Loop fold structure of proteins: resolution of Levinthas paradox

According to Levinthal a protein chain of ordinary size would require enormous time to sort its conformational states before the final fold is reached. Experimentally observed time of folding suggests an estimate of the chain length for which the time would be sufficient. This estimate by order of magnitude fits to experimentally observed universal closed loop elements of globular proteins - 25-30 residues.     

Exploration of the possible effect on survival of lead-time associated with implementation of cancer patient pathways among symptomatic first-time cancer patients in Denmark

BackgroundImplementation of standardised cancer patient pathways (CPPs) has provided faster diagnosis of cancer. Cancer survival has improved during the same time period. Concern has been raised that the faster diagnosis may have introduced lead-time bias by elongating the period from diagnosis to death.AimWe aimed to analyse the possible effect of lead time on survival due to expedited cancer diagnosis after the implementation of national CPPs among incident cancer patients diagnosed through Danish primary care.Material and methodsWe used actual observed differences in diagnostic intervals to estimate the lead-time effect. We used data from sub-cohorts from the Danish Cancer in Primary Care (CaP) cohort of first-time cancer patients: before and after CPP implementation. To calculate differences in absolute survival, we estimated the survival function after advancing the date of diagnosis in the before cohort to an earlier point in time and hereby adjusting for lead time for nine cancer types and all combined by using Kaplan-Meier analysis.ResultsAdvancing the date of diagnosis implied that the absolute one-year survival increased from 68.5% to 69.4%. This accounted for 13% of the observed differences in absolute one-year survival from before to after CPPs.ConclusionThe lead time caused by shorter diagnostic intervals after implementation of Cancer Patient Pathways seems to explain less than 15% of the observed changes in the one-year survival estimates for cancer patients in Denmark.     

Quantitation of DNA in buccal cell samples collected in epidemiological studies

Abstract

Buccal cell samples are increasingly used in epidemiological studies as a source of genomic DNA. The accurate and precise quantitation of human DNA is critical for the optimal use of these samples. However, it is complicated by the presence of bacterial DNA and wide inter-individual variation in DNA concentration from buccal cell collections. The paper evaluated the use of ultraviolet light (UV) spectroscopy, Höechst (H33258) and PicoGreen? as measures of total DNA, and real-time quantitative polymerase chain reaction (PCR) as a measure of human amplifiable DNA in buccal samples. Using serially diluted white blood cell DNA samples (at a concentration range of 300 to 0.5?ng µl^?1), UV spectroscopy showed the largest bias, followed by Höechst, especially for low concentrations. PicoGreen and real-time PCR provided the most accurate and precise estimates across the range of concentrations evaluated, although an increase in bias with decreasing concentrations was observed. The ratio of real-time PCR to PicoGreen provided a reasonable estimate of the percentage of human DNA in samples containing known mixtures of human and bacterial DNA. Quantification of buccal DNA from samples collected in a breast cancer case-control study by PicoGreen and real-time PCR indicated that cytobrush and mouthwash DNA samples contain similar percentages of human amplifiable DNA. Real-time PCR is recommended for the quantification of buccal cell DNA in epidemiological studies since it provides precise estimates of human amplifiable DNA across the wide range of DNA concentrations commonly observed in buccal cell DNA samples.     

应用CE-SDS测定抗CD52人源化单克隆抗体参比品单体纯度及非糖化重链比例

目的:测定抗CD52人源单克隆抗体参比品单体纯度及非糖基化重链比例。方法:采用PA800 plus毛细管电泳系统,非还原十二烷基苯硫酸钠-毛细管电泳(CE-SDS)测定抗CD52人源单克隆抗体单体纯度,以及用还原CE-SDS电泳测定非糖化重链比例。结果:非还原CE-SDS三次测定单体纯度平均值为93.57%,主峰的迁移时间及修正峰面积百分比RSD分别为0.16%和0.19%;还原CE-SDS电泳重链修正峰面积百分比平均值为66.89%,修正峰面积百分比及迁移时间RSD分别为0.09%和0%;轻链修正峰面积百分比平均值为32.30%;轻链修正峰面积及迁移时间RSD分别为0%和0%;非糖基化重链修正峰面积百分比平均值为0.87%,修正峰面积百分比及迁移时间RSD分别为6.66%和0.27%。结论:CE-SDS测定抗CD52人源单抗单体纯度及非糖化重链比例实验结果偏差较小,表明结果准确可靠。     

The breeding population of Peregrine Falcon Falco peregrinus in the United Kingdom,Isle of Man and Channel Islands in 2014

Capsule: Overall numbers of Peregrines are higher than previously recorded, due primarily to the growth of lowland populations, despite declines in many upland areas.

Aims: To estimate the breeding population of Peregrines, and changes in this population over time, as well as to relate variation in trends and observed breeding success to variation in region, breeding site type and other ecological influences.

Methods: Two types of survey methods were used. Site-based visits focussed on locations where Peregrines were known to have bred previously, while area-based searches aimed to find all Peregrines breeding in randomly chosen 5?km?×?5?km squares. Findings from each method were used to estimate population size in different parts of the survey area. Breeding outcome and site type were assessed for most of the pairs found during either survey.

Results: In 2014, the breeding population of Peregrines in the UK, Isle of Man and Channel Islands was estimated at 1769 pairs. This is 22% larger than the population estimate from the previous survey in 2002. Most of this increase is accounted for by increases in lowland England. Populations in some upland areas have declined.

Conclusions: The gap between the fortunes of lowland and upland Peregrines has continued to grow, along with the overall UK population. Likely reasons for the continued success of Peregrines in the lowlands include increasing uptake of breeding sites on human structures, abundant availability of prey in many lowland situations and, in many areas, a relative lack of conflict with humans. Factors likely to be limiting upland Peregrine populations vary between different regions, and include ongoing illegal killing and deliberate disturbance, and food supply.     

Comparing Different Policy Scenarios to Reduce the Consumption of Ultra-Processed Foods in UK: Impact on Cardiovascular Disease Mortality Using a Modelling Approach

BackgroundThe global burden of non-communicable diseases partly reflects growing exposure to ultra-processed food products (UPPs). These heavily marketed UPPs are cheap and convenient for consumers and profitable for manufacturers, but contain high levels of salt, fat and sugars. This study aimed to explore the potential mortality reduction associated with future policies for substantially reducing ultra-processed food intake in the UK.ResultsApproximately 175,000 cardiovascular disease (CVD) deaths might be expected in 2030 if current mortality patterns persist. However, halving the intake of Group 3 (processed) foods could result in approximately 22,055 fewer CVD related deaths in 2030 (minimum estimate 10,705, maximum estimate 34,625). An ideal scenario in which salt and fat intakes are reduced to the low levels observed in Group 1 and 2 could lead to approximately 14,235 (minimum estimate 6,680, maximum estimate 22,525) fewer coronary deaths and approximately 7,820 (minimum estimate 4,025, maximum estimate 12,100) fewer stroke deaths, comprising almost 13% mortality reduction.ConclusionsThis study shows a substantial potential for reducing the cardiovascular disease burden through a healthier food system. It highlights the crucial importance of implementing healthier UK food policies.     

Approaches to Nuclease Models: Synthesis and Conformational Studies of dTprA Conjugated with Histamine AT C8(A) and Ethylenediamine at C5′(T)

Abstract

Synthesis and spectroscopic characterization of a dinucleotide dT_prA 2 having imidazole containing side chain at C8 of adenine and aminoethylamino side chain at C5′ of nucleosugar is presented. Spectroscopic results suggest that such modifications do not drastically change the conformation of the new molecule relative to that of parent derivative. An anti glycosyl torsion would place the C8-conjugated histamine close to phosphate in right orientation for putative intramolecular interaction as in ribonuclease catalytic site.     

Simultaneous tetragyny in Northern Lapwing Vanellus vanellus

Capsule Fuel load is correlated with fuel deposition rate; stopover duration is affected by arrival fuel load.

Aims To determine the stopover duration, fuel management and flight ranges at departure of Blackcaps stopping over in northern Spain.

Methods Systematic mist-netting and ringing allowed the use of mark–recapture Cormack–Jolly–Seber models for the estimation of stopover duration. Trapped birds were measured and weighed in order to estimate mass gain. FLIGHT software was used to estimate flight ranges.

Results Stopover duration ranged from 3.6 to 13.6 days, and was negatively correlated with arrival body mass (assessed by body mass at the first capture event). On average, arrival body mass was 18.4 g, whilst body mass at departure was 19.8 g. No significant differences in arrival body mass and departure body mass were observed between age or sex classes. Mass deposition rate did not differ between age or sex classes (mean = 0.20 g/day). Birds recaptured one day after the first capture event lost mass, whilst recaptures from the second day onwards had a mean gain of mass; mass was observed to increase linearly with the stopover duration. Mass deposition rate was positively correlated with departure body mass. Finally, with a mean departure body mass of 19.8 g, a Blackcap stopping over in northern Spain should be able to fly up to 1100 km.

Conclusions Stopover duration assessed by Cormack–Jolly–Seber models was longer than that observed in birds recaptured more than once (‘minimum stopover duration’). Stopover was longer for birds arriving with less fuel. The positive relationship between departure body mass and mass deposition rate suggests a time-minimizing strategy. The lack of difference in fuel deposition rate between age and sex classes suggests a relatively abundant food supply at the study site, but other explanations might also account for the lack of age and sex differences, for example if competition for food was not determined by social hierarchies but by scramble competition. Departing fuel load would allow these birds to arrive at their wintering areas in southern Spain under still-air conditions, without needing to refuel.     

Thigh tissue composition exhibits a curvilinear relationship with aging: A cross-sectional study

Objectives:To explore whether quadratic model will better estimate the relationship between aging and thigh tissue composition in a cohort that range in age from young to older adults.Methods:51 healthy subjects participated in this investigation. All subjects underwent CT imaging for the thigh. Cross-sectional area of the fat and muscular tissues in the thigh were quantified. Hierarchical regression models were created. Age was entered first into the models to estimate its linear relationship with the thigh tissues. Then the squared value of the age variable was entered second to identify whether a quadratic model would better estimate the relationship between the variables.Results:The linear model was significant for thigh muscular tissue. Quadratic models were able to account for additional significant prediction of the cross-sectional area of thigh tissues. Muscular area decreased with aging until 60 years after that it didn’t change. Fat areas increased with aging until 45-50 years and then it decreased.Conclusions:The cross-sectional area of different thigh tissues exhibit a curvilinear pattern with aging. Muscular tissue area may not change after 60 years; this could be explained by the reduction in fat that may infiltrate inside the muscles and offset the muscular reduction.     

Breeding success and nest-site characteristics of Red-breasted Flycatchers Ficedula parva in a primeval forest

Capsule Predation is a major factor influencing the breeding success of Red-breasted Flycatchers under natural conditions.

Aims To examine the breeding success of Red-breasted Flycatchers in relation to nest-site characteristics and time of breeding.

Methods Data were collected during seven breeding seasons under natural conditions in Bia?owie?a National Park. We used survival time analysis to estimate changes in survival probability over time and breeding success in relation to first-egg date and nest-site characteristics.

Results Offspring fledged successfully from 51% of clutches, but the Kaplan–Meier estimate of survival was lower at 0.43. Of the unsuccessful clutches, 82% were lost to predators. The highest probability of loss was during egg-laying and in the second half of incubation. Breeding success was influenced by the height of the nest above the ground, but no relation to other nest-site characteristics was found.

Conclusion To avoid predation Red-breasted Flycatchers build nests in various sites that are more open than most cavity-nesting species. The position of the nest-sites allows the sitting female to observe her surroundings and to escape rapidly from the nest, giving the chance for a replacement clutch.     

Report of the Alpine Section, 1958

Background: Over 10,000 island endemic angiosperms are highly threatened by extinction. Yet, few of these species have the temporal change in their range documented and quantified, particularly within a potentially informative context of a long period of botanical study.

Aim: Here, we used Roussea simplex a mono-specific genus endemic to Mauritius, itself an island with long botanical history and advanced habitat destruction extent, to investigate how the distribution and population of this model oceanic island plant changed through time.

Methods: All known localities and population size estimates were compiled from published literature, herbarium specimens, surveys and personal communications to estimate changes in population size, extent of occurrence and area of occupancy and investigate main distribution patterns.

Results: Roussea simplex survives in nine high elevation sites. Since the 1930s, its range halved relative to its maximum known distribution and its population size decreased much faster than direct habitat loss would predict. It now qualifies as Endangered according to the IUCN Red List categories.

Conclusions: Even in an extremely deforested island, endemic plant population decline may be driven more by diminishing habitat quality than diminishing habitat extent. This renders habitat protection alone insufficient, therefore addressing ecological interactions is vital to stem population decline.     

In VivoInterference of Paromomycin with Mitochondrial Activity ofLeishmania

Paromomycin is an aminocyclitol aminoglycoside antibiotic used for the treatment of leishmaniasis. In view of the central role of mitochondria in cellular energetics and metabolism, its effect onin vivomitochondrial activities ofLeishmania donovanipromastigotes—the parasite flagellate form—was investigated. The approach used flow cytometry, amperometric measure of O₂consumption, and, as a global estimate of mitochondrial dehydrogenases, thiazolyl blue reduction (MTT test); somein vitrocontrols were also made. When added to promastigote cultures for 24–72 h at 150–200 μM(= LC₅₀), paromomycin doubled the generation time, inhibited respiration, and lowered its associated electric potential difference across mitochondrial membranes, as measured by rhodamine 123 fluorescence. The chemical analogue neomycin was ineffective. Furthermore, thein vivomitochondrial dehydrogenase activities were lower, seemingly because of the shortage of respiratory substrates. Indeed, succinate addition to paromomycin-treated cultures partly restored mitochondrial membrane potential. However, no immediate effect of paromomycin on respiration was observed, neither inhibition of redox chain nor increase of membrane permeability (uncoupling). It is proposed that paromomycin acts at a metabolic level upstream of the respiratory chain itself. This would have the observed delayed consequence because the cell energy supply would progressively decline since it depends upon the proton gradient—viz., membrane potential—generated by respiration. In conclusion, paromomycin is an antibiotic affecting the cell's energetic metabolism; the respiratory dysfunction it induces may be a crucial aspect of its action againstLeishmaniaand possibly other cells.     

Non-linear changes of lower extremity kinetics prior to gait transition

IntroductionThe purpose of this study was to examine the changes of lower extremity kinetics during walk-to-run (WR) transition and if the changes would follow a non-linear trend within the five strides before WR transition using a constant acceleration protocol.MethodsFourteen participants performed gait transition on the instrumented treadmill at a constant acceleration. Peak, time to peak, and movement and power of hip, knee and ankle joints were recorded and analyzed in sagittal plane for five strides before gait transition. Three Two-way MANOVA were employed to examine the differences of kinetic measures among the five strides. Univariate analysis and Post-Hoc Tukey’s test would be applied if needed. Also, Post hoc polynomial trend analyses were used to examine the trend of the kinetic measures that significantly changed during the five strides.ResultsCompared to the first four strides, significant differences were observed for peaks moments, joint powers, and time to peaks in the last stride before running at ankle, knee, and hip joints respectively. In general, the changes of kinetic variables were following a quadratic trend during the five strides before running.ConclusionJoint kinetic measures actively change in non-linear patterns during the five strides before running to prepare for the gait transition, indicating that the gait transition is an active reorganization rather than a passive reaction.     

Human adipose-derived mesenchymal stromal cell pigment epithelium–derived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells

Background aimsAdipose-derived mesenchymal stromal cells (ASCs) are promising tools for delivery of cytotherapy against cancer. However, ASCs can exert profound effects on biological behavior of tumor cells. Our study aimed to examine the influence of ASCs on gene expression and epigenetic methylation profiles of prostate cancer cells as well as the impact of expressing a therapeutic gene on modifying the interaction between ASCs and prostate cancer cells.MethodsASCs were modified by lentiviral transduction to express either green fluorescent protein as a control or pigment epithelium–derived factor (PEDF) as a therapeutic molecule. PC3 prostate cancer cells were cultured in the presence of ASC culture–conditioned media (CCM), and effects on PC3 or DU145. Ras cells were examined by means of real-time quantitative polymerase chain reaction, EpiTect methyl prostate cancer–focused real-time quantitative polymerase chain reaction arrays, and luciferase reporter assays.ResultsASCs transduced with lentiviral vectors were able to mediate expression of several tumor-inhibitory genes, some of which correlated with epigenetic methylation changes on cocultured PC3 prostate cancer cells. When PC3 cells were cultured with ASC-PEDF CCM, we observed a shift in the balance of gene expression toward tumor inhibition, which suggests that PEDF reduces the potential tumor-promoting activity of unmodified ASCs.ConclusionsThese results suggest that ASC-PEDF CCM can promote reprogramming of tumor cells in a paracrine manner. An improved understanding of genetic and epigenetic events in prostate cancer growth in response to PEDF paracrine therapy would enable a more effective use of ASC-PEDF, with the goal of achieving safer yet more potent anti-tumor effects.     

基于国际认证标准的医疗耗材供应链安全能力建设

目的 以符合目前世界公认最高的国际医疗机构相关认证标准为目标,建立模型加强医疗耗材供应链安全能力,保护患者和员工免受污染、伪劣和用途改变产品的危害。 方法 根据供应链安全模型,医疗耗材供应链管理的设计上采取了相应的措施 结果 提高了医疗耗材供应链安全能力,降低风险,符合在医院物流方面的更高品质要求 结论 将供应链安全模型运用于医疗耗材供应链管理中,能有效加强医疗耗材供应链安全能力。     

The effect of delay in viral production in within-host models during early infection

ABSTRACT

Delay in viral production may have a significant impact on the early stages of infection. During the eclipse phase, the time from viral entry until active production of viral particles, no viruses are produced. This delay affects the probability that a viral infection becomes established and timing of the peak viral load. Deterministic and stochastic models are formulated with either multiple latent stages or a fixed delay for the eclipse phase. The deterministic model with multiple latent stages approaches in the limit the model with a fixed delay as the number of stages approaches infinity. The deterministic model framework is used to formulate continuous-time Markov chain and stochastic differential equation models. The probability of a minor infection with rapid viral clearance as opposed to a major full-blown infection with a high viral load is estimated from a branching process approximation of the Markov chain model and the results are confirmed through numerical simulations. In addition, parameter values for influenza A are used to numerically estimate the time to peak viral infection and peak viral load for the deterministic and stochastic models. Although the average length of the eclipse phase is the same in each of the models, as the number of latent stages increases, the numerical results show that the time to viral peak and the peak viral load increase.     

Model for the Porphyrin-DNA Binding Site: ENDOR Investigations of Cu-Porphyrins Binding to DNA

Abstract

Proton ENDOR has been observed from frozen solutions (ca. 38K°) of copper meso-(4-N-tetra-methylpyridyl)porphyrin (CuTMpyP(4)) complexed with Salmon sperm DNA in water and D₂O. Lines from exchangeable protons of the DNA bases have been observed in these ENDOR spectra. Analyses of these ENDOR data show that the separations of these DNA protons from the copper atom are between 3.76 and 3.84 A with angles of 19.5 to 22.5 degrees between the Cu-H vectors and the g_z axis. A distant ENDOR response has also been observed from phosphorous nuclei in the DNA backbone. We estimate that the phosphorous atoms producing this ENDOR signal are 7.5–10 Å from the copper center of the porphyrin. These ENDOR data combined with results from an earlier NMR investigation (1) have been used to construct a computer simulated model of the binding site in which the porphyrin is partially intercalated and extends into the major groove of DNA. The two GC base pairs at this site are slightly inequivalent. For each, the G imino proton and one of the C amino protons are at appropriate positions to account for the ENDOR signals arising from exchangeable protons. It is unlikely that this inequivalence would persist at room temperature where dynamic processes would give an apparently symmetric interaction. Although the model accounts for all reported experimental data involving tetracationic porphyrin species which have been suggested to be intercalators, it is not a unique solution.     

Ultrasound-driven cardiac MRI

PurposeOne of the challenges of cardiac MR imaging is the compensation of respiratory motion, which causes the heart and the surrounding tissues to move. Commonly-used methods to overcome this effect, breath-holding and MR navigation, present shortcomings in terms of available acquisition time or need to periodically interrupt the acquisition, respectively. In this work, an implementation of respiratory motion compensation that obtains information from abdominal ultrasound and continuously adapts the imaged slice position in real time is presented.MethodsA custom workflow was developed, comprising an MR-compatible ultrasound acquisition system, a feature-motion-tracking system with polynomial predictive capability, and a custom MR sequence that continuously adapts the position of the acquired slice according to the tracked position. The system was evaluated on a moving phantom by comparing sharpness and image blurring between static and moving conditions, and in vivo by tracking the motion of the blood vessels of the liver to estimate the cardiac motion. Cine images of the heart were acquired during free breathing.ResultsIn vitro, the predictive motion correction yielded significantly better results than non-predictive or non-corrected acquisitions (p ≪ 0.01). In vivo, the predictive correction resulted in an image quality very similar to the breath-hold acquisition, whereas the uncorrected images show noticeable blurring artifacts.ConclusionIn this work, the possibility of using ultrasound navigation with tracking for the real-time adaptation of MR imaging slices was demonstrated. The implemented technique enabled efficient imaging of the heart with resolutions that would not be feasible in a single breath-hold.     

Modelling lung cancer mortality rates from smoking prevalence: Fill in the gap

BackgroundThe objective of this study is to estimate the gap between smoking prevalence and lung cancer mortality and provide predictions of lung cancer mortality based on previous smoking prevalence.Materials and methodsWe used data from the Spanish National Health Surveys (2003, 2006 and 2011) to obtain information about tobacco use and data from the Spanish National Statistics Institute to obtain cancer mortality rates from 1980 to 2013. We calculated the cross-correlation among the historical series of smoking prevalence and lung cancer mortality rate (LCMR) to estimate the most likely time gap between both series. We also predicted the magnitude and timing of the LCMR peak.ResultsAll cross-correlations were statistically significant and positive (all above 0.8). For men, the most likely gap ranges from 20 to 34 years. The age-adjusted LCMR increased by 3.2 deaths per 100,000 people for every 1 unit increase in the smoking prevalence 29 years earlier. The highest rate for men was observed in 1995 (55.6 deaths). For women, the most likely gap ranges from 10 to 37 years. The age-adjusted LCMR increased by 0.28 deaths per 100,000 people for every 1 unit increase in the smoking prevalence 32 years earlier. The maximum rate is expected to occur in 2026 (10.3 deaths).ConclusionThe time series of prevalence of tobacco smoking explains the mortality from lung cancer with a distance (or gap) of around 30 years. According to the lagged smoking prevalence, the lung cancer mortality among men is declining while in women continues to rise (maximum expected in 2026).