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Article: Abnormal cell sorting and altered early neurogenesis in a human cortical organoid model of Protocadherin-19 clustering epilepsy.

Niu, Wei / Deng, Lu / Mojica-Perez, Sandra P / Tidball, Andrew M / Sudyk, Roksolana / Stokes, Kyle / Parent, Jack M

2024 Volume 18, Page(s) 1339345

Abstract: Introduction: Protocadherin-19 (: Methods: To overcome these challenges and model mosaic : Results: We found that PCDH19 is highly expressed in early (days 20-35) WT neural rosettes where it co-localizes with N-Cadherin in ventricular zone (VZ)- ... ...

Abstract	Introduction: Protocadherin-19 ( Methods: To overcome these challenges and model mosaic Results: We found that PCDH19 is highly expressed in early (days 20-35) WT neural rosettes where it co-localizes with N-Cadherin in ventricular zone (VZ)-like regions. Mosaic PCE hCOs displayed abnormal cell sorting in the VZ with KO and WT cells completely segregated. This segregation remained robust when WT:KO cells were mixed at 2:1 or 1:2 ratios. PCE hCOs also exhibited altered expression of PCDH19 (in WT cells) and N-Cadherin, and abnormal deep layer neurogenesis. None of these abnormalities were observed in hCOs generated by mixing only WT or only KO (modeling male carrier) cells. Discussion: Our results using the mosaic PCE hCO model suggest that PCDH19 plays a critical role in human VZ radial glial organization and early cortical development. This model should offer a key platform for exploring mechanisms underlying PCE-related cortical hyperexcitability and testing of potential precision therapies.
Language	English
Publishing date	2024-04-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2024.1339345
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Book ; Online: Feed-forward Disturbance Compensation for Station Keeping in Wave-dominated Environments

Walker, Kyle L. / Stokes, Adam A. / Kiprakis, Aristides / Giorgio-Serchi, Francesco

2023

Abstract: When deploying robots in shallow ocean waters, wave disturbances can be significant, highly dynamic and pose problems when operating near structures; this is a key limitation of current control strategies, restricting the range of conditions in which ... ...

Abstract	When deploying robots in shallow ocean waters, wave disturbances can be significant, highly dynamic and pose problems when operating near structures; this is a key limitation of current control strategies, restricting the range of conditions in which subsea vehicles can be deployed. To improve dynamic control and offer a higher level of robustness, this work proposes a Cascaded Proportional-Derivative (C-PD) with Feed-forward (FF) control scheme for disturbance mitigation, exploring the concept of explicitly using disturbance estimations to counteract state perturbations. Results demonstrate that the proposed controller is capable of higher performance in contrast to a standard C-PD controller, with an average reduction of ~48% witnessed across various sea states. Additional analysis also investigated performance when considering coarse estimations featuring inaccuracies; average improvements of ~17% demonstrate the effectiveness of the proposed strategy to handle these uncertainties. The proposal in this work shows promise for improved control without a drastic increase in required computing power; if coupled with sufficient sensors, state estimation techniques and prediction algorithms, utilising feed-forward compensating control actions offers a potential solution to improve vehicle control under wave-induced disturbances. Comment: To published in proceedings of Oceans 2023: Limerick
Keywords	Computer Science - Robotics
Subject code	629
Publishing date	2023-04-11
Publishing country	us
Document type	Book ; Online
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Article ; Online: Protocol for selecting single human pluripotent stem cells using a modified micropipetter.

Mojica-Perez, Sandra P / Stokes, Kyle / Jaklic, Daniel C / Jahagirdar, Sheetal / Uhler, Michael / Parent, Jack M / Niu, Wei

STAR protocols

2023 Volume 4, Issue 4, Page(s) 102629

Abstract: Single-cell clonal selection is a critical procedure for generating a homogeneous population of human pluripotent stem cells. Here, we present a protocol that repurposes the STRIPPER Micropipetter, normally used for in vitro fertilization, to pick single ...

Abstract	Single-cell clonal selection is a critical procedure for generating a homogeneous population of human pluripotent stem cells. Here, we present a protocol that repurposes the STRIPPER Micropipetter, normally used for in vitro fertilization, to pick single stem cells. We describe steps for tool and reagent preparation, single-cell picking, and colony passaging. We then detail procedures for amplification and analysis. Our protocol does not require cell sorting and produces homogenous clonal cultures with more than 50% survival rate. For complete details on the use and execution of this protocol, please refer to Deng et al.
MeSH term(s)	Humans ; Pluripotent Stem Cells ; Cell Separation ; Fertilization in Vitro
Language	English
Publishing date	2023-10-09
Publishing country	United States
Document type	Journal Article
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2023.102629
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Article ; Online: BMAL1

Taleb, Zainab / Carmona-Alcocer, Vania / Stokes, Kyle / Haireek, Marta / Wang, Huaqing / Collins, Stephen M / Khan, Waliul I / Karpowicz, Phillip

Frontiers in cellular and infection microbiology

2022 Volume 12, Page(s) 773413

Abstract: Many physiological functions exhibit circadian rhythms: oscillations in biological processes that occur in a 24-hour period. These daily rhythms are maintained through a highly conserved molecular pacemaker known as the circadian clock. Circadian ... ...

Abstract	Many physiological functions exhibit circadian rhythms: oscillations in biological processes that occur in a 24-hour period. These daily rhythms are maintained through a highly conserved molecular pacemaker known as the circadian clock. Circadian disruption has been proposed to cause increased risk of Inflammatory Bowel Disease (IBD) but the underlying mechanisms remain unclear. Patients with IBD experience chronic inflammation and impaired regeneration of intestinal epithelial cells. Previous animal-based studies have revealed that colitis models of IBD are more severe in mice without a circadian clock but the timing of colitis, and whether its inflammatory and regenerative processes have daily rhythms, remains poorly characterized. We tested circadian disruption using
MeSH term(s)	ARNTL Transcription Factors/genetics ; Animals ; Circadian Clocks ; Circadian Rhythm ; Colitis/chemically induced ; Colitis/pathology ; Humans ; Inflammatory Bowel Diseases ; Mice
Chemical Substances	ARNTL Transcription Factors ; Bmal1 protein, mouse
Language	English
Publishing date	2022-02-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2022.773413
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Article ; Online: Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle.

Rahman, Fasih Ahmad / Angus, Sarah Anne / Stokes, Kyle / Karpowicz, Phillip / Krause, Matthew Paul

International journal of molecular sciences

2020 Volume 21, Issue 13

Abstract: Regenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM ... ...

Abstract	Regenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM remodeling, and impaired aged muscle regeneration. The regeneration process was compared in young (three month old) and aged (18 month old) C56BL/6J mice at 3, 5, and 7 days following cardiotoxin-induced damage to the tibialis anterior muscle. Immunohistochemical analyses were performed to assess regenerative capacity, ECM remodeling, and the macrophage response in relation to plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), and ECM protein expression. The regeneration process was impaired in aged muscle. Greater intracellular and extramyocellular PAI-1 expression was found in aged muscle. Collagen I was found to accumulate in necrotic regions, while macrophage infiltration was delayed in regenerating regions of aged muscle. Young muscle expressed higher levels of MMP-9 early in the regeneration process that primarily colocalized with macrophages, but this expression was reduced in aged muscle. Our results indicate that ECM remodeling is impaired at early time points following muscle damage, likely a result of elevated expression of the major inhibitor of ECM breakdown, PAI-1, and consequent suppression of the macrophage, MMP-9, and myogenic responses.
MeSH term(s)	Animals ; Extracellular Matrix/metabolism ; Extracellular Matrix/pathology ; Extracellular Matrix Proteins/metabolism ; Macrophage Activation ; Macrophages/metabolism ; Macrophages/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/cytology ; Muscle, Skeletal/injuries ; Muscle, Skeletal/metabolism ; Necrosis ; Regeneration
Chemical Substances	Extracellular Matrix Proteins
Language	English
Publishing date	2020-06-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21134575
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Article ; Online: Quantifying the differential functional behavior between the medial and lateral meniscus after posterior meniscus root tears.

Walczak, Brian E / Miller, Kyle / Behun, Michael A / Sienkiewicz, Lisa / Hartwig Stokes, Heather / McCabe, Ron / Baer, Geoffrey S

PloS one

2021 Volume 16, Issue 11, Page(s) e0259678

Abstract: Meniscus tears of the knee are among the most common orthopedic knee injury. Specifically, tears of the posterior root can result in abnormal meniscal extrusion leading to decreased function and progressive osteoarthritis. Despite contemporary surgical ... ...

Abstract	Meniscus tears of the knee are among the most common orthopedic knee injury. Specifically, tears of the posterior root can result in abnormal meniscal extrusion leading to decreased function and progressive osteoarthritis. Despite contemporary surgical treatments of posterior meniscus root tears, there is a low rate of healing and an incidence of residual meniscus extrusion approaching 30%, illustrating an inability to recapitulate native meniscus function. Here, we characterized the differential functional behavior of the medial and lateral meniscus during axial compression load and dynamic knee motion using a cadaveric model. We hypothesized essential differences in extrusion between the medial and lateral meniscus in response to axial compression and knee range of motion. We found no differences in the amount of meniscus extrusion between the medial and lateral meniscus with a competent posterior root (0.338mm vs. 0.235mm; p-value = 0.181). However, posterior root detachment resulted in a consistently increased meniscus extrusion for the medial meniscus compared to the lateral meniscus (2.233mm vs. 0.4705mm; p-value < 0.0001). Moreover, detachment of the posterior root of the medial meniscus resulted in an increase in extrusion at all angles of knee flexion and was most pronounced (4.00mm ± 1.26mm) at 30-degrees of knee flexion. In contrast, the maximum mean extrusion of the lateral meniscus was 1.65mm ± 0.97mm, occurring in full extension. Furthermore, only the medial meniscus extruded during dynamic knee flexion after posterior root detachment. Given the differential functional behaviors between the medial and lateral meniscus, these findings suggest that posterior root repair requires reducing overall meniscus extrusion and recapitulating the native functional responses specific to each meniscus.
MeSH term(s)	Humans ; Knee Injuries/physiopathology ; Knee Joint/physiology ; Lower Extremity/physiology ; Menisci, Tibial/physiology ; Meniscus/physiology ; Range of Motion, Articular/physiology
Language	English
Publishing date	2021-11-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0259678
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Article ; Online: Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle

Fasih Ahmad Rahman / Sarah Anne Angus / Kyle Stokes / Phillip Karpowicz / Matthew Paul Krause

International Journal of Molecular Sciences, Vol 21, Iss 4575, p

2020 Volume 4575

Abstract	Regenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM remodeling, and impaired aged muscle regeneration. The regeneration process was compared in young (three month old) and aged (18 month old) C56BL/6J mice at 3, 5, and 7 days following cardiotoxin-induced damage to the tibialis anterior muscle. Immunohistochemical analyses were performed to assess regenerative capacity, ECM remodeling, and the macrophage response in relation to plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), and ECM protein expression. The regeneration process was impaired in aged muscle. Greater intracellular and extramyocellular PAI-1 expression was found in aged muscle. Collagen I was found to accumulate in necrotic regions, while macrophage infiltration was delayed in regenerating regions of aged muscle. Young muscle expressed higher levels of MMP-9 early in the regeneration process that primarily colocalized with macrophages, but this expression was reduced in aged muscle. Our results indicate that ECM remodeling is impaired at early time points following muscle damage, likely a result of elevated expression of the major inhibitor of ECM breakdown, PAI-1, and consequent suppression of the macrophage, MMP-9, and myogenic responses.
Keywords	skeletal muscle ; regeneration ; extracellular matrix ; macrophage ; plasminogen activator inhibitor-1 ; aging ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Complementary roles of human hippocampal subfields in differentiation and integration of spatial context.

Stokes, Jared / Kyle, Colin / Ekstrom, Arne D

Journal of cognitive neuroscience

2014 Volume 27, Issue 3, Page(s) 546–559

Abstract: The unique circuitry of the hippocampus is thought to support the encoding and retrieval of context-rich episodic memories. Given the neuroanatomical differences between the hippocampal subfields, determining their functional roles during representation ... ...

Abstract	The unique circuitry of the hippocampus is thought to support the encoding and retrieval of context-rich episodic memories. Given the neuroanatomical differences between the hippocampal subfields, determining their functional roles during representation of contextual features in humans is an important yet unaddressed research goal. Prior studies suggest that, during the acquisition of information from the environment, the dentate gyrus (DG) and CA3 subfields rapidly differentiate competing contextual representations, whereas CA1, situated downstream from CA3/DG, is believed to process input from both CA3 and neocortical areas via the temporoammonic pathway. To further explore the functionality of these roles, we used high-resolution fMRI to investigate multivariate response patterns within CA3/DG and CA1 during the processing of spatial context. While undergoing functional imaging, participants viewed videos of virtual environments and were asked to discriminate between similar yet geometrically distinct cities. We manipulated a single contextual feature by systematically morphing the city configurations from one common geometric shape to another, resulting in four cities--two distinctively shaped cities and two intermediate "morphed" cities. Pattern similarity within CA3/DG scaled with geometric changes to the environment. In contrast, CA1 pattern similarity, as well as interregional pattern similarity between CA1 and parahippocampal cortex, increased for the regularly shaped configurations compared with the morphs. These results highlight different roles for subfields CA3/DG and CA1 in memory and advance our understanding of how subcomponents of the human hippocampal circuit represent contextual features of memories.
MeSH term(s)	Adolescent ; Adult ; CA1 Region, Hippocampal/physiology ; CA3 Region, Hippocampal/physiology ; Dentate Gyrus/physiology ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Memory, Episodic ; Pattern Recognition, Visual/physiology ; Space Perception/physiology ; Spatial Memory/physiology ; Young Adult
Language	English
Publishing date	2014-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1007410-7
ISSN	1530-8898 ; 0898-929X ; 1096-8857
ISSN (online)	1530-8898
ISSN	0898-929X ; 1096-8857
DOI	10.1162/jocn_a_00736
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Article ; Online: Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii.

Liu, Gary / Catacutan, Denise B / Rathod, Khushi / Swanson, Kyle / Jin, Wengong / Mohammed, Jody C / Chiappino-Pepe, Anush / Syed, Saad A / Fragis, Meghan / Rachwalski, Kenneth / Magolan, Jakob / Surette, Michael G / Coombes, Brian K / Jaakkola, Tommi / Barzilay, Regina / Collins, James J / Stokes, Jonathan M

Nature chemical biology

2023 Volume 19, Issue 11, Page(s) 1342–1350

Abstract: Acinetobacter baumannii is a nosocomial Gram-negative pathogen that often displays multidrug resistance. Discovering new antibiotics against A. baumannii has proven challenging through conventional screening approaches. Fortunately, machine learning ... ...

Abstract	Acinetobacter baumannii is a nosocomial Gram-negative pathogen that often displays multidrug resistance. Discovering new antibiotics against A. baumannii has proven challenging through conventional screening approaches. Fortunately, machine learning methods allow for the rapid exploration of chemical space, increasing the probability of discovering new antibacterial molecules. Here we screened ~7,500 molecules for those that inhibited the growth of A. baumannii in vitro. We trained a neural network with this growth inhibition dataset and performed in silico predictions for structurally new molecules with activity against A. baumannii. Through this approach, we discovered abaucin, an antibacterial compound with narrow-spectrum activity against A. baumannii. Further investigations revealed that abaucin perturbs lipoprotein trafficking through a mechanism involving LolE. Moreover, abaucin could control an A. baumannii infection in a mouse wound model. This work highlights the utility of machine learning in antibiotic discovery and describes a promising lead with targeted activity against a challenging Gram-negative pathogen.
MeSH term(s)	Animals ; Mice ; Anti-Bacterial Agents/pharmacology ; Acinetobacter baumannii ; Deep Learning ; Drug Resistance, Multiple, Bacterial ; Microbial Sensitivity Tests
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2023-05-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-023-01349-8
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Zs.A 6251: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A Tale of Two Temporal Coding Strategies: Common and Dissociable Brain Regions Involved in Recency versus Associative Temporal Order Retrieval Strategies.

Lieberman, Jennifer S / Kyle, Colin T / Schedlbauer, Amber / Stokes, Jared / Ekstrom, Arne D

Journal of cognitive neuroscience

2017 Volume 29, Issue 4, Page(s) 739–754

Abstract: Numerous studies indicate the importance of the hippocampus to temporal order retrieval. However, behavioral studies suggest that there are different ways to retrieve temporal order information from encoded sequences, one involving an associative ... ...

Abstract	Numerous studies indicate the importance of the hippocampus to temporal order retrieval. However, behavioral studies suggest that there are different ways to retrieve temporal order information from encoded sequences, one involving an associative strategy (retrieving associations using neighboring items in a list) and another involving a recency strategy (determining which of two items came first). It remains unresolved, however, whether both strategies recruit the hippocampus or only associative strategies, consistent with the hippocampus's role in relational processing. To address this, we developed a paradigm in which we dissociated associative versus recency-based retrieval, involving the same stimulus presentation during retrieval. Associative retrieval involved an increase in RT (and decrease in performance) with greater distances between intervals, consistent with the need to retrieve intervening associations. Recency-based retrieval involved an increase in RT (and decrease in performance) with shorter distances between intervals, suggesting the use of a strength-based coding mechanism to retrieve information. We employed fMRI to determine the neural basis of the different strategies. Both strategies showed significant levels of hippocampal activation and connectivity that did not differ between tasks. In contrast, both univariate and connectivity pattern analyses revealed differences in extrahippocampal areas such as parietal and frontal cortices. A covariate analysis suggested that differences could not be explained by task difficulty alone. Together, these findings suggest that the hippocampus plays a role in both forms of temporal order retrieval, with neocortical networks mediating the different cognitive demands for associative versus recency-based temporal order retrieval.
Language	English
Publishing date	2017-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1007410-7
ISSN	1530-8898 ; 0898-929X ; 1096-8857
ISSN (online)	1530-8898
ISSN	0898-929X ; 1096-8857
DOI	10.1162/jocn_a_01081
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