@article{monangi_xu_khanam_khan_deb_pervin_price_kennedy_al mahmud_fan_et al._2021, title={Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis}, volume={6}, ISSN={["2059-7908"]}, DOI={10.1136/bmjgh-2021-005856}, abstractNote={Background Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations. Methods Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis. Findings In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi. Interpretation While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.}, number={9}, journal={BMJ GLOBAL HEALTH}, author={Monangi, Nagendra and Xu, Huan and Khanam, Rasheda and Khan, Waqasuddin and Deb, Saikat and Pervin, Jesmin and Price, Joan T. and Kennedy, Stephen H. and Al Mahmud, Abdullah and Fan, Yuemei and et al.}, year={2021}, month={Sep} }
 @article{nosbisch_rahman_mohan_elston_bear_haugh_2020, title={Mechanistic models of PLC/PKC signaling implicate phosphatidic acid as a key amplifier of chemotactic gradient sensing}, volume={16}, ISSN={["1553-7358"]}, DOI={10.1371/journal.pcbi.1007708}, abstractNote={Chemotaxis of fibroblasts and other mesenchymal cells is critical for embryonic development and wound healing. Fibroblast chemotaxis directed by a gradient of platelet-derived growth factor (PDGF) requires signaling through the phospholipase C (PLC)/protein kinase C (PKC) pathway. Diacylglycerol (DAG), the lipid product of PLC that activates conventional PKCs, is focally enriched at the up-gradient leading edge of fibroblasts responding to a shallow gradient of PDGF, signifying polarization. To explain the underlying mechanisms, we formulated reaction-diffusion models including as many as three putative feedback loops based on known biochemistry. These include the previously analyzed mechanism of substrate-buffering by myristoylated alanine-rich C kinase substrate (MARCKS) and two newly considered feedback loops involving the lipid, phosphatidic acid (PA). DAG kinases and phospholipase D, the enzymes that produce PA, are identified as key regulators in the models. Paradoxically, increasing DAG kinase activity can enhance the robustness of DAG/active PKC polarization with respect to chemoattractant concentration while decreasing their whole-cell levels. Finally, in simulations of wound invasion, efficient collective migration is achieved with thresholds for chemotaxis matching those of polarization in the reaction-diffusion models. This multi-scale modeling framework offers testable predictions to guide further study of signal transduction and cell behavior that affect mesenchymal chemotaxis.}, number={4}, journal={PLOS COMPUTATIONAL BIOLOGY}, author={Nosbisch, Jamie L. and Rahman, Anisur and Mohan, Krithika and Elston, Timothy C. and Bear, James E. and Haugh, Jason M.}, year={2020}, month={Apr} }
 @article{rahman_haugh_2017, title={Kinetic Modeling and Analysis of the Akt/Mechanistic Target of Rapamycin Complex 1 (mTORC1) Signaling Axis Reveals Cooperative, Feedforward Regulation}, volume={292}, ISSN={["1083-351X"]}, DOI={10.1074/jbc.m116.761205}, abstractNote={Mechanistic target of rapamycin complex 1 (mTORC1) controls biosynthesis and has been implicated in uncontrolled cell growth in cancer. Although many details of mTORC1 regulation are well understood, a systems-level, predictive framework synthesizing those details is currently lacking. We constructed various mathematical models of mTORC1 activation mediated by Akt and aligned the model outputs to kinetic data acquired for growth factor-stimulated cells. A model based on a putative feedforward loop orchestrated by Akt consistently predicted how the pathway was altered by depletion of key regulatory proteins. Analysis of the successful model also elucidates two dynamical motifs: neutralization of a negative regulator, which characterizes how Akt indirectly activates mTORC1, and seesaw enzyme regulation, which describes how activated and inhibited states of mTORC1 are controlled in concert to produce a nonlinear, ultrasensitive response. Such insights lend quantitative understanding of signaling networks and their precise manipulation in various contexts.}, number={7}, journal={JOURNAL OF BIOLOGICAL CHEMISTRY}, publisher={American Society for Biochemistry & Molecular Biology (ASBMB)}, author={Rahman, Anisur and Haugh, Jason M.}, year={2017}, month={Feb}, pages={2866–2872} }
 @article{ahmed_grant_edwards_rahman_cirit_goshe_haugh_2014, title={Data-driven modeling reconciles kinetics of ERK phosphorylation, localization, and activity states}, volume={10}, ISSN={["1744-4292"]}, DOI={10.1002/msb.134708}, abstractNote={Abstract}, number={1}, journal={MOLECULAR SYSTEMS BIOLOGY}, publisher={Wiley-Blackwell}, author={Ahmed, Shoeb and Grant, Kyle G. and Edwards, Laura E. and Rahman, Anisur and Cirit, Murat and Goshe, Michael B. and Haugh, Jason M.}, year={2014}, month={Jan} }
 @article{rahman_haugh_2014, title={Deactivation of a Negative Regulator: A Distinct Signal Transduction Mechanism, Pronounced in Akt Signaling}, volume={107}, ISSN={["1542-0086"]}, DOI={10.1016/j.bpj.2014.10.003}, abstractNote={Kinase cascades, in which enzymes are sequentially activated by phosphorylation, are quintessential signaling pathways. Signal transduction is not always achieved by direct activation, however. Often, kinases activate pathways by deactivation of a negative regulator; this indirect mechanism, pervasive in Akt signaling, has yet to be systematically explored. Here, we show that the indirect mechanism has properties that are distinct from direct activation. With comparable parameters, the indirect mechanism yields a broader range of sensitivity to the input, beyond saturation of regulator phosphorylation, and kinetics that become progressively slower, not faster, with increasing input strength. These properties can be integrated in network motifs to produce desired responses, as in the case of feedforward loops.}, number={10}, journal={BIOPHYSICAL JOURNAL}, publisher={Elsevier BV}, author={Rahman, Anisur and Haugh, Jason M.}, year={2014}, month={Nov}, pages={L29–L32} }
 @article{asokan_johnson_rahman_king_rotty_lebedeva_haugh_bear_2014, title={Mesenchymal Chemotaxis Requires Selective Inactivation of Myosin II at the Leading Edge via a Noncanonical PLC gamma/PKC alpha Pathway}, volume={31}, ISSN={["1878-1551"]}, DOI={10.1016/j.devcel.2014.10.024}, abstractNote={Chemotaxis, migration toward soluble chemical cues, is critical for processes such as wound healing and immune surveillance and is exhibited by various cell types, from rapidly migrating leukocytes to slow-moving mesenchymal cells. To study mesenchymal chemotaxis, we observed cell migration in microfluidic chambers that generate stable gradients of platelet-derived growth factor (PDGF). Surprisingly, we found that pathways implicated in amoeboid chemotaxis, such as PI3K and mammalian target of rapamycin signaling, are dispensable for PDGF chemotaxis. Instead, we find that local inactivation of Myosin IIA, through a noncanonical Ser1/2 phosphorylation of the regulatory light chain, is essential. This site is phosphorylated by PKCα, which is activated by an intracellular gradient of diacylglycerol generated by PLCγ. Using a combination of live imaging and gradients of activators/inhibitors in the microfluidic chambers, we demonstrate that this signaling pathway and subsequent inhibition of Myosin II activity at the leading edge are required for mesenchymal chemotaxis.}, number={6}, journal={DEVELOPMENTAL CELL}, publisher={Elsevier BV}, author={Asokan, Sreeja B. and Johnson, Heath E. and Rahman, Anisur and King, Samantha J. and Rotty, Jeremy D. and Lebedeva, Irina P. and Haugh, Jason M. and Bear, James E.}, year={2014}, month={Dec}, pages={747–760} }