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Influenza virus infects millions of people annually and can cause global pandemics. Hemagglutinin (HA) is the primary component of commercial influenza vaccines (CIV), and antibody titer to HA is a primary correlate of protection. Continual antigenic variation of HA requires that CIVs are reformulated yearly. Structural organization of HA complexes have not previously been correlated with induction of broadly reactive antibodies, yet CIV formulations vary in how HA is organized. Using electron microscopy to study four current CIVs, we find structures including: individual HAs, starfish structures with up to 12 HA molecules, and novel spiked-nanodisc structures that display over 50 HA molecules along the complex’s perimeter. CIV containing these spiked nanodiscs elicit the highest levels of heterosubtypic cross-reactive antibodies in female mice. Here, we report that HA structural organization can be an important CIV parameter and can be associated with the induction of cross-reactive antibodies to conserved HA epitopes.

Due to the changing complex healthcare environment, educational innovation is essential to meet the needs of current and future neonatal-perinatal medicine (NPM) leaders. Greater clinical demands, decreased academic funding, and expanded graduate medical education program requirements have negatively impacted time for teaching and educational scholarship potentially limiting innovation in the field. By focusing on adult learning principles, embracing technology, and promoting collaboration, today's educators are preparing the next generation of neonatologists. Current innovations include regionalizing simulation boot camps, leveraging virtual learning to increase accessibility, developing niche training opportunities, and incorporating population health principles within existing quality initiatives. Areas in need of additional innovation include faculty and fellow development for teaching skills, expansion of educational networks, and dissemination and financial support of educational scholarship. These efforts and future innovations will require medical institutions and national NPM organizations to further invest in the medical educator as part of their missions.

Isoprene is the dominant non-methane organic compound emitted to the atmosphere1-3. It drives ozone and aerosol production, modulates atmospheric oxidation and interacts with the global nitrogen cycle4-8. Isoprene emissions are highly uncertain1,9, as is the nonlinear chemistry coupling isoprene and the hydroxyl radical, OH-its primary sink10-13. Here we present global isoprene measurements taken from space using the Cross-track Infrared Sounder. Together with observations of formaldehyde, an isoprene oxidation product, these measurements provide constraints on isoprene emissions and atmospheric oxidation. We find that the isoprene-formaldehyde relationships measured from space are broadly consistent with the current understanding of isoprene-OH chemistry, with no indication of missing OH recycling at low nitrogen oxide concentrations. We analyse these datasets over four global isoprene hotspots in relation to model predictions, and present a quantification of isoprene emissions based directly on satellite measurements of isoprene itself. A major discrepancy emerges over Amazonia, where current underestimates of natural nitrogen oxide emissions bias modelled OH and hence isoprene. Over southern Africa, we find that a prominent isoprene hotspot is missing from bottom-up predictions. A multi-year analysis sheds light on interannual isoprene variability, and suggests the influence of the El Nino/Southern Oscillation.

To determine the effect of implementing a 2015 policy for the screening, prevention, and management of metabolic bone disease for very low birth weight (VLBW) infants in two Level IV NICUs.Retrospective cohort study of VLBW infants in the 2 years prior to (2013-2014) and after (2016-2017) policy implementation.We identified 316 VLBW infants in 2013-2014 and 292 in 2016-2017 who met study criteria. After policy implementation, vitamin D supplementation began earlier (20.1 ± 15.5 days vs 30.2 ± 20.1 days, p 0.0005), the percentage of infants with alkaline phosphatase obtained increased (89.7% vs 76.3%, p 0.0005), while the percentage of infants with alkaline phosphatase800 IU/L (11.7 vs 4.5%, p = 0.0001) and phosphorous4 mg/dL (14.2% vs 7.9%, p = 0.014) fell significantly.After policy implementation, vitamin D supplementation began significantly earlier and the rate of detecting abnormal biochemical markers of metabolic bone disease decreased significantly.

BACKGROUND: Many factors are implicated in the potential 'under-treatment' of prostate cancer but little is known about the between-hospital variation. METHODS: The National Prostate Cancer Audit (NPCA) database was used to identify high-risk localised or locally advanced prostate cancer patients in England, between January 2014 and December 2017, and the treatments received. Hospital-level variation in radical local treatment was explored visually using funnel plots. The intra-class correlation coefficient (ICC) quantified the between-hospital variation in a random-intercept multivariable logistic regression model. RESULTS: 53,888 men, from 128 hospitals, were included and 35,034 (65.0%) received radical local treatment. The likelihood of receiving radical local treatment was increased in men who were younger (the strongest predictor), more affluent, those with fewer comorbidities, and in those with a non-Black ethnic background. There was more between-hospital variation (P

Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance., Dysregulated phosphorylation is well-known in cancers, but it has largely been studied in isolation from mutations. Here the authors introduce HotPho, a tool that can discover spatial interactions between phosphosites and mutations, which are associated with activating mutation and genetic dependencies in cancer.

Background: Low birth weight in term-born individuals correlates with adverse cardiometabolic outcomes; excess glucocorticoid exposure has been linked to these relationships. We hypothesized that cortisol and adrenal androgens would correlate inversely with birthweight and directly with markers of cardiometabolic risk in school-aged children born extremely preterm; further, preterm-born would have increased cortisol and adrenal androgens compared to term-born children. Methods: Saliva samples were obtained at age 6 from 219 preterm-born children followed since birth and 40 term-born children and analyzed for dehydroepiandrosterone (DHEA) and cortisol. Cortisol was also measured at home (awakening, 30’ later, evening). Results: For preterm-born children, cortisol and DHEA correlated inversely with weight and length Z-scores at 36 weeks PMA and positively with systolic BP. DHEA was higher in preterm-born than term-born children (boys p

A library-free, peptide-centric search tool, PECAN, robustly identifies peptides from data-independent acquisition mass-spectrometry-based proteomics data. Data-independent acquisition (DIA) is an emerging mass spectrometry (MS)-based technique for unbiased and reproducible measurement of protein mixtures. DIA tandem mass spectrometry spectra are often highly multiplexed, containing product ions from multiple cofragmenting precursors. Detecting peptides directly from DIA data is therefore challenging; most DIA data analyses require spectral libraries. Here we present PECAN ( http://pecan.maccosslab.org ), a library-free, peptide-centric tool that robustly and accurately detects peptides directly from DIA data. PECAN reports evidence of detection based on product ion scoring, which enables detection of low-abundance analytes with poor precursor ion signal. We demonstrate the chromatographic peak picking accuracy and peptide detection capability of PECAN, and we further validate its detection with data-dependent acquisition and targeted analyses. Lastly, we used PECAN to build a plasma proteome library from DIA data and to query known sequence variants.

Aim: Zirconium-89 has gained great interest for PET, when imaging at late time points is required. Desferrioxamine B (DFO), is mostly used for this radionuclide as bifunctional chelator (BFC) and w ...

Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.

Methamphetamine (METH) causes significant loss of some striatal projection and interneurons. Recently, our group reported on the proliferation of new cells 36 h after METH and some of the new cells survive up to 12 weeks (Tulloch et al., Neuroscience 193:162-169, 2011b). We hypothesized that some of these cells will differentiate and express striatal neuronal phenotypes. To test this hypothesis, mice were injected with METH (30 mg/kg) followed by a single BrdU injection (100 mg/kg) 36 h after METH. One week after METH, a population of BrdU-positive cells expressed the neuronal progenitor markers nestin (18 %) and β-III-tubulin (30 %). At 8 weeks, 14 % of the BrdU-positive cells were also positive for the mature neuron marker, NeuN. At 12 weeks, approximately 7 % of the BrdU-positive cells co-labeled with ChAT, PV or DARPP-32. We measured motor coordination on the rotarod and psychomotor activity in the open-field. At 12 weeks, METH-injected mice exhibited delayed motor coordination deficits. In contrast, open-field tests revealed that METH-injected mice compared to saline mice displayed psychomotor deficits at 2.5 days but not at 2 or more weeks after METH. Taken together, these data demonstrate that some of the new cells generated in the striatum differentiate and express the phenotypes of striatal neurons. However, the proportion of these new neurons is low compared to the proportion that died by apoptosis 24 h after the METH injection. More studies are needed to determine if the new neurons are functional.

Many of the factors that motivate individuals occur within the context of the family, and can be influenced through family socialization processes. To better understand the influence family socialization processes may have on financial capabilities and financial behaviors, 334 married couples were sampled. Structural equation modeling was used to examine both direct and indirect associations. Findings indicated direct relationships between materialism and financial strain, between religiosity and determination of needs, and between financial strain and saving for retirement. Indirect relationships were found between materialism and saving for retirement through financial strain. Our study found evidence to support the Family Financial Socialization theoretical framework. Financial counselors may benefit by understanding how couples socialize each other as they prepare for retirement.

Top-down proteomics, the analysis of intact proteins in their endogenous form, preserves valuable information about post-translation modifications, isoforms and proteolytic processing. The quality of top-down liquid chromatography-tandem MS (LC-MS/MS) data sets is rapidly increasing on account of advances in instrumentation and sample-processing protocols. However, top-down mass spectra are substantially more complex than conventional bottom-up data. New algorithms and software tools for confident proteoform identification and quantification are needed. Here we present Informed-Proteomics, an open-source software suite for top-down proteomics analysis that consists of an LC-MS feature-finding algorithm, a database search algorithm, and an interactive results viewer. We compare our tool with several other popular tools using human-in-mouse xenograft luminal and basal breast tumor samples that are known to have significant differences in protein abundance based on bottom-up analysis.

This study examines return volatility among the Swiss, German, UK, and US bond markets by comparing both in-country and US-based returns and risk measures. Our findings include: (1) volatility of in-country bond market returns has been much higher in the US and UK than in Switzerland or Germany; (2) although adding to return volatility, currency returns have generally enhanced overall returns to US-based investors in European bonds; (3) low correlations between US bond market returns and European bond market returns offer potential diversification benefits; (4) overall, the risk per unit of return has been much greater in the US bond market and much lower in the German market than in the Swiss or UK markets; and (5) the risk per unit of return has been much more stable for the Swiss and German bond markets than for the UK or US markets. Our results show that global bond market investors can achieve the greatest efficiency in terms of risk per unit of return by hedging currency risk. The relatively low correlations of returns among these markets afford a global investor the opportunity to improve risk-return efficiency by diversifying among the three markets. This study offers important insights for US-based investors seeking the optimal bond portfolio allocation in risk-return space.

This Data Descriptor announces the submission to public repositories of the PNNL Biodiversity Library, a large collection of global proteomics data for 112 bacterial and archaeal organisms. The data comprises 35,162 tandem mass spectrometry (MS/MS) datasets from ~10 years of research. All data has been searched, annotated and organized in a consistent manner to promote reuse by the community. Protein identifications were cross-referenced with KEGG functional annotations which allows for pathway oriented investigation. We present the data as a freely available community resource. A variety of data re-use options are described for computational modelling, proteomics assay design and bioengineering. Instrument data and analysis files are available at ProteomeXchange via the MassIVE partner repository under the identifiers PXD001860 and MSV000079053.

Background In an effort to identify the best practice for finding genes in prokaryotic genomes and propose it as a standard for automated annotation pipelines, 1,004,576 peptides were collected from various publicly available resources, and were used as a basis to evaluate various gene-calling methods. The peptides came from 45 bacterial replicons with an average GC content from 31 % to 74 %, biased toward higher GC content genomes. Automated, manual, and semi-manual methods were used to tally errors in three widely used gene calling methods, as evidenced by peptides mapped outside the boundaries of called genes. Results We found that the consensus set of identical genes predicted by the three methods constitutes only about 70 % of the genes predicted by each individual method (with start and stop required to coincide). Peptide data was useful for evaluating some of the differences between gene callers, but not reliable enough to make the results conclusive, due to limitations inherent in any proteogenomic study. Conclusions A single, unambiguous, unanimous best practice did not emerge from this analysis, since the available proteomics data were not adequate to provide an objective measurement of differences in the accuracy between these methods. However, as a result of this study, software, reference data, and procedures have been better matched among participants, representing a step toward a much-needed standard. In the absence of sufficient amount of exprimental data to achieve a universal standard, our recommendation is that any of these methods can be used by the community, as long as a single method is employed across all datasets to be compared. Electronic supplementary material The online version of this article (doi:10.1186/s40793-015-0034-9) contains supplementary material, which is available to authorized users.

The objectives of this study were to measure by in-vivo techniques the radiation doses received by the anorectum during pelvic radiotherapy and compare these with doses predicted by a GE TARGET™ treatment planning system. Nine patients with cancers of the prostate, bladder, cervix or uterus were planned with computed tomography (CT) using the TARGET system. A Scanditronix rectal probe containing five n-type photon-detecting diodes was placed in the anorectum during the planning CT scans. The probe position was standardized with the five diodes at 2 cm intervals from the anal verge. The probe diodes were calibrated for 10 MV photons. Doses were measured for each diode for two consecutive fractions in the first four patients and for five consecutive fractions in the remaining five. Thermoluminescent dosimeters were used initially to verify diode doses. The TARGET and diode measured doses were compared. In all patients diodes situated in the target volume were within 7% of predicted doses. This improved to 2.5% after measurement on five fractions. At the edges of the target volume, wide variability existed between measured and predicted doses (measured dose range −68% to +68% of predicted dose). Outside the target volume, considerable doses (up to 0.3 Gy per fraction) were measured in the anal canal, which were not predicted by TARGET. We conclude that TARGET planned doses are accurate within the confines of the target volume. The greatest variability was seen at the edges of the target volume, where dose can vary by 50% across a 1 cm distance in the anterior–posterior plane. TARGET does not account for scattered dose beyond the field edges and therefore underestimates the dose received by the anal canal.

Smaller individual series on the outcome of laparoscopic hernioplasty techniques have been reported. This study reports on the complications of 3,229 laparoscopic hernia repairs performed by the authors in 2,559 patients. The TAPP (transabdominal preperitoneal) technique was the most frequently performed: 1,944 (60%). The totally preperitoneal technique was performed 578 (18%) times. The IPOM (intraperitoneal onlay mesh) repair was performed 345 (11%) times. The plug-and-patch technique was used 286 (9%) times and simple closure of the hernia defect without mesh was used in 76 (2%) repairs. Overall, there were 336 (10%) complications: 17 (0.5%) major and 265 (8%) minor. There were 54 (1.6%) recurrences, with a mean follow-up of 22 months. The TAPP technique had 19 (1%) recurrences and 141 (7%) complications. There were four bowel obstructions in this subgroup from herniation of small bowel through the peritoneal closure and trocar sites. The totally preperitoneal technique had no recurrence and 60 (10%) complications. The IPOM group had 7 (2%) recurrences and 47 (14%) complications. The plug-and-patch technique had 26 (9%) recurrences and 24 (8%) complications. The simple closure of the internal ring had 2 (3%) recurrences and 10 (13%) complications. Laparoscopic hernioplasty is not without complications. Laparoscopic hernioplasty is not without complications. Training, experience, and attention to technique will prevent some of these complications.

Two cell types central to the support of spermatogenesis, the Sertoli cell and the interstitial (Leydig) cell, were isolated from the same cohort of young male rats and challenged with cadmium chloride to compare their susceptibility to the metal. Both cell types were cultured under similar conditions, and similar biochemical endpoints were chosen to minimize experimental variability. These endpoints include the uptake of 109Cd, reduction of the vital tetrazolium dye MTT, incorporation of 3H-leucine, change in heat-stable cadmium binding capacity, and production of lactate. Using these parameters, it was observed that the Sertoli cell cultures were adversely affected in a dose-and time-dependent manner, while the interstitial cell cultures, treated with identical concentrations of CdCl2, were less affected. The 72-hr LC50's for Sertoli cells and interstitial cells were 4.1 and 19.6 microM CdCl2, respectively. Thus, different cell populations within the same tissue may differ markedly in susceptibility to a toxicant. These in vitro data suggest that the Sertoli cell, in relation to the interstitium, is particularly sensitive to cadmium. Because the Sertoli cell provides functional support for the seminiferous epithelium, the differential sensitivity of this cell type may, in part, explain cadmium-induced testicular dysfunction, particularly at doses that leave the vascular epithelium intact.

Following its development for cataract surgery, and gaining widespread use in neurosurgery and liver resection, ultrasonic dissection has been adapted for laparoscopic use. The turbulence, heat, and pressure generated by imploding bubbles disrupts tissues high in water content. This phenomenon is called cavitation and is the principal means by which ultrasonic dissection is accomplished. A randomized, prospective trial demonstrated the utility of the device for laparoscopic cholecystectomy. It was particularly effective in the presence of acute periportal inflammation or fat. Additional experience with a wide range of laparoscopic procedures is being accumulated by several investigators around the world. The laparoscopic use of ultrasonic dissection will be most valuable whenever selective, precise, and, therefore, safe dissection is desired.

Endoscopic surgery has led to changes in surgical practice which may rival the introduction of anesthesia and antibiotics in significance. As a result, an exciting synergy has rapidly emerged between technology and clinical practice. However, questions of training, credentialing, and patient safety have been raised as traditional procedures have been adapted to the minimally invasive approach and new ones are described. Many surgeons have been reluctant to venture beyond laparoscopic cholecystectomy. Halting first efforts at advanced procedures may prolong operative times, increase risk, and raise costs. Older methods of surgical education are not adequate to meet the current need (Fig. 1).

In the microscopic theory of Bose-condensed liquids, the condensate wave function leads to a coupling of the density fluctuations and the single-particle excitations. A simple parametrized model of this based on coupling weakly damped zero-sound modes with strongly damped free-particle-like excitations similar to Q/sup 2//2m explains why the phonon-roton resonance in S(Q,w) for superfluid /sup 4/He exists above and below Tlambda but only pays the role of an elementary excitation below Tlambda. It is pointed out that this model also predicts that S(Q,w) should exhibit a weak, low-frequency peak centered at Q/sup 2//2m, with weight roughly proportional to the condensate fraction n/OMICRON/. As a stimulus to further experimental searches for this branch, some model calculations are given for S(Q,w) for Q similar to 1A/sup -1/.

Thermostability of 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta HSD) activity was examined in testes and adrenal glands from several inbred lines and feral mice. A thermolabile variant of 3 beta HSD was detected in the feral Brno mice. The thermostability (t1/2) of 3 beta HSD was approximately 7 min for both testes and adrenal glands from C57BL/6J mice, compared with 4 min for both tissues from Brno mice. Comparison of testicular and adrenal 3 beta HSD thermostability in six kinds of mice indicated that the t1/2 of 3 beta HSD was correlated in the two tissues and could be classified into two distinct types, thermolabile and thermostable. In contrast, quantitative variants in 3 beta HSD activity were not correlated in the two tissues. These data are consistent with the hypothesis that testicular and adrenal 3 beta HSD is encoded by the same structural gene but that expression of 3 beta HSD activity is independently controlled in testes and adrenal glands.

The advantages of the generalized feedback shift register pseudorandom number algorithm over all other pseudorandom number generators are described. These advantages are: (1) It produces multidimensional pseudorandom numbers; (2) it has arbitrarily long period, independent of word size of the computer on which it is implemented; (3) it is faster than other pseudorandom number generators; (4) the “same” floating-point pseudorandom number sequence is obtained on any machine; that is, the high-order mantissa bits of each pseudorandom number agree on all machines: examples are given for IBM 360, SPERRY-RAND-UNIVAC 1108, CONTROL DATA 6000, and HEWLETT-PACKARD 2100 series computers; and (5) it can be coded in compiler languages (is portable). This pseudorandom number generator is ideal for mini- and microcomputers, since only two additions and an exclusive-or are needed for its execution.

A digital integrated circuit computer that produces random (as opposed to pseudorandom) foreperiods is described. Also contained in the device is a precision digital interval timer.

Let vectorA containN elements. When vectorA is sorted the relationA(1) ⩽A(2) ⩽ ⋯ ⩽A(N) holds.A partial sort is a procedure by which theJth, 1 ⩽J ⩽N, element ofA,A(J), is found without completely sorting vectorA.A(J) is the Jth-order statistic ofA. A partial sort technique based on the Quicksort algorithm requires storage ofA. In this article an alternate technique based on confidence intervals of ranks and a rejection procedure findsA(J). This procedure only requires a small working storage and is suited to the case when the elements ofA, for largeN, are serially computed. The minimum number of working storage locations needed for the algorithm to terminate successfully with set probability for specifiedJ andN was computed. Partial sorting, especially this technique, is useful for computing critical values for statistics for which the sampling distributions are analytically known. Error bounds, which can be estimated from a segment of the ordered sample, are given for the estimated critical value. The technique is applied in several examples to estimate the mathematical constant π.

We report an example of four generation familial retinoblastoma in which there are three distinct categories of RB gene expression: frank retinoblastoma, unilateral or bilateral; retinoma; and no visible evidence of retinal pathology other than normal degeneration with age. Two large sibships derived from matings informative for RB and EsD provide strong confirmatory evidence for tight linkage between these loci (P = 0.0002), and thus assignment of RB to chromosome 13q14. There is a striking difference (P less than 2%) in RB penetrance between the two principal generations, which suggests that an additional epistatic, host-resistance gene may also be segregating within the family.

A section of the blind spot was mapped by obtaining detection and averaged EEG threshold measurements using three stimulus light intensities. It was found that averaged EEG and detection measures of the blind spot were equally sensitive when the two highest stimulus intensities were used, although more observations of the stimulus were required with averaged EEG. Detection thresholds were superior to averaged EEG measures with the dimmest stimulus.

The discovery of a serum protein polymorphism in the Atlantic salmon has revealed the existence of genetically isolated populations sufficiently distinct to merit their separation into subspecies and races.

THE application of the theory of ionisation to stellar spectra by Saha and others has led to estimates of the temperature of the reversing layers of stars. It is shown by Fowler and Milne (Mon. Not. R.A.S., 83, 7, 415) that the effective temperature at a given point in the stellar sequence may be deduced, on certain assumptions, from the knowledge that a line of known series relations there reaches its maximum intensity. For stars of type earlier than Ao the lines available for such estimates are those associated with Si+++, He, and C+. The intensities of these lines have recently been measured on a number of objective prism spectra at the Harvard College Observatory.

IN NATURE (May 14, p. 707) Dr. E. A. Baker discusses the calibration curves of photographic plates. The curves he gives certainly show a good agreement in sensitivity between the different batches of plates used under his conditions of standardisation. Concerning the reference to Harvard results (Harvard Circular 302), it may be of interest to note several points not fully discussed in the original paper on spectrophotometric method.