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7 recordsLinked to original sources

bioRxiv2018

Outcomes of early NIH-funded investigators: Experience of the National Institute of Allergy and Infectious Diseases

Survival of junior scientists in academic biomedical research is difficult in todays highly competitive funding climate. National Institute of Health (NIH) data on first-time R01 grantees indicate the rate at which early investigators drop out from a NIH-supported research career is most rapid 4 to 5 years from the first R01 award. The factors associated with a high risk of dropping out, and whether these factors impact all junior investigators equally, are unclear. We identified a cohort of 1,496 investigators who received their first R01-equivalent (R01-e) awards from the National Institute of Allergy and Infectious Diseases between 2003 and 2010, and studied all their subsequent NIH grant applications through 2016. Ultimately, 57% of the cohort were successful in obtaining new R01-e funding, despite highly competitive conditions. Among those investigators who failed to compete successfully for new funding (43%), the average time to dropping out was 5 years. Investigators who successfully obtained new grants showed remarkable within-person consistency across multiple grant submission behaviors, including submitting more applications per year, more renewal applications, and more applications to multiple NIH Institutes. Funded investigators appeared to have two advantages over their unfunded peers at the outset: they had better scores on their first R01-e grants and they demonstrated an early ability to write applications that would be scored, not triaged. The cohort rapidly segregated into two very different groups on the basis of PI consistency in the quality and frequency of applications submitted after their first R01-e award. Lastly, we identified a number of specific demographic factors, intitutional characteristics, and grant submission behaviors that were associated with successful outcomes, and assessed their predictive value and relative importance for the likelihood of obtaining additional NIH funding.

scientific communication and education↗

bioRxiv2018

Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling

Bile acids are critical biological detergents in the gastrointestinal tract and also act as messengers to regulate a multitude of intracellular signaling events, including mitogenic signaling, lipid metabolism and endo/exocytosis. In particular, bile acids stimulate many receptors and ion channels on the cell surface, the mechanisms of which are still poorly understood. Membrane-associating proteins depend on the local spatial distribution of lipids in the plasma membrane (PM) for their function. Here, we report that the highly amphipathic secondary bile acid deoxycholic acid (DCA), a major constituent in the human bile, at doses <1M enhances the nanoclustering of phosphatidic acid (PA) but disrupts the local segregation of phosphoinositol 4,5-bisphosphate (PIP2) in the basolateral PM of the human colorectal adenocarcinoma Caco-2 cells. PA has been shown to be a key structural component of the signaling nano-domains of epidermal growth factor receptor (EGFR) on the cell surface. We show that DCA promotes the co-localization between PA and EGFR, the PA-driven EGFR dimerization/oligomerization and EGFR signaling. Depletion of PA abolishes the stimulatory effects of DCA on the EGFR oligomerization and signaling. This effect occurs in the cultured Caco-2 cells and the ex vivo human intestinal enteroids. We propose a novel mechanism, where the amphiphilic DCA monomers alter the nano-assemblies of anionic phospholipids and in turn change the dynamic structural integrity of the lipid-driven oligomerization of cell surface receptors and their signal transduction.

biophysics↗

bioRxiv2018

The effect of nutrient storage on courtship behavior and copulation frequency in the fruit fly, Drosophila melanogaster.

Nutrient storage and metabolism effects on reproductive behavior are well studied in higher vertebrates like mammals, but are less understood in simpler systems. Drosophila melanogaster is well suited to study the ramifications of diet and metabolic energy storage on reproductive behaviors as they are commonly used to explore energy mobilization pathways. We tested, for the first time, courtship of the naturally occurring adipose (adp60) mutant which over-accumulates triglycerides and glycogen on a normal diet. We also fed wild type (WT) flies either a normal diet, high fat diet or food deprived them before measuring courtship, copulations, and glycogen and triglyceride levels. Adipose mutants decreased both courtship and copulation frequency, yet showed the highest glycogen and triglyceride levels. We suggest the adp60 physique and/or an altered ability to utilize mobilize energy explains these effects. Food deprived WT flies had the lowest glycogen and triglycerides but exhibited shortened courtship latencies with increased courtship behaviors. This may be due to a decreased lifespan of food deprived flies leading to a greater reproductive drive. However, high fat fed flies copulated more frequently and had the highest triglycerides among WT groups, yet equal glycogen levels to the normal fed WT group. Thus, a high fat diet either increases male attractivity or male courtship persistence. Taken together, available diet and nutrient storage affects male fly reproductive behavior in a unique manner, which may be explained by their natural history, and provides a paradigm for understanding energetics based on reproductive potential.

animal behavior and cognition↗

bioRxiv2018

Taxonomy, phylogeny and biogeography of African spurfowls (Galliformes, Phasianidae, Coturnicinae, Pternistis spp.)

During much of the 20th Century, partridge/quail-like, Afro-Asian phasianine birds referred to commonly as African spurfowls, francolins and/or partridges had a tortuous taxonomic history. Because of striking autapomorphic differences in plumage, vocalizations and ecology in some of these taxa, as many as nine genera and nearly 200 clinal and/or idiosyncratic subspecies, embedded within a polyphyletic Perdicinae, were recognized. In 1963, two clades, 28 francolin and spurfowl species (fisante in Afrikaans) and 13 Afro-Asiatic francolins and partridges (patryse in Afrikaans), were combined into a single genus (Francolinus) - the largest within the Galliformes - comprising about 100 subspecies. Furthermore, fisante and patryse were partitioned into several unnamed \"Groups\" and four \"Unplaced\" species. Here, we use morphological, behavioural and DNA evidence to produce: a comprehensive revision of the taxonomy and phylogeny of the fisante clade; a stable classification system for tis component taxa; and hypotheses vis-a-vis eco-biogeographical processes that promoted their speciation and cladogenesis. We shift Francolinus spp. sensu stricto (members of the Spotted Group) and the Unplaced Francolinus gularis from the fisante clade to the patryse [discussed in Mandiwana-Neudani et al., in review]. An Unplaced fisant, F. nahani, is linked with Ptilopachus petrosus (another African endemic partridge ) within the Odontophoridae (New World Quails ). We recognize 25 species of fisante (hereafter spurfowls), including seven with subspecies. They comprise 34 terminal taxa placed within a single genus, Pternistis, sister to Ammoperdix and Perdicula spp., Coturnix quails and Alectoris partridges , within the now monophyletic Coturnicinae. Only one of four putative Groups of spurfowls, the Bare-throated Group, is monophyletic. The other three Groups (Montane, Scaly and Vermiculated) are para- or polyphyletic. Several species pairs of spurfowls, most notably P. afer and cranchii, hybridize in para/sympatry. One Bare-throated spurfowl, P. rufopictus, may be the product of stabilized hybridization between P. afer and/or cranchii and P. leucoscepus.

evolutionary biology↗

bioRxiv2018

A proteome-wide screen reveals widespread roles for the phosphatase Cdc14 in the Candida albicans cell cycle

The chromosome complement of the human fungal pathogen Candida albicans is unusually unstable, suggesting that process of nuclear division is error prone. The Cdc14 phosphatase plays a key role in organising the intricate choreography of mitosis and cell division. In order to understand the role of Cdc14 in C. albicans we used quantitative proteomics to identify proteins that physically interact with CaCdc14. To distinguish genuine Cdc14-interactors from proteins that bound non-specifically bound to the affinity matrix we used an orthogonal approach of a substrate trapping mutant combined with mass spectrometry analysis using stable isotope labelling in cell culture (SILAC). The results identified 126 proteins that interact with Cdc14 of which 80% are novel. In this set, 53 proteins play known roles in the cell regulating the attachment of the mitotic spindle to kinetochores, mitotic exit, cytokinesis, licensing of DNA replication by re-activating pre-replication complexes, and DNA repair. Five Cdc14-interacting proteins with previously unknown functions localized to the Spindle Pole Bodies (SPBs). Intriguingly, 83 proteins that only interacted with Cdc14 in yeast were significantly enriched in components of the ergosterol biosynthesis pathway targeted by azole anti-fungal drugs. Thus we have greatly expanded the set of known substrates of this key cell cycle regulator in C. albicans.\n\nAuthor summaryCandida albicans is an important fungal pathogen causing life-threatening bloodstream infections in humans, as well as debilitating mucosal infections. Here we used Mass Spectroscopy to identify proteins that physically interacted with an enzyme called Cdc14. By removing phosphate groups from proteins, and thus regulating their function, this enzyme orchestrates the intricate molecular mechanisms of nuclear division to ensure that each daughter cell receives a full complement of chromosomes. C. albicans is unusual in the way that changes in chromosome number and composition are much more common than in other organisms. This suggests that the process of nuclear division may be more error prone in C. albicans. Our work identified 126 proteins that physically associate with Cdc14 and are thus potential substrates, including 53 proteins that we know are involved in many cell cycle processes that are necessary for nuclear and cell division. Thus, we have laid the ground work to study how changes in chromosomal composition may arise due to errors in nuclear division in this important pathogen. Unexpectedly, we found that Cdc14 may also act on proteins involved in the synthesis of ergosterol, a key lipid in the cell membrane. Azoles, a major class of antifungal drugs, inhibit the synthesis of ergosterol, so Cdc14 may also be involved in the action of azoles and thus one possible way in which drug resistance arises.

cell biology↗

bioRxiv2018

Characteristics of the mitochondrial and cellular uptake of MPP+, as probed by the fluorescent mimic, 4′I-MPP+

The discovery that 1-methyl-4-phenylpyridinium (MPP+) selectively destroys dopaminergic neurons and causes Parkinsons disease (PD) symptoms in mammals has strengthened the environmental hypothesis of PD. The current model for the dopaminergic toxicity of MPP+ is centered on the uptake into dopaminergic neurons, accumulation into the mitochondria, inhibition of the complex-I leading to ATP depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death. However, some aspects of this mechanism and the details of the cellular and mitochondrial accumulation of MPP+ are still poorly understood. The aim of this study was to characterize a structural and functional MPP+ mimic which is suitable to study the cellular distribution and mitochondrial uptake of MPP+ in live cells and use it to identify the molecular details of these processes to advance the understanding of the mechanism of the selective dopaminergic toxicity of MPP+. Here we report the characterization of the fluorescent MPP+ derivative, 1-methyl-4-(4-iodophenyl)pyridinium (4I-MPP+), as a suitable candidate for this purpose. Using this novel probe, we show that cytosolic/mitochondrial Ca2+ play a critical role through sodium-calcium exchanger (NCX) in the mitochondrial and cellular accumulation of MPP+ suggesting for the first time that MPP+ and related mitochondrial toxins may also exert their toxic effects through the perturbation of Ca2+ homeostasis in dopaminergic cells. We also found that the specific mitochondrial NCX (mNCX) inhibitors protect dopaminergic cells from the MPP+ and 4I-MPP+ toxicity, most likely through the inhibition of the mitochondrial uptake, which could potentially be exploited for the development of pharmacological agents to protect the central nervous system (CNS) dopaminergic neurons from PD-causing environmental toxins.

neuroscience↗

bioRxiv2018

Escherichia coli Bcteriuria in pregnant women in Ghana: Antibiotic resistance pattern, Virulence Factors and Resistant genetic markers.

The relevance of Escherichia coli associated bacteriuria infection in pregnant women is poorly understood, despite these strains sharing a similar virulence profile with other extra intestinal pathogenic E. coli producing severe obstetric and neonatal infections. We characterized and determined the antimicrobial susceptibility, resistant genes and virulence profiles of 82 E. coli isolates associated with asymptomatic bacteriuria in some pregnant in five very distinct hospitals in the Volta region from January, 2016 to April, 2016 using Kirby-Bauer disc diffusion and polymerase chain reaction.\n\nHigh levels of antimicrobial resistance was observed to Ampicillin (79.3%), Tetracycline (70.7%) and Cotrimoxazole (59.8%), except for Cefuroxime (32.9%). Resistant genes analyses revealed 58.5% were positive for BlaTEM and 14.6% for aph(3)-Ia(aphA2). Virulence factors (VFs) was more widespread in pregnant women in the 2nd and 3rd trimesters than 1st trimester. VFs relating to adhesion (papC and iha), Protectins (traT), aerobactin acquisition (iutA) and iron acquisition systems (fyuA and irp2) were more prevalent in the resistant E. coli isolates. This study provides additional evidence for a link in bacteriuria and transmission of extra-intestinal E. coli in pregnant women to cause multi-resistant severe obstetric or neonatal infections. Considering the involvement of extra-intestinal E. coli in infections, our results may be helpful to develop strategies to prevent maternal and/ neonatal infections. In addition continuous surveillance is required to guide appropriate antibiotic usage in pregnant women.

microbiology↗