Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention

The Quantitative-MFG Test: A linear mixed effect model to detect maternal-offspring gene interactions

Maternal-offspring gene interactions, aka maternal-fetal genotype (MFG) incompatibilities, are neglected in complex diseases and quantitative trait studies. They are implicated in birth to adult onset diseases but there are limited ways to investigate their influence on quantitative traits. We present the Quantitative-MFG (QMFG) test, a linear mixed model where maternal and offspring genotypes are fixed effects and residual correlations between family members are random effects. The QMFG handles families of any size, common or general scenarios of MFG incompatibility, and additional covariates. We develop likelihood ratio tests (LRTs) and rapid score tests and show they provide correct inference. In addition, the LRT’s alternative model provides unbiased parameter estimates. We show that testing the association of SNPs by fitting a standard model, which only considers the offspring genotypes, has very low power or can lead to incorrect conclusions. We also show that offspring genetic effects are missed if the MFG modeling assumptions are too restrictive. With GWAS data from the San Antonio Family Heart Study, we demonstrate that the QMFG score test is an effective and rapid screening tool. The QMFG test therefore has important potential to identify pathways of complex diseases for which the genetic etiology remains to be discovered

Adverse and Positive Childhood Experiences of Clinical Mental Health Counselors as Predictors of Compassion Satisfaction, Burnout, and Secondary Traumatic Stress

Despite an emphasis on self-care to avoid burnout and increase compassion satisfaction within the counseling profession, there is a dearth of research on the developmental experiences of counselors that may increase the likelihood of burnout. We examined the impact of mental health counselors’ (N = 140) experiences of adverse childhood experiences and positive childhood experiences on their present rates of compassion satisfaction, burnout, and secondary traumatic stress. We used a cross-sectional, non-experimental correlational design and reported descriptive statistics as well as results of multiple regression models. Results indicated significant relationships among counselors’ rates of adverse childhood experiences, positive childhood experiences, and compassion satisfaction and burnout. We include implications for the use of both the adverse and positive childhood experiences assessments in the training of counseling students and supervisees

Identifying missing dictionary entries with frequency-conserving context models

In an effort to better understand meaning from natural language texts, we explore methods aimed at organizing lexical objects into contexts. A number of these methods for organization fall into a family defined by word ordering. Unlike demographic or spatial partitions of data, these collocation models are of special importance for their universal applicability. While we are interested here in text and have framed our treatment appropriately, our work is potentially applicable to other areas of research (e.g., speech, genomics, and mobility patterns) where one has ordered categorical data (e.g., sounds, genes, and locations). Our approach focuses on the phrase (whether word or larger) as the primary meaning-bearing lexical unit and object of study. To do so, we employ our previously developed framework for generating word-conserving phrase-frequency data. Upon training our model with the Wiktionary, an extensive, online, collaborative, and open-source dictionary that contains over 100000 phrasal definitions, we develop highly effective filters for the identification of meaningful, missing phrase entries. With our predictions we then engage the editorial community of the Wiktionary and propose short lists of potential missing entries for definition, developing a breakthrough, lexical extraction technique and expanding our knowledge of the defined English lexicon of phrases

Cryptic marine barriers to gene flow in a vulnerable coastal species, the dugong (Dugong dugon)

Despite the lack of obvious physical barriers and their ability to travel significant distances, many marine mammals exhibit substantial population structuring over relatively short geographical distances. The dugong (Dugong dugon), the only extant representative of family Dugongidae, is listed as Vulnerable to Extinction globally. We investigated the genetic population structure of dugongs in the shallow coastal waters along >2,000 km of the eastern Queensland coast, including the Great Barrier Reef region. Microsatellite genotypes for 22 loci in 293 dugongs, SNP genotypes based on 10,690 loci in 43 dugongs, and 410 bp mitochondrial control-region sequences from 639 dugongs were analyzed. Clustering analysis techniques consistently identified an abrupt genetic break in the Whitsunday Islands region (20.3°S), which interrupts an overall pattern of isolation-by-distance. Geographic distance was relatively more important than sea-surface temperature and seagrass distribution in explaining pairwise microsatellite genetic distances. The cause of reduced dispersal across this region is unknown but might relate to an unusual tidal and current mix, termed the “sticky-water” effect, and/or a break in the geographical distribution of off-shore seagrass meadows. The genetic structure suggests distinct breeding units north and south of the Whitsunday Islands region for consideration in further developing management plans for Queensland dugongs

Hot orogens and supercontinent amalgamation: A Gondwanan example from southern India

The Southern Granulite Terrane in southern India preserves evidence for regional-scale high to ultrahigh temperature metamorphism related to the amalgamation of the supercontinent Gondwana. Here we present accessory mineral (zircon and monazite) geochronological and geochemical datasets linked to the petrological evolution of the rocks as determined by phase equilibria modelling. The results constrain the duration of high to ultrahigh temperature (> 900 °C) metamorphism in the Madurai Block to be c. 40 Ma with peak conditions achieved c. 60 Ma after the formation of an orogenic plateau related to the collision of the microcontinent Azania with East Africa at c. 610 Ma. A 1D numerical model demonstrates that the attainment of temperatures > 900 °C requires that the crust be moderately enriched in heat producing elements and that the duration of the orogenic event is sufficiently long to allow conductive heating through radioactive decay. Both of these conditions are met by the available data for the Madurai Block. Our results constrain the length of time it takes for the crust to evolve from collision to peak P–T (i.e. the prograde heating phase) then back to the solidus during retrogression. This evolution illustrates that not all metamorphic ages date sutures

Effects of Social Cues on Biosecurity Compliance in Livestock Facilities: Evidence From Experimental Simulations

Disease outbreaks in U.S. animal livestock industries have economic impacts measured in hundreds of millions of dollars per year. Biosecurity, or procedures intended to protect animals against disease, is known to be effective at reducing infection risk at facilities. Yet, to the detriment of animal health, humans do not always follow biosecurity protocols. Human behavioral factors have been shown to influence willingness to follow biosecurity protocols. Here we show how social cues may affect cooperation with a biosecurity practice. Participants were immersed in a simulated swine production facility through a graphical user interface and prompted to make a decision that addressed their willingness to comply with a biosecurity practice. We tested the effect of varying three experimental variables: (1) the risk of acquiring an infection, (2) the delivery method of the infection risk information (numerical vs. graphical), and (3) the behavior of an automated coworker in the facility. We provide evidence that participants changed their behavior when they observed a simulated worker making a choice to follow or not follow a biosecurity protocol, even though the simulated worker had no economic effect on the participants\u27 payouts. These results advance the understanding of human behavioral effects on biosecurity protocol decisions, demonstrating that social cues need to be considered by livestock facility managers when developing policies to make agricultural systems more disease resilient

A porcine model system of BRCA1 driven breast cancer

BRCA1 is a breast and ovarian tumor suppressor. Hereditary mutations in BRCA1 result in a predisposition to breast cancer, and BRCA1 expression is down-regulated in ~30% of sporadic cases. The function of BRCA1 remains poorly understood, but it appears to play an important role in DNA repair and the maintenance of genetic stability. Mouse models of BRCA1 deficiency have been developed in an attempt to understand the role of the gene in vivo. However, the subtle nature of BRCA1 function and the well-known discrepancies between human and murine breast cancer biology and genetics may limit the utility of mouse systems in defining the function of BRCA1 in cancer and validating the development of novel therapeutics for breast cancer. In contrast to mice, pig biological systems and cancer genetics appear to more closely resemble their human counterparts. To determine if BRCA1 inactivation in pig cells promotes their transformation and may serve as a model for the human disease, we developed an immortalized porcine breast cell line and stably inactivated BRCA1 using miRNA. The cell line developed characteristics of breast cancer stem cells and exhibited a transformed phenotype. These results validate the concept of using pigs as a model to study BRCA1 defects in breast cancer and establish the first porcine breast tumor cell line