Publications by authors named "Daniel Vogt"

55 Publications

Sequential perturbations to mouse corticogenesis following in utero maternal immune activation.

Elife 2021 Mar 5;10. Epub 2021 Mar 5.

Center for Neuroscience, UC Davis, Davis, United States.

In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time-course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by 6 hr following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA.
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http://dx.doi.org/10.7554/eLife.60100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979158PMC
March 2021

Integrated RNA Sequencing Reveals Epigenetic Impacts of Diesel Particulate Matter Exposure in Human Cerebral Organoids.

Dev Neurosci 2020 3;42(5-6):195-207. Epub 2021 Mar 3.

Department of Pediatrics & Human Development, Michigan State University, Grand Rapids, Michigan, USA,

Autism spectrum disorder (ASD) manifests early in childhood. While genetic variants increase risk for ASD, a growing body of literature has established that in utero chemical exposures also contribute to ASD risk. These chemicals include air-based pollutants like diesel particulate matter (DPM). A combination of single-cell and direct transcriptomics of DPM-exposed human-induced pluripotent stem cell-derived cerebral organoids revealed toxicogenomic effects of DPM exposure during fetal brain development. Direct transcriptomics, sequencing RNA bases via Nanopore, revealed that cerebral organoids contain extensive RNA modifications, with DPM-altering cytosine methylation in oxidative mitochondrial transcripts expressed in outer radial glia cells. Single-cell transcriptomics further confirmed an oxidative phosphorylation change in cell groups such as outer radial glia upon DPM exposure. This approach highlights how DPM exposure perturbs normal mitochondrial function and cellular respiration during early brain development, which may contribute to developmental disorders like ASD by altering neurodevelopment.
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http://dx.doi.org/10.1159/000513536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990702PMC
March 2021

Regulatory Elements Inserted into AAVs Confer Preferential Activity in Cortical Interneurons.

eNeuro 2020 Nov/Dec;7(6). Epub 2020 Dec 17.

Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California San Francisco Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158

Cortical interneuron (CIN) dysfunction is thought to play a major role in neuropsychiatric conditions like epilepsy, schizophrenia and autism. It is therefore essential to understand how the development, physiology, and functions of CINs influence cortical circuit activity and behavior in model organisms such as mice and primates. While transgenic driver lines are powerful tools for studying CINs in mice, this technology is limited in other species. An alternative approach is to use viral vectors such as AAV, which can be used in multiple species including primates and also have potential for therapeutic use in humans. Thus, we sought to discover gene regulatory enhancer elements (REs) that can be used in viral vectors to drive expression in specific cell types. The present study describes the systematic genome-wide identification of putative REs (pREs) that are preferentially active in immature CINs by histone modification chromatin immunoprecipitation and sequencing (ChIP-seq). We evaluated two novel pREs in AAV vectors, alongside the well-established enhancer, and found that they drove CIN-specific reporter expression in adult mice. We also showed that the identified pRE could drive sufficient expression of channelrhodopsin for optogenetic rescue of behavioral deficits in the mouse model of fast-spiking CIN dysfunction.
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http://dx.doi.org/10.1523/ENEURO.0211-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768279PMC
June 2021

A CRISPR-Cas9 screen identifies mitochondrial translation as an essential process in latent KSHV infection of human endothelial cells.

Proc Natl Acad Sci U S A 2020 11 29;117(45):28384-28392. Epub 2020 Oct 29.

Department of Microbiology, University of Washington, Seattle, WA 98109

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The main proliferating component of KS tumors is a cell of endothelial origin termed the spindle cell. Spindle cells are predominantly latently infected with only a small percentage of cells undergoing viral replication. As there is no direct treatment for latent KSHV, identification of host vulnerabilities in latently infected endothelial cells could be exploited to inhibit KSHV-associated tumor cells. Using a pooled CRISPR-Cas9 lentivirus library, we identified host factors that are essential for the survival or proliferation of latently infected endothelial cells in culture, but not their uninfected counterparts. Among the many host genes identified, there was an enrichment in genes localizing to the mitochondria, including genes involved in mitochondrial translation. Antibiotics that inhibit bacterial and mitochondrial translation specifically inhibited the expansion of latently infected endothelial cells and led to increased cell death in patient-derived PEL cell lines. Direct inhibition of mitochondrial respiration or ablation of mitochondrial genomes leads to increased death in latently infected cells. KSHV latent infection decreases mitochondrial numbers, but there are increases in mitochondrial size, genome copy number, and transcript levels. We found that multiple gene products of the latent locus localize to the mitochondria. During latent infection, KSHV significantly alters mitochondrial biology, leading to enhanced sensitivity to inhibition of mitochondrial respiration, which provides a potential therapeutic avenue for KSHV-associated cancers.
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http://dx.doi.org/10.1073/pnas.2011645117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668072PMC
November 2020

A Human Variant Screening Platform in Gabaergic Cortical Interneurons for Genotype to Phenotype Assessments.

Front Mol Neurosci 2020 18;13:573409. Epub 2020 Sep 18.

Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI, United States.

The and genes are connected to multiple syndromes from Tuberous Sclerosis Complex (TSC) to autism spectrum disorder (ASD), with uncertainty if genetic variants cause all or subsets of phenotypes based on the location and type of change. For , few have addressed if non-TSC associated genetic variants have direct contributions to changes in neurological genotype-to-phenotype impacts, including elevated rates of ASD and seizures. Dominant variants cause TSC, yet has many heritable variants not dominant for TSC that are poorly understood in neurological function, with some associated with ASD. Herein, we examined how missense variants in , R336W, T360N, T393I, S403L, and H732Y, impacted the development of cortical inhibitory interneurons, cell-types whose molecular, cellular, and physiological properties are altered after the loss of mouse . We found these variants complemented a known phenotype caused by loss of , increased cell size. However, distinct variants, particularly S403L showed deficits in complementing an increase in parvalbumin levels and exhibited smaller amplitude after hyperpolarizations. Overall, these data show that subtle phenotypes can be induced by some missense variants and provide an system to assess variants' neurological impact better.
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http://dx.doi.org/10.3389/fnmol.2020.573409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539171PMC
September 2020

Cortical distribution of GABAergic interneurons is determined by migration time and brain size.

Development 2020 07 22;147(14). Epub 2020 Jul 22.

Department of Psychiatry, Neuroscience Program and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA 94158, USA

Cortical interneurons (CINs) originate in the ganglionic eminences (GEs) and migrate tangentially to the cortex guided by different attractive and repulsive cues. Once inside the cortex, the cellular and molecular mechanisms determining the migration of CINs along the rostrocaudal axis are less well understood. Here, we investigated the cortical distribution of CINs originating in the medial and caudal GEs at different time points. Using molecular and genetic labeling, we showed that, in the mouse, early- and late-born CINs (E12 versus E15) are differentially distributed along the rostrocaudal axis. Specifically, late-born CINs are preferentially enriched in cortical areas closer to their respective sites of origin in the medial or caudal GE. Surprisingly, our experiments failed to show a preferential migration pattern along the rostrocaudal axis for medial- or caudal-born CINs. Moreover, transplantation experiments suggested that the rostrocaudal dispersion of CINs depends on the developmental stage of the host brain and is limited by the migration time and the increasing size of the developing brain. These data suggest that the embryonic expansion of the cortex contributes to the rostrocaudal distribution of CINs.
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http://dx.doi.org/10.1242/dev.185033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390637PMC
July 2020

KSHV requires vCyclin to overcome replicative senescence in primary human lymphatic endothelial cells.

PLoS Pathog 2020 06 18;16(6):e1008634. Epub 2020 Jun 18.

Department of Microbiology, University of Washington, Seattle, Washington, United States of America.

Kaposi's Sarcoma Herpesvirus (KSHV) is present in the main tumor cells of Kaposi's Sarcoma (KS), the spindle cells, which are of endothelial origin. KSHV is also associated with two B-cell lymphomas, Primary Effusion Lymphoma (PEL) and Multicentric Castleman's Disease. In KS and PEL, KSHV is primarily latent in the infected cells, expressing only a few genes. Although KSHV infection is required for KS and PEL, it is unclear how latent gene expression contributes to their formation. Proliferation of cancer cells occurs despite multiple checkpoints intended to prevent dysregulated cell growth. The first of these checkpoints, caused by shortening of telomeres, results in replicative senescence, where cells are metabolically active, but no longer divide. We found that human dermal lymphatic endothelial cells (LECs) are more susceptible to KSHV infection than their blood-specific endothelial cell counterparts and maintain KSHV latency to higher levels during passage. Importantly, KSHV infection of human LECs but not human BECs promotes their continued proliferation beyond this first checkpoint of replicative senescence. The latently expressed viral cyclin homolog is essential for KSHV-induced bypass of senescence in LECs. These data suggest that LECs may be an important reservoir for KSHV infection and may play a role during KS tumor development and that the viral cyclin is a critical oncogene for this process.
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http://dx.doi.org/10.1371/journal.ppat.1008634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326280PMC
June 2020

and control mouse pallial interneuron fate and maturation through neuropsychiatric disease gene regulation.

Elife 2020 05 26;9. Epub 2020 May 26.

Department of Psychiatry, University of California San Francisco, San Francisco, United States.

() and transcription factors (TFs) have compensatory roles in repressing somatostatin (SST) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. and conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) and are positively regulated by and to drive IN morphological maturation; (2) and promote expression which specifies parvalbumin (PV) INs; (3) , and are candidate markers of immature PV hippocampal INs (HIN). Furthermore, / neonatal cDKOs have decreased CINs and increased HINs, that express , an HIN specific marker. Our findings not only elucidate key gene targets of and that control IN development, but also identify for the first time TFs that differentially regulate CIN vs. HIN production.
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http://dx.doi.org/10.7554/eLife.54903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282818PMC
May 2020

deletion results in depletion of the transcription factor and a specific loss of parvalbumin cortical interneurons.

Proc Natl Acad Sci U S A 2020 03 2;117(11):6189-6195. Epub 2020 Mar 2.

Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503;

Neurofibromatosis 1 (NF1) is caused by mutations in the gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of , without changes in somatostatin (SST)-positive CINs. We discovered that loss of results in a dose-dependent decrease in expression, the transcription factor necessary to establish SST and PV CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.
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http://dx.doi.org/10.1073/pnas.1915458117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084085PMC
March 2020

Ultra-gentle soft robotic fingers induce minimal transcriptomic response in a fragile marine animal.

Curr Biol 2020 02;30(4):R157-R158

Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, NY 10024, USA; Baruch College, City University of New York, Department of Natural Sciences, New York, NY 10010, USA; The Graduate Center, PhD Program in Biology, City University of New York, New York, NY 10017, USA. Electronic address:

Tessler et al. demonstrate that a 'soft' robot causes less stress to a jellyfish while handling compared to a traditional 'hard' robot.
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http://dx.doi.org/10.1016/j.cub.2020.01.032DOI Listing
February 2020

Interneuron Transplantation Rescues Social Behavior Deficits without Restoring Wild-Type Physiology in a Mouse Model of Autism with Excessive Synaptic Inhibition.

J Neurosci 2020 03 27;40(11):2215-2227. Epub 2020 Jan 27.

Weill Institute for Neurosciences,

Manipulations that enhance GABAergic inhibition have been associated with improved behavioral phenotypes in autism models, suggesting that autism may be treated by correcting underlying deficits of inhibition. Interneuron transplantation is a method for increasing recipient synaptic inhibition, and it has been considered a prospective therapy for conditions marked by deficient inhibition, including neuropsychiatric disorders. It is unknown, however, whether interneuron transplantation may be therapeutically effective only for conditions marked by reduced inhibition, and it is also unclear whether transplantation improves behavioral phenotypes solely by normalizing underlying circuit defects. To address these questions, we studied the effects of interneuron transplantation in male and female mice lacking the autism-associated gene, , in GABAergic interneurons. mutant mice exhibit social behavior deficits, elevated synaptic inhibition in prefrontal cortex, abnormal baseline and social interaction-evoked electroencephalogram (EEG) signals, and an altered composition of cortical interneuron subtypes. Transplantation of wild-type embryonic interneurons from the medial ganglionic eminence into the prefrontal cortex of neonatal mutants rescued social behavior despite exacerbating excessive levels of synaptic inhibition. Furthermore, transplantation did not normalize recipient EEG signals measured during baseline states. Interneuron transplantation can thus correct behavioral deficits even when those deficits are associated with elevated synaptic inhibition. Moreover, transplantation does not exert therapeutic effects solely by restoring wild-type circuit states. Our findings indicate that interneuron transplantation could offer a novel cell-based approach to autism treatment while challenging assumptions that effective therapies must reverse underlying circuit defects. Imbalances between neural excitation and inhibition are hypothesized to contribute to the pathophysiology of autism. Interneuron transplantation is a method for altering recipient inhibition, and it has been considered a prospective therapy for neuropsychiatric disorders, including autism. Here we examined the behavioral and physiological effects of interneuron transplantation in a mouse genetic model of autism. They demonstrate that transplantation rescues recipient social interaction deficits without correcting a common measure of recipient inhibition, or circuit-level physiological measures. These findings demonstrate that interneuron transplantation can exert therapeutic behavioral effects without necessarily restoring wild-type circuit states, while highlighting the potential of interneuron transplantation as an autism therapy.
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http://dx.doi.org/10.1523/JNEUROSCI.1063-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083289PMC
March 2020

STING is dispensable during KSHV infection of primary endothelial cells.

Virology 2020 01 25;540:150-159. Epub 2019 Nov 25.

Department of Microbiology, University of Washington, Seattle, WA, 98109, USA. Electronic address:

During DNA virus infections, detection of cytosolic DNA by the cGAS-STING pathway leads to activation of IFN-β. Kaposi's Sarcoma Herpesvirus (KSHV), an oncogenic DNA virus, is the etiological agent of Kaposi's Sarcoma, an endothelial cell (EC)-based tumor. To investigate the role of STING during KSHV infection of primary ECs we identified a primary lymphatic EC sample that is defective for STING activation and we also knocked out STING in blood ECs. Ablation of STING in EC does not increase susceptibility to KSHV latent infection nor does it increase KSHV spread after lytic reactivation indicating STING signaling does not restrict KSHV. In contrast, STING ablation increases Adenovirus spread at low MOI, but STING is dispensable for blocking replication. These experiments reveal that the importance of STING depends on the DNA virus and that STING appears more important for restricting spread to bystander cells than for inhibition of viral replication.
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http://dx.doi.org/10.1016/j.virol.2019.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961814PMC
January 2020

A Wearable Soft Haptic Communicator Based on Dielectric Elastomer Actuators.

Soft Robot 2020 Aug 10;7(4):451-461. Epub 2020 Jan 10.

School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts.

Dielectric elastomer actuators exhibit an unusual combination of large displacements, moderate bandwidth, low power consumption, and mechanical impedance comparable with human skin, making them attractive for haptic devices. In this article, we propose a wearable haptic communication device based on a two-by-two array of dielectric elastomer linear actuators. We briefly describe the architecture of the actuators and their mechanical and electrical integration into a wearable armband. We then characterize the actuators' force, displacement, and thermal properties in a bench-top configuration. We also report on the power and drive circuit design. Finally, we perform a set of preliminary perception evaluations on participants using our haptic device, including detection threshold tests and identification tests for locations and directions on the forearm. Human testing with individual actuators demonstrates that the broadband actuation can be easily perceived on the forearm, providing the basis for both the development of a wearable actuator array and its use in more extensive perception evaluation as described herein.
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http://dx.doi.org/10.1089/soro.2019.0113DOI Listing
August 2020

A rapid approach to profiling diverse fungal communities using the MinION™ nanopore sequencer.

Biotechniques 2020 02 18;68(2):72-78. Epub 2019 Dec 18.

School of Environmental & Forest Sciences, College of the Environment, University of Washington, Box 352100, Seattle, WA 98195-2100, USA.

The Oxford Nanopore Technologies MinION™ sequencer holds the capability to generate long amplicon reads; however, only a small amount of information is available regarding methodological approaches and the ability to identify a broad diversity of fungal taxa. To assess capabilities, three fungal mock communities were sequenced, each of which had varying ratios of 16 taxa. The data were processed through our selected pipeline. The MinION recovered all mock community members, when mixed at equal ratios. When a taxon was represented at a lower ratio, it was not recovered or decreased in relative abundance. Despite high error rates, highly accurate consensus sequences can be derived. This methodological approach identified all mock community taxa, demonstrating the MinION can be used as a practical alternative to profile fungal communities.
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http://dx.doi.org/10.2144/btn-2019-0072DOI Listing
February 2020

Tsc1 represses parvalbumin expression and fast-spiking properties in somatostatin lineage cortical interneurons.

Nat Commun 2019 11 1;10(1):4994. Epub 2019 Nov 1.

Department of Pediatrics and Human Development, 400 Monroe Ave. NW, Grand Rapids, MI, 49503, USA.

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis Complex (TSC) gene, Tsc1, which inhibits the mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. Milder intermediate phenotypes also occur when only one allele of Tsc1 is deleted. Notably, treatment of adult mice with rapamycin, which inhibits MTOR, reverses the phenotypes. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to TSC neuropsychiatric symptoms. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.
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http://dx.doi.org/10.1038/s41467-019-12962-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825152PMC
November 2019

Ultragentle manipulation of delicate structures using a soft robotic gripper.

Sci Robot 2019 Aug;4(33)

John A. Paulson School of Engineering and Applied Sciences and the Wyss Institute for Biologically Inspired Engineering, Harvard University, 29 Oxford Street, Cambridge, MA 02138, USA.

Here, we present ultragentle soft robotic actuators capable of grasping delicate specimens of gelatinous marine life. Although state-of-the-art soft robotic manipulators have demonstrated gentle gripping of brittle animals (e.g., corals) and echinoderms (e.g., sea cucumbers) in the deep sea, they are unable to nondestructively grasp more fragile soft-bodied organisms, such as jellyfish. Through an exploration of design parameters and laboratory testing of individual actuators, we confirmed that our nanofiber-reinforced soft actuators apply sufficiently low contact pressure to ensure minimal harm to typical jellyfish species. We then built a gripping device using several actuators and evaluated its underwater grasping performance in the laboratory. By assessing the gripper's region of acquisition and robustness to external forces, we gained insight into the necessary precision and speed with which grasping maneuvers must be performed to achieve successful collection of samples. Last, we demonstrated successful manipulation of three live jellyfish species in an aquarium setting using a hand-held prototype gripper. Overall, our ultragentle gripper demonstrates an improvement in gentle sample collection compared with existing deep-sea sampling devices. Extensions of this technology may improve a variety of in situ characterization techniques used to study the ecological and genetic features of deep-sea organisms.
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http://dx.doi.org/10.1126/scirobotics.aax5425DOI Listing
August 2019

Biocompatible Soft Fluidic Strain and Force Sensors for Wearable Devices.

Adv Funct Mater 2019 Feb 6;29(7). Epub 2018 Dec 6.

School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.

Fluidic soft sensors have been widely used in wearable devices for human motion capturing. However, thus far, the biocompatibility of the conductive liquid, the linearity of the sensing signal, and the hysteresis between the loading and release processes have limited the sensing quality as well as the applications of these sensors. In this paper, silicone based strain and force sensors composed of a novel biocompatible conductive liquid (potassium iodide and glycerol solution) are introduced. The strain sensors exhibit negligible hysteresis up to 5 Hz, with a gauge factor of 2.2 at 1 Hz. The force sensors feature a novel multi-functional layered structure, with micro-cylinder-filled channels to achieve high linearity, low hysteresis (5.3% hysteresis at 1 Hz), and good sensitivity (100% resistance increase at a 5 N load). The sensors' gauge factors are stable at various temperatures and humidity levels. These bio-compatible, low hysteresis, and high linearity sensors are promising for safe and reliable diagnostic devices, wearable motion capture, and compliant human-computer interfaces.
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http://dx.doi.org/10.1002/adfm.201807058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675035PMC
February 2019

Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer.

Mol Autism 2019 8;10:17. Epub 2019 Apr 8.

1Biomedical Research Networking Center of Mental Health (CIBERSAM), Madrid, Spain.

Background: Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported.

Methods: Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis and report gene, pathway, and drug set-based overlaps between them.

Results: Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD.

Conclusions: Comparisons of ASD and cancer differential gene expression meta-analysis results suggest that brain, kidney, thyroid, and pancreatic cancers are candidates for direct comorbid associations with ASD. On the other hand, lung and prostate cancers are candidates for inverse comorbid associations with ASD. Joint perturbations in a set of specific biological processes underlie these associations which include several pathways previously implicated in both cancer and ASD encompassing immune system alterations, impairments of energy metabolism, cell cycle, and signaling through PI3K and G protein-coupled receptors among others. These findings could help to explain epidemiological observations pointing towards direct and inverse comorbid associations between ASD and specific cancer types and depict a complex scenario regarding the molecular patterns of association between ASD and cancer.
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http://dx.doi.org/10.1186/s13229-019-0262-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454734PMC
May 2019

Mafb and c-Maf Have Prenatal Compensatory and Postnatal Antagonistic Roles in Cortical Interneuron Fate and Function.

Cell Rep 2019 01;26(5):1157-1173.e5

Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV) and somatostatin (SST) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages. Analyses of Maf mutant mice revealed redundant functions of Mafb and c-Maf in secondary MGE progenitors, where they repress the generation of SST cortical and hippocampal interneurons. By contrast, Mafb and c-Maf have distinct roles in postnatal cortical interneuron (CIN) morphological maturation, synaptogenesis, and cortical circuit integration. Thus, Mafb and c-Maf have redundant and opposing functions at different steps in CIN development.
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http://dx.doi.org/10.1016/j.celrep.2019.01.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602795PMC
January 2019

CTCF Governs the Identity and Migration of MGE-Derived Cortical Interneurons.

J Neurosci 2019 01 30;39(1):177-192. Epub 2018 Oct 30.

Children's Health Research Institute, London, Ontario, Canada,

The CCCTC-binding factor (CTCF) is a central regulator of chromatin topology recently linked to neurodevelopmental disorders such as intellectual disability, autism, and schizophrenia. The aim of this study was to identify novel roles of CTCF in the developing mouse brain. We provide evidence that CTCF is required for the expression of the LIM homeodomain factor LHX6 involved in fate determination of cortical interneurons (CINs) that originate in the medial ganglionic eminence (MGE). Conditional ablation in the MGE of mice of either sex leads to delayed tangential migration, abnormal distribution of CIN in the neocortex, a marked reduction of CINs expressing parvalbumin and somatostatin (Sst), and an increased number of MGE-derived cells expressing and other markers of basal forebrain projection neurons. Likewise, -null MGE cells transplanted into the cortex of wild-type hosts generate fewer Sst-expressing CINs and exhibit lamination defects that are efficiently rescued upon reexpression of LHX6. Collectively, these data indicate that CTCF regulates the dichotomy between and to achieve correct specification and migration of MGE-derived CINs. This work provides evidence that CCCTC-binding factor (CTCF) controls an early fate decision point in the generation of cortical interneurons mediated at least in part by Lhx6. Importantly, the abnormalities described could reflect early molecular and cellular events that contribute to human neurological disorders previously linked to CTCF, including schizophrenia, autism, and intellectual disability.
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http://dx.doi.org/10.1523/JNEUROSCI.3496-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331652PMC
January 2019

A Dexterous, Glove-Based Teleoperable Low-Power Soft Robotic Arm for Delicate Deep-Sea Biological Exploration.

Sci Rep 2018 10 3;8(1):14779. Epub 2018 Oct 3.

School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.

Modern marine biologists seeking to study or interact with deep-sea organisms are confronted with few options beyond industrial robotic arms, claws, and suction samplers. This limits biological interactions to a subset of "rugged" and mostly immotile fauna. As the deep sea is one of the most biologically diverse and least studied ecosystems on the planet, there is much room for innovation in facilitating delicate interactions with a multitude of organisms. The biodiversity and physiology of shallow marine systems, such as coral reefs, are common study targets due to the easier nature of access; SCUBA diving allows for in situ delicate human interactions. Beyond the range of technical SCUBA (~150 m), the ability to achieve the same level of human dexterity using robotic systems becomes critically important. The deep ocean is navigated primarily by manned submersibles or remotely operated vehicles, which currently offer few options for delicate manipulation. Here we present results in developing a soft robotic manipulator for deep-sea biological sampling. This low-power glove-controlled soft robot was designed with the future marine biologist in mind, where science can be conducted at a comparable or better means than via a human diver and at depths well beyond the limits of SCUBA. The technology relies on compliant materials that are matched with the soft and fragile nature of marine organisms, and uses seawater as the working fluid. Actuators are driven by a custom proportional-control hydraulic engine that requires less than 50 W of electrical power, making it suitable for battery-powered operation. A wearable glove master allows for intuitive control of the arm. The manipulator system has been successfully operated in depths exceeding 2300 m (3500 psi) and has been field-tested onboard a manned submersible and unmanned remotely operated vehicles. The design, development, testing, and field trials of the soft manipulator is placed in context with existing systems and we offer suggestions for future work based on these findings.
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http://dx.doi.org/10.1038/s41598-018-33138-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170437PMC
October 2018

Shipboard design and fabrication of custom 3D-printed soft robotic manipulators for the investigation of delicate deep-sea organisms.

PLoS One 2018 1;13(8):e0200386. Epub 2018 Aug 1.

Department of Natural Sciences, Baruch College and The Graduate Center PhD Program in Biology, City University of New York, New York, NY, United States of America.

Soft robotics is an emerging technology that has shown considerable promise in deep-sea marine biological applications. It is particularly useful in facilitating delicate interactions with fragile marine organisms. This study describes the shipboard design, 3D printing and integration of custom soft robotic manipulators for investigating and interacting with deep-sea organisms. Soft robotics manipulators were tested down to 2224m via a Remotely-Operated Vehicle (ROV) in the Phoenix Islands Protected Area (PIPA) and facilitated the study of a diverse suite of soft-bodied and fragile marine life. Instantaneous feedback from the ROV pilots and biologists allowed for rapid re-design, such as adding "fingernails", and re-fabrication of soft manipulators at sea. These were then used to successfully grasp fragile deep-sea animals, such as goniasterids and holothurians, which have historically been difficult to collect undamaged via rigid mechanical arms and suction samplers. As scientific expeditions to remote parts of the world are costly and lengthy to plan, on-the-fly soft robot actuator printing offers a real-time solution to better understand and interact with delicate deep-sea environments, soft-bodied, brittle, and otherwise fragile organisms. This also offers a less invasive means of interacting with slow-growing deep marine organisms, some of which can be up to 18,000 years old.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200386PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070194PMC
January 2019

Soft Somatosensitive Actuators via Embedded 3D Printing.

Adv Mater 2018 Apr 27;30(15):e1706383. Epub 2018 Feb 27.

John A. Paulson School of Engineering and Applied Sciences, Wyss Institute for Biologically Inspired Engineering, Harvard University, Pierce Hall Rm 211, 29 Oxford Street, Cambridge, MA, 02138, USA.

Humans possess manual dexterity, motor skills, and other physical abilities that rely on feedback provided by the somatosensory system. Herein, a method is reported for creating soft somatosensitive actuators (SSAs) via embedded 3D printing, which are innervated with multiple conductive features that simultaneously enable haptic, proprioceptive, and thermoceptive sensing. This novel manufacturing approach enables the seamless integration of multiple ionically conductive and fluidic features within elastomeric matrices to produce SSAs with the desired bioinspired sensing and actuation capabilities. Each printed sensor is composed of an ionically conductive gel that exhibits both long-term stability and hysteresis-free performance. As an exemplar, multiple SSAs are combined into a soft robotic gripper that provides proprioceptive and haptic feedback via embedded curvature, inflation, and contact sensors, including deep and fine touch contact sensors. The multimaterial manufacturing platform enables complex sensing motifs to be easily integrated into soft actuating systems, which is a necessary step toward closed-loop feedback control of soft robots, machines, and haptic devices.
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http://dx.doi.org/10.1002/adma.201706383DOI Listing
April 2018

Undulatory Swimming Performance and Body Stiffness Modulation in a Soft Robotic Fish-Inspired Physical Model.

Soft Robot 2017 Sep 16;4(3):202-210. Epub 2017 May 16.

3 Department of Organismic and Evolutionary Biology, Harvard University , Cambridge, Massachusetts.

Undulatory motion of the body is the dominant mode of locomotion in fishes, and numerous studies of body kinematics and muscle activity patterns have provided insights into the mechanics of swimming. However, it has not been possible to investigate how key parameters such as the extent of bilateral muscle activation affect propulsive performance due to the inability to manipulate muscle activation in live, freely swimming fishes. In this article we extend previous work on passive flexible mechanical models of undulatory propulsion by using actively controlled pneumatic actuators attached to a flexible foil to gain insight into undulatory locomotion and mechanisms for body stiffness control. Two soft actuators were attached on each side of a flexible panel with stiffness comparable to that of a fish body. To study how bilateral contraction can be used to modify axial body stiffness during swimming, we ran a parameter sweep of actuator contraction phasing and frequency. Thrust production by the soft pneumatic actuators was tested at cyclic undulation frequencies ranging from 0.3 to 1.2 Hz in a recirculating flow tank at flow speeds up to 28 cm/s. Overall, this system generated more thrust at higher tail beat frequencies, with a plateau in thrust above 0.8 Hz. Self-propelled speed was found to be 0.8 foil lengths per second or ∼13 cm/s when actuated at 0.55 Hz. This active pneumatic model is capable of producing substantial trailing edge amplitudes with a maximum excursion equivalent to 1.4 foil lengths, and of generating considerable thrust. Altering the extent of bilateral co-contraction in a range from -22% to 17% of the cycle period showed that thrust was maximized with some amount of simultaneous left-right actuation of ∼3% to 6% of the cycle period. When the system is exposed to water flow, thrust was substantially reduced for conditions of greatest antagonistic overlap in left-right actuation, and also for the largest latencies introduced. This experimental platform provides a soft robotic testbed for studying aquatic propulsion with active control of undulatory kinematics.
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http://dx.doi.org/10.1089/soro.2016.0053DOI Listing
September 2017

Fluid-driven origami-inspired artificial muscles.

Proc Natl Acad Sci U S A 2017 12 27;114(50):13132-13137. Epub 2017 Nov 27.

John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;

Artificial muscles hold promise for safe and powerful actuation for myriad common machines and robots. However, the design, fabrication, and implementation of artificial muscles are often limited by their material costs, operating principle, scalability, and single-degree-of-freedom contractile actuation motions. Here we propose an architecture for fluid-driven origami-inspired artificial muscles. This concept requires only a compressible skeleton, a flexible skin, and a fluid medium. A mechanical model is developed to explain the interaction of the three components. A fabrication method is introduced to rapidly manufacture low-cost artificial muscles using various materials and at multiple scales. The artificial muscles can be programed to achieve multiaxial motions including contraction, bending, and torsion. These motions can be aggregated into systems with multiple degrees of freedom, which are able to produce controllable motions at different rates. Our artificial muscles can be driven by fluids at negative pressures (relative to ambient). This feature makes actuation safer than most other fluidic artificial muscles that operate with positive pressures. Experiments reveal that these muscles can contract over 90% of their initial lengths, generate stresses of ∼600 kPa, and produce peak power densities over 2 kW/kg-all equal to, or in excess of, natural muscle. This architecture for artificial muscles opens the door to rapid design and low-cost fabrication of actuation systems for numerous applications at multiple scales, ranging from miniature medical devices to wearable robotic exoskeletons to large deployable structures for space exploration.
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http://dx.doi.org/10.1073/pnas.1713450114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740677PMC
December 2017

Cortical interneuron development: a tale of time and space.

Development 2017 11;144(21):3867-3878

Department of Psychiatry, University of California, San Francisco, CA 94158, USA

Cortical interneurons are a diverse group of neurons that project locally and are crucial for regulating information processing and flow throughout the cortex. Recent studies in mice have advanced our understanding of how these neurons are specified, migrate and mature. Here, we evaluate new findings that provide insights into the development of cortical interneurons and that shed light on when their fate is determined, on the influence that regional domains have on their development, and on the role that key transcription factors and other crucial regulatory genes play in these events. We focus on cortical interneurons that are derived from the medial ganglionic eminence, as most studies have examined this interneuron population. We also assess how these data inform our understanding of neuropsychiatric disease and discuss the potential role of cortical interneurons in cell-based therapies.
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http://dx.doi.org/10.1242/dev.132852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702067PMC
November 2017

Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis.

Cereb Cortex 2018 11;28(11):3797-3815

Department of Psychiatry, Neuroscience Program and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA, USA.

The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.
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http://dx.doi.org/10.1093/cercor/bhx241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188538PMC
November 2018

Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons.

Cereb Cortex 2018 11;28(11):3868-3879

Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.

Human mutations in CNTNAP2 are associated with an array of neuropsychiatric and neurological syndromes, including speech and language disorders, epilepsy, and autism spectrum disorder (ASD). We examined Cntnap2's expression and function in GABAergic cortical interneurons (CINs), where its RNA is present at highest levels in chandelier neurons, PV+ neurons and VIP+ neurons. In vivo functions were studied using both constitutive Cntnap2 null mice and a transplantation assay, the latter to assess cell autonomous phenotypes of medial ganglionic eminence (MGE)-derived CINs. We found that Cntnap2 constitutive null mutants had normal numbers of MGE-derived CINs, but had reduced PV+ CINs. Transplantation assays showed that Cntnap2 cell autonomously regulated the physiology of parvalbumin (PV)+, fast-spiking CINs; no phenotypes were observed in somatostatin+, regular spiking, CINs. We also tested the effects of 4 human CNTNAP2 ASD missense mutations in vivo, and found that they impaired PV+ CIN development. Together, these data reveal that reduced CNTNAP2 function impairs PV+ CINs, a cell type with important roles in regulating cortical circuits.
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http://dx.doi.org/10.1093/cercor/bhx248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455910PMC
November 2018

and control subtype and laminar identity of MGE-derived neocortical interneurons.

Development 2017 08 10;144(15):2837-2851. Epub 2017 Jul 10.

Department of Psychiatry, Neuroscience Program and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA 94158, USA

Distinct cortical interneuron (CIN) subtypes have unique circuit functions; dysfunction in specific subtypes is implicated in neuropsychiatric disorders. Somatostatin- and parvalbumin-expressing (SST and PV) interneurons are the two major subtypes generated by medial ganglionic eminence (MGE) progenitors. Spatial and temporal mechanisms governing their cell-fate specification and differential integration into cortical layers are largely unknown. We provide evidence that and ( and ) transcription factor expression in an arc-shaped progenitor domain within the MGE promotes time-dependent survival of this neuroepithelium and the time-dependent specification of layer V SST CINs. and autonomously repress PV fate in MGE progenitors, in part through directly driving expression. These results have identified, in mouse, a transcriptional pathway that controls SST-PV fate.
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http://dx.doi.org/10.1242/dev.150664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560044PMC
August 2017
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