Graph algorithms for predicting subcellular localization at the pathway level

Protein subcellular localization is an important factor in normal cellular processes and disease. While many protein localization resources treat it as static, protein localization is dynamic and heavily influenced by biological context. Biological pathways are graphs that represent a specific biological context and can be inferred from large-scale data. We develop graph algorithms to predict the localization of all interactions in a biological pathway as an edge-labeling task. We compare a variety of models including graph neural networks, probabilistic graphical models, and discriminative classifiers for predicting localization annotations from curated pathway databases. We also perform a case study where we construct biological pathways and predict localizations of human fibroblasts undergoing viral infection. Pathway localization prediction is a promising approach for integrating publicly available localization data into the analysis of large-scale biological data.Comment: 35 pages, 14 figure

Automating parameter selection to avoid implausible biological pathway models

Abstract A common way to integrate and analyze large amounts of biological “omic” data is through pathway reconstruction: using condition-specific omic data to create a subnetwork of a generic background network that represents some process or cellular state. A challenge in pathway reconstruction is that adjusting pathway reconstruction algorithms’ parameters produces pathways with drastically different topological properties and biological interpretations. Due to the exploratory nature of pathway reconstruction, there is no ground truth for direct evaluation, so parameter tuning methods typically used in statistics and machine learning are inapplicable. We developed the pathway parameter advising algorithm to tune pathway reconstruction algorithms to minimize biologically implausible predictions. We leverage background knowledge in pathway databases to select pathways whose high-level structure resembles that of manually curated biological pathways. At the core of this method is a graphlet decomposition metric, which measures topological similarity to curated biological pathways. In order to evaluate pathway parameter advising, we compare its performance in avoiding implausible networks and reconstructing pathways from the NetPath database with other parameter selection methods across four pathway reconstruction algorithms. We also demonstrate how pathway parameter advising can guide reconstruction of an influenza host factor network. Pathway parameter advising is method agnostic; it is applicable to any pathway reconstruction algorithm with tunable parameters

Cardiovascular health care and health literacy among immigrants in Europe: a review of challenges and opportunities during the COVID-19 pandemic

Objectives: Europe is a destination for many migrants, a group whose proportion of the overall population will increase over the next decades. The cardiovascular (CV) risk distribution and outcomes, as well as health literacy, are likely to differ from the host population. Challenges related to migrant health status, cardiovascular risk distribution and health literacy are compounded by the ongoing coronavirus disease 2019 (COVID-2019) crisis. Methods: We performed a narrative review of available evidence on migrant CV and health literacy in Europe. Results: Health literacy is lower in migrants but can be improved through targeted interventions. In some subgroups of migrants, rates of cardiovascular disease (CVD) risk factors, most importantly hypertension and diabetes, are higher. On the other hand, there is strong evidence for a so-called healthy migrant effect, describing lower rates of CV risk distribution and mortality in a different subset of migrants. During the COVID-19 pandemic, CV risk factors, as well as health literacy, are key elements in optimally managing public health responses in the ongoing pandemic. Conclusions: Migrants are both an opportunity and a challenge for public health in Europe. Research aimed at better understanding the healthy migrant effect is necessary. Implementing the beneficial behaviors of migrants could improve outcomes in the whole population. Specific interventions to screen for risk factors, manage chronic disease and increase health literacy could improve health care for migrants. This pandemic is a challenge for the whole population, but active inclusion of immigrants in established health care systems could help improve the long-term health outcomes of migrants in Europe

Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight

Maintenance of a reduced body weight is accompanied by decreased energy expenditure that is due largely to increased skeletal muscle work efficiency. In addition, decreased sympathetic nervous system tone and circulating concentrations of leptin, thyroxine, and triiodothyronine act coordinately to favor weight regain. These “weight-reduced” phenotypes are similar to those of leptin-deficient humans and rodents. We examined metabolic, autonomic, and neuroendocrine phenotypes in 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) under 3 sets of experimental conditions: (a) maintaining usual weight by ingesting a liquid formula diet; (b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and (c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre–weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight. During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre–weight-loss levels. These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state

HIV-1 virological synapse formation enhances infection spread by dysregulating Aurora Kinase B.

HIV-1 spreads efficiently through direct cell-to-cell transmission at virological synapses (VSs) formed by interactions between HIV-1 envelope proteins (Env) on the surface of infected cells and CD4 receptors on uninfected target cells. Env-CD4 interactions bring the infected and uninfected cellular membranes into close proximity and induce transport of viral and cellular factors to the VS for efficient virion assembly and HIV-1 transmission. Using novel, cell-specific stable isotope labeling and quantitative mass spectrometric proteomics, we identified extensive changes in the levels and phosphorylation states of proteins in HIV-1 infected producer cells upon mixing with CD4+ target cells under conditions inducing VS formation. These coculture-induced alterations involved multiple cellular pathways including transcription, TCR signaling and, unexpectedly, cell cycle regulation, and were dominated by Env-dependent responses. We confirmed the proteomic results using inhibitors targeting regulatory kinases and phosphatases in selected pathways identified by our proteomic analysis. Strikingly, inhibiting the key mitotic regulator Aurora kinase B (AURKB) in HIV-1 infected cells significantly increased HIV activity in cell-to-cell fusion and transmission but had little effect on cell-free infection. Consistent with this, we found that AURKB regulates the fusogenic activity of HIV-1 Env. In the Jurkat T cell line and primary T cells, HIV-1 Env:CD4 interaction also dramatically induced cell cycle-independent AURKB relocalization to the centromere, and this signaling required the long (150 aa) cytoplasmic C-terminal domain (CTD) of Env. These results imply that cytoplasmic/plasma membrane AURKB restricts HIV-1 envelope fusion, and that this restriction is overcome by Env CTD-induced AURKB relocalization. Taken together, our data reveal a new signaling pathway regulating HIV-1 cell-to-cell transmission and potential new avenues for therapeutic intervention through targeting the Env CTD and AURKB activity

Kinase activity.

Kinase activities from the phosphorylation log2 fold changes at 5 min using PhosFate Profiler. PhosFate Profiler computes an enrichment score for kinases using the Kolmogorov–Smirnov statistical test, a p-value, and a kinase activity, where a positive score indicates an increase and a negative score a decrease in kinase activity. (XLSX)</p

HIV Env CTD relocalizes AURKB adjacent to inner centromeres.

(A) Jurkat cells expressing a fluorescent AURKB, fluorescent γ-tubulin and full length or ΔCTD variants of a CXCR4 HIV envelope (NL43), a CCR5 tropic HIV envelope (SF162) or amphotropic MLV envelope were mixed for 20 minutes with HeLa cells expressing fluorescent CD4-CFP, fixed, mounted and imaged at 60X by confocal microscopy. (B) HIV producer cells (Jurkat) were co-transfected with plasmids containing an HIV genome expressing the HIV matrix fused to a fluorescent protein (iRFP670) and plasmids encoding WT env or a variant lacking the cytoplasmic tail domain (CTD) and plasmids encoding a fluorescent (GFP) AURKB fusion and plasmids encoding fluorescently tagged (mCherry) variants of the inner centromere protein CENPB. Transfected cells were mixed with cells expressing the HIV receptor and co-receptors (TZM-bl) or receptor negative (HeLa) cells for 20 minutes, fixed, mounted and imaged at 60X by confocal microscopy. Consistent with relocalization to the CPC, AURKB relocalized to puncta adjacent to CENPB puncta. This relocalization requires the Env CTD and receptor on target cells. (C) Quantitation of AURKB relocalization. HIV producer cells (Jurkat) were co-transfected with plasmids containing an HIV genome and plasmids encoding X4 tropic (NL43) or R5 tropic (SF162) WT env, a variant lacking the cytoplasmic tail domain (CTD), or amphotropic MLV envelope along with plasmids encoding fluorescent fusion proteins GFP-AURKB and mCherry-CENPB. Transfected cells were mixed with cells expressing the HIV receptor and co-receptors (TZM-bl) or receptor free cells (HeLa) cells for 20 minutes, fixed, mounted and imaged at 60X by confocal microscopy. 10 individual fields were counted and transfected cells with AURKB puncta were counted. The data shown are the average mean values from 10 independent fields and are representative of three independent experiments. Error bars indicate the standard deviation of the data in all panels. P-values were calculated using a standard Student’s t-test and significant changes between CD4 expressing HeLa cells relative to CD4 negative HeLa are indicated.</p