Sexual conflict in action: An antagonistic relationship between maternal and paternal sex allocation in the tammar wallaby,Notamacropus eugenii

Sex ratio biases are often inconsistent, both among and within species and populations. While some of these inconsistencies may be due to experimental design, much of the variation remains inexplicable. Recent research suggests that an exclusive focus on mothers may account for some of the inconsistency, with an increasing number of studies showing variation in sperm sex ratios and seminal fluids. Using fluorescent in‐situ hybridization, we show a significant population‐level Y‐chromosome bias in the spermatozoa of wild tammar wallabies, but with significant intraindividual variation between males. We also show a population‐level birth sex ratio trend in the same direction toward male offspring, but a weaning sex ratio that is significantly female‐biased, indicating that males are disproportionately lost during lactation. We hypothesize that sexual conflict between parents may cause mothers to adjust offspring sex ratios after birth, through abandonment of male pouch young and reactivation of diapaused embryos. Further research is required in a captive, controlled setting to understand what is driving and mechanistically controlling sperm sex ratio and offspring sex ratio biases and to understand the sexually antagonistic relationship between mothers and fathers over offspring sex. These results extend beyond sex allocation, as they question studies of population processes that assume equal input of sex chromosomes from fathers, and will also assist with future reproduction studies for management and conservation of marsupials.     

Of 11 candidate steroids,corticosterone concentration standardized for mass is the most reliable steroid biomarker of nutritional stress across different feather types

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Modeling Patient-Derived Glioblastoma with Cerebral Organoids

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Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics

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How phenotypic matching based on neutral mating cues enables speciation in locally adapted populations

Maynard Smith's (American Naturalist, 1966, 100, 637) suggestion that in some cases a prerequisite for speciation is the existence of local ecological adaptations has not received much attention to date. Here, we test the hypothesis using a model like that of Maynard Smith but differing in the way animals disperse between niches. In previous studies, males disperse randomly between niches but females stay put in their natal niche. As a first step toward generalizing the model, we here analyze the case that equal proportions of the two sexes disperse between niches before breeding. Supporting Maynard Smith's (1966) hypothesis, we find that once local adaptations are established, a neutral mating cue at an independent locus can rapidly enable speciation in populations with a suitable mechanism for phenotype matching. We find that stable ecological polymorphisms are relatively insensitive to the strength of selection, but depend crucially on the extent of dispersal between niches, with a threshold of ~5% if population sizes in two niches are equal. At higher levels of dispersal, ecological differentiation is lost. These results contrast with those of earlier studies and shed light on why parapatric speciation is limited by the extent of gene flow. Our testable model provides a candidate explanation for the rapid speciation rates, diversity of appearance and occurrence of “species flocks” observed among some African cichlids and neotropical birds and may also have implications for the occurrence of punctuational change on phylogenies.     

Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans

Background

Little is known about the role of amino acids in cellular signaling pathways, especially as it pertains to pathways that regulate the rate of aging. However, it has been shown that methionine or tryptophan restriction extends lifespan in higher eukaryotes and increased proline or tryptophan levels increase longevity in C. elegans. In addition, leucine strongly activates the TOR signaling pathway, which when inhibited increases lifespan.

Results

Therefore each of the 20 proteogenic amino acids was individually supplemented to C. elegans and the effects on lifespan were determined. All amino acids except phenylalanine and aspartate extended lifespan at least to a small extent at one or more of the 3 concentrations tested with serine and proline showing the largest effects. 11 of the amino acids were less potent at higher doses, while 5 even decreased lifespan. Serine, proline, or histidine-mediated lifespan extension was greatly inhibited in eat-2 worms, a model of dietary restriction, in daf-16/FOXO, sir-2.1, rsks-1 (ribosomal S6 kinase), gcn-2, and aak-2 (AMPK) longevity pathway mutants, and in bec-1 autophagy-defective knockdown worms. 8 of 10 longevity-promoting amino acids tested activated a SKN-1/Nrf2 reporter strain, while serine and histidine were the only amino acids from those to activate a hypoxia-inducible factor (HIF-1) reporter strain. Thermotolerance was increased by proline or tryptophan supplementation, while tryptophan-mediated lifespan extension was independent of DAF-16/FOXO and SKN-1/Nrf2 signaling, but tryptophan and several related pyridine-containing compounds induced the mitochondrial unfolded protein response and an ER stress response. High glucose levels or mutations affecting electron transport chain (ETC) function inhibited amino acid-mediated lifespan extension suggesting that metabolism plays an important role. Providing many other cellular metabolites to C. elegans also increased longevity suggesting that anaplerosis of tricarboxylic acid (TCA) cycle substrates likely plays a role in lifespan extension.

Conclusions

Supplementation of C. elegans with 18 of the 20 individual amino acids extended lifespan, but lifespan often decreased with increasing concentration suggesting hormesis. Lifespan extension appears to be caused by altered mitochondrial TCA cycle metabolism and respiratory substrate utilization resulting in the activation of the DAF-16/FOXO and SKN-1/Nrf2 stress response pathways.

Electronic supplementary material

The online version of this article (doi:10.1186/s12863-015-0167-2) contains supplementary material, which is available to authorized users.     

Development of the infant intestinal microbiome: A bird's eye view of a complex process

Infants undergo profound shifts in colonizing intestinal microorganisms during their first year, especially during and after birth and during weaning. Microbiota are passed to infants through the placenta, during the vaginal birth process, and from early diet and other environmental exposures. These microbiota play an active role in the development of healthy infant metabolic and immunologic systems; profound shifts in microbiotal populations can be persistent, are associated with immediate alterations in gene expression, metabolic, immunologic, and neurologic function, and with downstream metabolic and immunologic consequences such as obesity, allergies, asthma, autoimmune diseases, and potentially neurologic conditions. Many modern exposures, including Cesarean section, formula feeding, and antibiotics, have been associated with microbiome shifts, and also with downstream diseases; while many published studies considered exposures individually, a more comprehensive understanding of their interaction and impact will consider the entirety of the infant's environment. It is not possible, nor desirable, to return to a world without toilets, sewers, tap water, delivery room antisepsis, Cesarean sections, antibiotics, immunizations, and refrigerators; our other alternative is to better understand these complex changes in infant developmental and molecular physiology. Protecting and repairing the developmental processes of the healthy infant microbiome is the modern medical frontier. Birth Defects Research (Part C) 105:228–239, 2015. © 2015 Wiley Periodicals, Inc.     

The 2012/2013 ABRF Proteomic Research Group Study: Assessing Longitudinal Intralaboratory Variability in Routine Peptide Liquid Chromatography Tandem Mass Spectrometry Analyses*

Questions concerning longitudinal data quality and reproducibility of proteomic laboratories spurred the Protein Research Group of the Association of Biomolecular Resource Facilities (ABRF-PRG) to design a study to systematically assess the reproducibility of proteomic laboratories over an extended period of time. Developed as an open study, initially 64 participants were recruited from the broader mass spectrometry community to analyze provided aliquots of a six bovine protein tryptic digest mixture every month for a period of nine months. Data were uploaded to a central repository, and the operators answered an accompanying survey. Ultimately, 45 laboratories submitted a minimum of eight LC-MSMS raw data files collected in data-dependent acquisition (DDA) mode. No standard operating procedures were enforced; rather the participants were encouraged to analyze the samples according to usual practices in the laboratory. Unlike previous studies, this investigation was not designed to compare laboratories or instrument configuration, but rather to assess the temporal intralaboratory reproducibility. The outcome of the study was reassuring with 80% of the participating laboratories performing analyses at a medium to high level of reproducibility and quality over the 9-month period. For the groups that had one or more outlying experiments, the major contributing factor that correlated to the survey data was the performance of preventative maintenance prior to the LC-MSMS analyses. Thus, the Protein Research Group of the Association of Biomolecular Resource Facilities recommends that laboratories closely scrutinize the quality control data following such events. Additionally, improved quality control recording is imperative. This longitudinal study provides evidence that mass spectrometry-based proteomics is reproducible. When quality control measures are strictly adhered to, such reproducibility is comparable among many disparate groups. Data from the study are available via ProteomeXchange under the accession code PXD002114.The broad-reaching use and application of mass spectrometry-based proteomics in the international research community continues to exponentially grow and expand. As the technology has developed and practitioners have become skilled in performing complex workflows, the community has not only gained interest in assessing data across laboratories but also in maintaining consistent quality control within a laboratory. Koecher et al. raised the issue of quality control measures and how this aspect of mass spectrometry-based proteomics is generally neglected in scientific publications (1). Fortunately, studies characterizing the stability of liquid chromatography-tandem MS (LC-MSMS)¹ quality control performance among numerous laboratories are emerging. The relationship between sample preparation schemes, data acquisition and reduction strategies, and bioinformatic analyses have been comprehensively reviewed by Tabb (2).Several studies exist where intra- and interlaboratory reproducibility between multiple sites has been assessed under different settings. Perhaps the most systematic and detailed of these investigations are from the Human Proteome Organization (HuPO) test sample working group (3); the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (NCI CPTAC) (4); and the ProteoRed Consortium (5, 6). The HuPO group utilized an equimolar mixture of 20 highly purified recombinant human proteins (5 pmol per protein) distributed to 27 different laboratories and analyzed without constraint according to optimized LCMS and database search protocols from each of the laboratories (3). The study was not an assessment of instrument performance for highly sensitive detection of proteins, as all participating laboratories had acquired raw data of sufficient quality to identify all 20 proteins (and a specific subset of tryptic peptides). The study revealed, however, that discrepancies in peptide identification and protein assignment were the result of differences in data analysis strategies rather than data collection.The NCI CPTAC group used a standardized Saccharomyces cerevisiae proteome digest that was analyzed on ion-trap-based LCMS platforms in five independent laboratories according to both an established standard operating procedure (SOP) and with no SOP constraint (4). All data analysis was centralized, and thus, any observed variations were entirely because of the LCMS platform. By applying the performance metrics developed by Rudnick et al. (7), several key points emerged: (1) as expected, intralaboratory variation was less than interlaboratory variation; and (2) overall, the interlaboratory variation in peptide identifications and some of the other performance metrics were comparable between instruments, although there were large differences in the average values for some metrics (e.g. MS1 signal intensity, dynamic sampling).The ProteoRed Consortium initiated the ProteoRed Multicenter Experiment for Quality Control (PMEQC) (5, 6). This longitudinal QC multicenter study involved 12 institutes, and was designed to assess: (1) intralaboratory repeatability of LC-MSMS proteomic data; (2) interlaboratory reproducibility; and (3) reproducibility across multiple instrument platforms. Participants received samples of undigested or tryptically digested yeast proteins and were requested to follow strict analytical guidelines. Data analysis was centralized and performed under standard procedures using a common workflow. The study revealed that the overall performance with respect to metrics such as reproducibility, sensitivity, dynamic range etc. was directly related to the degree of operator expertise, and less dependent on instrumentation.Several studies not specifically focused on quality control have also yielded insight into proteomic reproducibility. The HuPO plasma proteome project (HuPO PPP) distributed 20 human samples (five serum plus 3 × 5 plasma samples treated with three different anticoagulants) to 35 laboratories spanning 13 countries (8). The purpose of this large-scale study was not to assess reproducibility per se, but rather to generate the largest and most comprehensive data set on the protein composition of human plasma/serum. On a smaller scale, the ISB standard 18 protein mixture (purified proteins from cow, horse, rabbit, chicken, E. coli, and B. licheniformus) was also assessed between laboratories on eight different LCMS platforms (9). These data reside in a comprehensive, multiplatform database as a resource for the proteomic community. Additional interlaboratory assessments have consisted of multiple reaction monitoring-based measurements of peptides/proteins in plasma (10, 11) and protein–protein interactions at both the biochemical and proteomic level (12).For team leaders/directors of proteomic laboratories and any researcher collaborating with such groups, major questions that may arise concerning data consistency are: how well are quality controls being implemented in the daily operations? Do the quality control measures effectively support data reproducibility? To address this, the Protein Research Group of the Association of Biomolecular Resource Facilities (ABRF-PRG) designed a study whereby LC-MSMS data obtained from the analysis of a commercially available bovine protein mixture predigested with trypsin were collected at routine intervals over a period of 9 months. Raw MS data files from a total of 64 participating laboratories were accumulated, and HPLC and MS performance were evaluated through QC metrics (13). The main impetus of the study was to recognize key sources of variability in HPLC and MS analyses under extended and routine operating conditions for each laboratory and to catalog the state of quality control in a diverse set of proteomic laboratories.No standard operating protocol was imposed on the participants; instead, contributors were encouraged to employ the methods that were typically applied in individual laboratories. Optimization of instrument methods on the provided sample was discouraged. A survey was conducted with each sample submission to catalog individual laboratory practices, instrument configurations, acquisition settings, including routine and nonroutine maintenance procedures. Unlike previous investigations where emphasis was placed on the preparation, distribution, and evaluation of protein standards to appraise and/or standardize LCMS platforms between laboratories, the key interest in this study was purely to determine the intralaboratory performance, reproducibility, and consistency of participating laboratories over an extended period of time.The rapidly expanding number of proteomic laboratories have incorporated divergent HPLC systems, mass spectrometers, solvent systems, columns etc. As a result, analyzing data from a large number of laboratories necessitates tools that can accommodate data from a broad range of platforms. For example, to expect a small laboratory with a decade-old three-dimensional ion trap mass spectrometer to achieve the same sensitivity as a laboratory with a high-resolution hybrid instrument would be unfair. Correspondingly, the data analysis needs to include axes beyond simple peptide-level sensitivity. Nevertheless, the laboratory with the older instrumentation may be consistently better at maximizing performance from the chosen instrument platform compared with a laboratory with the latest high-end equipment.The focus of this study was to estimate the degree of variability in intralaboratory performance over a 9-month period. This goal was achieved using quality metrics that are applicable to most LC-MSMS workflows. The inclusion of data from many laboratories will enable the proteomic community to determine the current state of quality control within a typical laboratory. The survey data enabled the mapping of some alterations in instrument performance to documented laboratory events, e.g. mass spectrometer calibration. The study was designed neither to compare one laboratory with another, nor to discriminate between classes of instrumentation.Questions of data quality and performance in the proteomic community are appropriately aligned with the heightened awareness of a perceived lack of reproducibility of scientific findings in general (1). This community has endeavored to provide tools to assess proteomic data quality, and this study provides additional insight into the application of such tools and the quality of data within respective laboratories.     

Retained in HIV Care But Not on Antiretroviral Treatment: A Qualitative Patient-Provider Dyadic Study

Background

Patients retained in HIV care but not on antiretroviral therapy (ART) represent an important part of the HIV care cascade in the United States. Even in an era of more tolerable and efficacious ART, decision making in regards to ART offer and uptake remains complex and calls for exploration of both patient and provider perspectives. We sought to understand reasons for lack of ART usage in patients meeting the Health Resources Services Administration definition of retention as well as what motivated HIV primary care appointment attendance in the absence of ART.

Methods and Findings

We conducted a qualitative study consisting of 70 in-depth interviews with ART-naïve and ART-experienced patients off ART and their primary care providers in two urban safety-net HIV clinics in San Francisco and New York. Twenty patients and their providers were interviewed separately at baseline, and 15 dyads were interviewed again after at least 3 mo and another clinic visit in order to understand any ART use in the interim. We applied dyadic analysis to our data. Nearly all patients were willing to consider ART, and 40% of the sample went on ART, citing education on newer antiretroviral drugs, acceptance of HIV diagnosis, social support, and increased confidence in their ability to adhere as facilitators. However, the strength of the provider recommendation of ART played an important role. Many patients had internalized messages from providers that their health was too good to warrant ART. In addition, providers, while demonstrating patient-centered care through sensitivity to patients experiencing psychosocial instability, frequently muted the offer of ART, at times unintentionally. In the absence of ART, lab monitoring, provider relationships, access to social services, opiate pain medications, and acute symptoms motivated care. The main limitations of this study were that treatment as prevention was not explored in depth and that participants were recruited from academic HIV clinics in the US, making the findings most generalizable to this setting.

Conclusions

Provider communication with regard to ART is a key focus for further exploration and intervention in order to increase ART uptake for those retained in HIV care.