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1416 Publications

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    10/18/21 | The power of peer networking for improving STEM faculty job applications: a successful pilot program
    Guardia CM, Kane E, Tebo AG, Sanders AA, Kaya D, Grogan KE
    bioRxiv. 10/2021:. doi: 10.1101/2021.10.16.464662

    In order to successfully obtain a faculty position, postdoctoral fellows or ‘postdocs’, must submit an application which requires considerable time and effort to produce. These job applications are often reviewed by mentors and colleagues, but rarely are postdocs offered the opportunity to solicit feedback multiple times from reviewers with the same breadth of expertise often found on an academic search committee. To address this gap, this manuscript describes an international peer reviewing program for small groups of postdocs with a broad range of expertise to reciprocally and iteratively provide feedback to each other on their application materials. Over 145 postdocs have participated, often multiple times, over three years. A survey of participants in this program revealed that nearly all participants would recommend participation in such a program to other faculty applicants. Furthermore, this program was more likely to attract participants who struggled to find mentoring and support elsewhere, either because they changed fields or because of their identity as a woman or member of an underrepresented population in STEM. Participation in programs like this one could provide early career academics like postdocs with a diverse and supportive community of peer mentors during the difficult search for a faculty position. Such psychosocial support and encouragement has been shown to prevent attrition of individuals from these populations and programs like this one target the largest ‘leak’ in the pipeline, that of postdoc to faculty. Implementation of similar peer reviewing programs by universities or professional scientific societies could provide a valuable mechanism of support and increased chances of success for early-career academics in their search for independence.Competing Interest StatementThe authors have declared no competing interest.

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    09/11/21 | Erratum: Label-free imaging of fibroblast membrane interfaces and protein signatures with vibrational infrared photothermal and phase signals: publisher's note.
    Samolis PD, Langley D, O'Reilly BM, Oo Z, Hilzenrat G, Erramilli S, Sgro AE, McArthur S, Sander MY
    Biomed Opt Express. 09/2021;12(9):5400. doi: 10.1364/BOE.438946

    [This corrects the article on p. 303 in vol. 12, PMID: 33520386.].

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    09/06/21 | Nitrite reductase activity within an antiparallel de novo scaffold.
    Koebke KJ, Tebo AG, Manickas EC, Deb A, Penner-Hahn JE, Pecoraro VL
    JBIC Journal of Biological Inorganic Chemistry. 09/2021;26(7):855 - 862. doi: 10.1007/s00775-021-01889-1

    Copper nitrite reductase (CuNiR) is a copper enzyme that converts nitrite to nitric oxide and is an important part of the global nitrogen cycle in bacteria. The relatively simple CuHis3 binding site of the CuNiR active site has made it an enticing target for small molecule modeling and de novo protein design studies. We have previously reported symmetric CuNiR models within parallel three stranded coiled coil systems, with activities that span a range of three orders of magnitude. In this report, we investigate the same CuHis3 binding site within an antiparallel three helical bundle scaffold, which allows the design of asymmetric constructs. We determine that a simple CuHis3 binding site can be designed within this scaffold with enhanced activity relative to the comparable construct in parallel coiled coils. Incorporating more complex designs or repositioning this binding site can decrease this activity as much as 15 times. Comparing these constructs, we reaffirm a previous result in which a blue shift in the 1s to 4p transition energy determined by Cu(I) X-ray absorption spectroscopy is correlated with an enhanced activity within imidazole-based constructs. With this step and recent successful electron transfer site designs within this scaffold, we are one step closer to a fully functional de novo designed nitrite reductase.

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    09/02/21 | Principles of signaling pathway modulation for enhancing human naive pluripotency induction.
    Bayerl J, Ayyash M, Shani T, Manor YS, Gafni O, Massarwa R, Kalma Y, Aguilera-Castrejon A, Zerbib M, Amir H, Sheban D, Geula S, Mor N, Weinberger L, Naveh Tassa S, Krupalnik V, Oldak B, Livnat N, Tarazi S, Tawil S, Wildschutz E, Ashouokhi S, Lasman L, Rotter V, Hanna S, Ben-Yosef D, Novershtern N, Viukov S, Hanna JH
    Cell Stem Cell. 09/2021;28(9):1549-1565.e12. doi: 10.1016/j.stem.2021.04.001

    Isolating human MEK/ERK signaling-independent pluripotent stem cells (PSCs) with naive pluripotency characteristics while maintaining differentiation competence and (epi)genetic integrity remains challenging. Here, we engineer reporter systems that allow the screening for defined conditions that induce molecular and functional features of human naive pluripotency. Synergistic inhibition of WNT/β-CATENIN, protein kinase C (PKC), and SRC signaling consolidates the induction of teratoma-competent naive human PSCs, with the capacity to differentiate into trophoblast stem cells (TSCs) and extraembryonic naive endodermal (nEND) cells in vitro. Divergent signaling and transcriptional requirements for boosting naive pluripotency were found between mouse and human. P53 depletion in naive hPSCs increased their contribution to mouse-human cross-species chimeric embryos upon priming and differentiation. Finally, MEK/ERK inhibition can be substituted with the inhibition of NOTCH/RBPj, which induces alternative naive-like hPSCs with a diminished risk for deleterious global DNA hypomethylation. Our findings set a framework for defining the signaling foundations of human naive pluripotency.

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    08/19/21 | Ventral stress fibers induce plasma membrane deformation in human fibroblasts.
    Ghilardi SJ, Aronson MS, Sgro AE
    Mol Biol Cell. 08/2021;32(18):1707-1723. doi: 10.1091/mbc.E21-03-0096

    Interactions between the actin cytoskeleton and the plasma membrane are important in many eukaryotic cellular processes. During these processes, actin structures deform the cell membrane outward by applying forces parallel to the fiber's major axis (as in migration) or they deform the membrane inward by applying forces perpendicular to the fiber's major axis (as in the contractile ring during cytokinesis). Here we describe a novel actin-membrane interaction in human dermal myofibroblasts. When labeled with a cytosolic fluorophore, the myofibroblasts displayed prominent fluorescent structures on the ventral side of the cell. These structures are present in the cell membrane and colocalize with ventral actin stress fibers, suggesting that the stress fibers bend the membrane to form a "cytosolic pocket" that the fluorophores diffuse into, creating the observed structures. The existence of this pocket was confirmed by transmission electron microscopy. While dissolving the stress fibers, inhibiting fiber protein binding, or inhibiting myosin II binding of actin removed the observed pockets, modulating cellular contractility did not remove them. Taken together, our results illustrate a novel actin-membrane bending topology where the membrane is deformed outward rather than being pinched inward, resembling the topological inverse of the contractile ring found in cytokinesis.

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    05/26/21 | An Accumulation-of-Evidence Task Using Visual Pulses for Mice Navigating in Virtual Reality
    Pinto L, Koay SA, Engelhard B, Yoon AM, Deverett B, Thiberge SY, Witten IB, Tank DW, Brody CD
    Frontiers in Behavioral Neuroscience. Jun-03-2018;12:. doi: 10.3389/fnbeh.2018.00036

    The gradual accumulation of sensory evidence is a crucial component of perceptual decision making, but its neural mechanisms are still poorly understood. Given the wide availability of genetic and optical tools for mice, they can be useful model organisms for the study of these phenomena; however, behavioral tools are largely lacking. Here, we describe a new evidence-accumulation task for head-fixed mice navigating in a virtual reality (VR) environment. As they navigate down the stem of a virtual T-maze, they see brief pulses of visual evidence on either side, and retrieve a reward on the arm with the highest number of pulses. The pulses occur randomly with Poisson statistics, yielding a diverse yet well-controlled stimulus set, making the data conducive to a variety of computational approaches. A large number of mice of different genotypes were able to learn and consistently perform the task, at levels similar to rats in analogous tasks. They are sensitive to side differences of a single pulse, and their memory of the cues is stable over time. Moreover, using non-parametric as well as modeling approaches, we show that the mice indeed accumulate evidence: they use multiple pulses of evidence from throughout the cue region of the maze to make their decision, albeit with a small overweighting of earlier cues, and their performance is affected by the magnitude but not the duration of evidence. Additionally, analysis of the mice's running patterns revealed that trajectories are fairly stereotyped yet modulated by the amount of sensory evidence, suggesting that the navigational component of this task may provide a continuous readout correlated to the underlying cognitive variables. Our task, which can be readily integrated with state-of-the-art techniques, is thus a valuable tool to study the circuit mechanisms and dynamics underlying perceptual decision making, particularly under more complex behavioral contexts.


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    05/19/21 | Multimodal patterns of inhibitory activity in cerebellar cortex
    Chie Satou , Rainer W. Friedrich
    Neuron. 05/2021;109:1590-1592. doi:

    In this issue of Neuron, Gurnani and Silver (2021) report that activity across Golgi cells, a major type of inhibitory interneuron in the cerebellar cortex, is multidimensional and modulated by behavior. These results suggest multiple functions for inhibition in cerebellar computations.

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    05/05/21 | Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis.
    Aguilera-Castrejon A, Oldak B, Shani T, Ghanem N, Itzkovich C, Slomovich S, Tarazi S, Bayerl J, Chugaeva V, Ayyash M, Ashouokhi S, Sheban D, Livnat N, Lasman L, Viukov S, Zerbib M, Addadi Y, Rais Y, Cheng S, Stelzer Y, Keren-Shaul H, Shlomo R, Massarwa R, Novershtern N, Maza I, Hanna JH
    Nature. 05/2021;593(7857):119-124. doi: 10.1038/s41586-021-03416-3

    The mammalian body plan is established shortly after the embryo implants into the maternal uterus, and our understanding of post-implantation developmental processes remains limited. Although pre- and peri-implantation mouse embryos are routinely cultured in vitro, approaches for the robust culture of post-implantation embryos from egg cylinder stages until advanced organogenesis remain to be established. Here we present highly effective platforms for the ex utero culture of post-implantation mouse embryos, which enable the appropriate development of embryos from before gastrulation (embryonic day (E) 5.5) until the hindlimb formation stage (E11). Late gastrulating embryos (E7.5) are grown in three-dimensional rotating bottles, whereas extended culture from pre-gastrulation stages (E5.5 or E6.5) requires a combination of static and rotating bottle culture platforms. Histological, molecular and single-cell RNA sequencing analyses confirm that the ex utero cultured embryos recapitulate in utero development precisely. This culture system is amenable to the introduction of a variety of embryonic perturbations and micro-manipulations, the results of which can be followed ex utero for up to six days. The establishment of a system for robustly growing normal mouse embryos ex utero from pre-gastrulation to advanced organogenesis represents a valuable tool for investigating embryogenesis, as it eliminates the uterine barrier and allows researchers to mechanistically interrogate post-implantation morphogenesis and artificial embryogenesis in mammals.

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    04/01/21 | Arnold tongues in oscillator systems with nonuniform spatial driving.
    Golden A, Sgro AE, Mehta P
    Phys Rev E. 04/2021;103(4-1):042211. doi: 10.1103/PhysRevE.103.042211

    Nonlinear oscillator systems are ubiquitous in biology and physics, and their control is a practical problem in many experimental systems. Here we study this problem in the context of the two models of spatially coupled oscillators: the complex Ginzburg-Landau equation (CGLE) and a generalization of the CGLE in which oscillators are coupled through an external medium (emCGLE). We focus on external control drives that vary in both space and time. We find that the spatial distribution of the drive signal controls the frequency ranges over which oscillators synchronize to the drive and that boundary conditions strongly influence synchronization to external drives for the CGLE. Our calculations also show that the emCGLE has a low density regime in which a broad range of frequencies can be synchronized for low drive amplitudes. We study the bifurcation structure of these models and find that they are very similar to results for the driven Kuramoto model, a system with no spatial structure. We conclude by discussing qualitative implications of our results for controlling coupled oscillator systems such as the social amoebae Dictyostelium and populations of Belousov Zhabotinsky (BZ) catalytic particles using spatially structured external drives.

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    03/15/21 | Enhanced Photoinduced Electron Transfer Through a Tyrosine Relay in a De Novo Designed Protein Scaffold Bearing a Photoredox Unit and a Fe <sup>II</sup> S <sub>4</sub> Site
    Tebo A, Quaranta A, Pecoraro VL, Aukauloo A
    ChemPhotoChem. 03/2021;5(7):665 - 668. doi: 10.1002/cptc.v5.710.1002/cptc.202100014

    Electron transfer (ET) processes in biology over long distances often proceed via a series of hops, which reduces the distance dependence of the rate of ET. The protein matrix itself can be involved in mediating ET directly through the participation of redox-active amino acids. We have designed an electron transfer chain incorporated into a de novo protein scaffold, which is capable of photoinduced intramolecular electron transfer between a photoredox unit and a FeIIS4 site through a tyrosine amino acid relay. The kinetics were characterized by nanosecond laser pulse photolysis and revealed that electron transfer from [RuIIIbpymal]3+ proceeds most efficiently via a tyrosine located ∼16 Å from Rubpymal (bpymal=1-((1-([2,2′-bipyridin]-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-1H-pyrrole-2,5-dione). Removal of the tyrosine as the electron relay station results in a 20-fold decrease in the apparent rate constant for the electron transfer.

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