum components may provide an index of glycemia during the preceding days or weeks.


Meta-analyses of colorectal cancer risk factors.
Demographic, behavioral, and environmental factors have been associated with increased risk of colorectal cancer (CRC). We reviewed the published evidence and explored associations between risk factors and CRC incidence. We identified 12 established non-screening CRC risk factors and performed a comprehensive review and meta-analyses to quantify each factor's impact on CRC risk. We used random-effects models of the logarithms of risks across studies: inverse-variance weighted averages for dichotomous factors and generalized least squares for dose-response for multi-level factors. Significant risk factors include inflammatory bowel disease (RR = 2.93, 95 % CI 1.79-4.81); CRC history in first-degree relative (RR = 1.80, 95 % CI 1.61-2.02); body mass index (BMI) to overall population (RR = 1.10 per 8 kg/m(2) increase, 95 % CI 1.08-1.12); physical activity (RR = 0.88, 95 % CI 0.86-0.91 for 2 standard deviations increased physical activity score); cigarette smoking (RR = 1.06, 95 % CI 1.03-1.08 for 5 pack-years); and consumption of red meat (RR = 1.13, 95 % CI 1.09-1.16 for 5 servings/week), fruit (RR = 0.85, 95 % CI 0.75-0.96 for 3 servings/day), and vegetables (RR = 0.86, 95 % CI 0.78-0.94 for 5 servings/day). We developed a comprehensive risk modeling strategy that incorporates multiple effects to predict an individual's risk of developing CRC. Inflammatory bowel disease and history of CRC in first-degree relatives are associated with much higher risk of CRC. Increased BMI, red meat intake, cigarette smoking, low physical activity, low vegetable consumption, and low fruit consumption were associated with moderately increased risk of CRC.


Meloidogyne hispanica n. sp. (Nematoda: Meloidogynidae), the 'Seville Root-Knot Nematode'.
Meloidogyne hispanica n. sp. is described and illustrated from specimens obtained from peach rootstock, Prunus persica silvestris Batsch, from the Seville district of Spain. The perineal pattern of the female is oval shaped to rectangular with low dorsal arch and often widely spaced lateral lines with fringe-like striae. The stylet, 14.1 mum long, has broad, distinctly set off knobs. Males have a high, rounded head cap that slopes posteriorly. Labial disc and medial lips are fused to form elongate lip structures. The robust styler, 23.5 mum long, has large, rounded knobs that are slightly set off from the shaft. Mean second-stage juveniles length is 392.6 mum. The truncate head region is generally not annulated. The distinctly rounded and raised labial disc and the crescent-shaped medial lips form dumbbell-shaped lip structures. The stylet, 11.1 mum long, has rounded, posteriorly sloping knobs. The slender tail, 46.4 mum long, has large irregular-sized annules in the posterior region and ends in a bluntly rounded tip. Tomato was a good host; tobacco, pepper, and watermelon were poor hosts; cotton and peanut were nonhosts. Meloidogyne hispanica n. sp. reproduces by mitotic parthenogenesis and has a somatic chromosome number of 2n = 33-36. The esterase pattern is unique among Meloidogyne species.


An energy-efficient gating mechanism in the acetylcholine receptor channel suggested by molecular and Brownian dynamics.
Acetylcholine receptors mediate electrical signaling between nerve and muscle by opening and closing a transmembrane ion conductive pore. Molecular and Brownian dynamics simulations are used to shed light on the location and mechanism of the channel gate. Four separate 5 ns molecular dynamics simulations are carried out on the imaged structure of the channel, a hypothetical open structure with a slightly wider pore and a mutant structure in which a central ring of hydrophobic residues is replaced by polar groups. Water is found to partially evacuate the pore during molecular simulations of the imaged structure, whereas ions face a large energy barrier and do not conduct through the channel in Brownian dynamics simulations. The pore appears to be in a closed configuration despite containing an unobstructed pathway across the membrane as a series of hydrophobic residues in the center of the channel provide an unfavorable home to water and ions. When the channel is widened slightly, water floods into the channel and ions conduct at a rate comparable to the currents measured experimentally in open channels. The pore remains permeable to ions provided the extracellular end of the pore-lining helix is restrained near the putative open configuration to mimic the presence of the ligand binding domain. Replacing some of the hydrophobic residues with polar ones decreases the barrier for ion permeation but does not result in significant currents. The channel is posited to utilize an energy efficient gating mechanism in which only minor conformational changes of the hydrophobic region of the pore are required to create macroscopic changes in conductance.


Phage tf-1: a filamentous bacteriophage specific for bacteria harbouring the IncT plasmid pIN25.
Phage tf-1 is a filamentous phage which is about 800 nm in length, 10 nm in width and has slightly tapered ends. The phage was isolated from sewage and formed plaques or propagated only on Escherichia coli, Salmonella typhimurium and Klebsiella oxytoca strains harbouring the IncT plasmid pIN25 at 30 degrees C. It adsorbed in large numbers to pIN25-encoded long thick flexible conjugative pili formed at 30 degrees C and also to the short form of these pili synthesized at 37 degrees C. The reason for the failure to form plaques at 37 degrees C is not known. The adsorption site is a short length of the pilus shaft extending 100-200 nm back from the distal tip. Efficient phage tf-1 adsorption to the same site was found for pili determined by other IncT plasmids in spite of the fact that phage tf-1 did not plate or propagate on strains harbouring them. However, areas of specific partial clearing on lawns of these plasmid-containing bacteria were produced by phage in high concentrations. Lack of plaque-formation could be due to inefficient intracellular assembly coupled to avid adsorption of any liberated phage to pili. The phage differs from all but one other filamentous phage by being sensitive to diethyl ether.


Emerging Frontiers in the Study of Molecular Evolution.
A collection of the editors of Journal of Molecular Evolution have gotten together to pose a set of key challenges and future directions for the field of molecular evolution. Topics include challenges and new directions in prebiotic chemistry and the RNA world, reconstruction of early cellular genomes and proteins, macromolecular and functional evolution, evolutionary cell biology, genome evolution, molecular evolutionary ecology, viral phylodynamics, theoretical population genomics, somatic cell molecular evolution, and directed evolution. While our effort is not meant to be exhaustive, it reflects research questions and problems in the field of molecular evolution that are exciting to our editors.


Angiomotin-Like 1 Links Paramyxovirus M Proteins to NEDD4 Family Ubiquitin Ligases.
To define the links between paramyxovirus budding and cellular ESCRT machinery, we previously identified angiomotin-like 1 (AMOTL1) in a screen for host factors that bind to the matrix (M) protein of parainfluenza virus 5 (PIV5). This protein harbors three L/PPXY sequences, allowing it to interact with WW domain containing proteins including NEDD4 family members. We hypothesize that paramyxoviruses use AMOTL1 as a linker to indirectly recruit the same NEDD4 ubiquitin ligases for budding that other enveloped viruses recruit directly through their PPXY late domains. In support of this hypothesis, we found that AMOTL1 could link together M proteins and NEDD4 family proteins in three-way co-IP experiments. Both PIV5 and mumps virus M proteins could be linked to the NEDD4 family proteins NEDD4-1, NEDD4L, and NEDL1, provided that AMOTL1 was co-expressed as a bridging protein. AMOT and AMOTL2 could not substitute for AMOTL1, as they lacked the ability to bind with paramyxovirus M proteins. Attachment of a PPXY late domain sequence to PIV5 M protein obviated the need for AMOTL1 as a linker between M and NEDD4 proteins. Together, these results suggest a novel host factor recruitment strategy for paramyxoviruses to achieve particle release.


Does waterpipe smoking increase the risk of Helicobacter pylori infection?
In this study, we aimed to evaluate whether waterpipe smoking can be associated with the transmission of Helicobacter pylori infection or not. Between March 2018 and April 2019, 445 patients aged over 18 years old who were admitted to outpatient clinics with dyspeptic complaints were recruited for the study. Patients are divided into two groups - Group 1 is H. pylori-positive patients and Group 2 is negative. Waterpipe smoking, smoking, age, gender, and educational status were compared among groups. Two hundred and sixty-one women (58%) and 184 men (42%), totally 445 patients, tested for H. pylori infection. Seventy-nine of 261 (30%) women and 60 of 184 (32%) men had H. pylori positive. One hundred and sixty-two of 445 (36%) patients were smoking cigarette and 66 of 445 (14%) patients were using waterpipe tobacco. Waterpipe smoking individuals were found to be associated with the H. pylori positivity (P < 0.001); whereas, age, gender, educational level, and smoking were not found to be statistically significant (all P > 0.05). In binary logistic regression analysis, waterpipe tobacco smoking was found to be the only independent predictor of H. pylori infection (P < 0.001, odds ratio = 5.51, confidence interval: 3.158-9.617). Waterpipe smoking seems to be an important risk factor for H. pylori infection and may be one of the reasons of high prevalence of H. pylori infection.