bluuebunny/crossref_metadata_2025_split huggingface dataset:
Designer DNA NanoGripper
Authors: Zhou Lifeng , Xiong Yanyu , Cooper Laura , Shepherd Skye , Song Tingjie , Dwivedy Abhisek , Rong Lijun , Wang Tong , Cunningham Brian T. , Wang Xing 
Published: April 2023

ABSTRACTDNA has shown great biocompatibility, programmable mechanical properties, and structural addressability at the nanometer scale, making it a versatile material for building high precision nanorobotics for biomedical applications. Herein, we present design principle, synthesis, and characterization of a DNA nanorobotic hand, called the “NanoGripper”, that contains a palm and four bendable fingers as inspired by human hands, bird claws, and bacteriophages evolved in nature. Each NanoGripper finger has three phalanges connected by two flexible and rotatable joints that are bendable in response to binding to other entities. Functions of the NanoGripper have been enabled and driven by the interactions between moieties attached to the fingers and their binding partners. We showcase that the NanoGripper can be engineered to interact with and capture various objects with different dimensions, including gold nanoparticles, gold NanoUrchins, and SARS-CoV-2 virions. When carrying multiple DNA aptamer nanoswitches programmed to generate fluorescent signal enhanced on a photonic crystal platform, the NanoGripper functions as a sensitive viral biosensor that detects intact SARS-CoV-2 virions in human saliva with a limit of detection of ∼ 100 copies/mL, providing RT-PCR equivalent sensitivity. Additionally, we use confocal microscopy to visualize how the NanoGripper-aptamer complex can effectively block viral entry into the host cells, indicating the viral inhibition. In summary, we report the design, synthesis, and characterization of a complex nanomachine that can be readily tailored for specific applications. The study highlights a path toward novel, feasible, and efficient solutions for the diagnosis and therapy of other diseases such as HIV and influenza.One-sentence summaryDesign, synthesis, characterization, and functional showcase of a human-hand like designer DNA nanobot
Discovery of Type IV filament membrane alignment complex homologs inH. pylorithat promote soft-agar migration
Authors: Sagoo Jashwin , Abedrabbo Samar , Liu Xiaolin , Ottemann Karen M. 
Published: April 2023

AbstractThe stomach pathogenHelicobacter pyloriutilizes two scaffold proteins, CheW and CheV1, to build critical chemotaxis arrays. Chemotaxis helps bacteria establish and maintain infection. Mutants lacking either of these chemotaxis proteins have different soft agar phenotypes: deletion ofcheWcreates non-chemotactic strains, while deletion ofcheV1results in 50% loss of chemotaxis. In this work, we characterized thecheV1deletion mutant phenotype in detail.cheV1deletion mutants had poor soft-agar migration initially, but regained migration ability over time. This improved bacterial migration was stable, suggesting a genetic suppressor phenotype, termed Che+. Whole-genome sequencing analysis of four distinctcheV1Che+ strains revealed single nucleotide polymorphisms (SNPs) in a common gene, HPG27_252 (HP0273). These SNPs were predicted to truncate the encoded protein. To confirm the role of HPG27_252 in thecheV1phenotype, we created a targeted deletion of HPG27_252 and found that loss of HPG27_252 enhanced soft-agar migration. HPG27_252 and CheV1 appear to interact directly, based on bacterial two-hybrid analysis. HPG27_252 is predicted to encode a 179 amino acid, 21 kDa protein annotated as a hypothetical protein. Computational analysis revealed this protein to be a remote homolog of the PilO Type IV filament membrane alignment complex protein. AlthoughH. pyloriis not known to possess Type IV filaments, our analysis showed it retains an operon of genes for homologs of PilO, PilN, and PilM, but does not possess other Type IV pili genes. Our data suggest the PilO homolog plays a role in regulatingH. pylorichemotaxis and motility, suggesting new ideas about evolutionary steps for controlling migration through semi-solid media.
LEVERAGING THE POWER OF 3D BRAIN-WIDE IMAGING AND MAPPING TOOLS FOR BRAIN INJURY RESEARCH IN MURINE MODELS
Authors: Anwer Mehwish , LeDue Jeffrey , Wang Zefang , Wang Sarah , Cheng Wai Hang , Burdyniuk Mariia , Cheung Honor , Fan Jianjia , Barron Carlos , Cripton Peter A , Cembrowski Mark S , Rossi Fabio , Murphy Timothy H , Wellington Cheryl L 
Published: April 2023

ABSTRACTDespite the fundamental importance of understanding impaired brain activity exhibited in post-traumatic epilepsy and other neurological impairments associated with traumatic brain injury (TBI), knowledge of how brain injury affects neuronal activity remains remarkably incomplete. We describe a whole-brain imaging and analysis approach to identify alterations in neuronal activity after TBI as a complementary method to conventional two-dimensional (2D) histological approaches. Here we report an easy-to-follow experimental pipeline to quantify changes in the whole mouse brain using tissue clearing, light sheet microscopy (LSM) and an optimised open-access atlas registration workflow. We validated the outcome of the pipeline using high throughput image analysis software and a secondary atlas registration method. Using the CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) TBI model, TRAP2 mice were subjected to repeated mild TBI or sham treatment followed by tamoxifen injection to lock c-Fos activity after TBI. Brains were SHIELD fixed and passively cleared for imaging of c-Fos+ cells throughout the rostro-caudal axis of the brain using a light sheet microscope equipped with a specialized whole-brain imaging chamber. Volumetric images were stitched and 3D rendered using Arivis Vision4D image analysis software. For quantitative analysis, 2D image stacks were exported to segment c-Fos+ cells and register them to the Allen Mouse Brain Atlas using the BrainQuant3D python package. As a result, c-Fos+ cell counts were estimated throughout the brain and heatmaps were generated. We identified a brain-wide reduction in c-Fos cell density in the TBI group compared to sham controls, indicative of TBI-induced changes in whole brain neuronal activity. Further studies using multi-dimensional imaging coupled with analysis tools will deepen our understanding of post-TBI brain-wide dynamics.
Geographical Survey of the Mycobiome and Microbiome of Southern California Glassy-winged Sharpshooters
Authors: Ettinger Cassandra L. , Wu-Woods Jessica , Kurbessoian Tania L. , Brown Dylan J. , de Souza Pacheco Inaiara , Vindiola Beatriz G. , Walling Linda L. , Atkinson Peter W. , Byrne Frank J. , Redak Richard , Stajich Jason E. 
Published: April 2023

AbstractThe glassy-winged sharpshooter,Homalodisca vitripennisGermar, is an invasive xylem-feeding leafhopper with a devastating economic impact on California agriculture through transmission of the plant pathogen,Xylella fastidiosa. While studies have focused onX. fastidiosaor known symbionts ofH. vitripennis, little work has been done at the scale of the microbiome (the bacterial community) or mycobiome (the fungal community). Here we characterize the mycobiome and the microbiome ofH. vitripennisacross Southern California and explore correlations with captivity and host insecticide-resistance status. Using high-throughput sequencing of the ribosomal internal transcribed spacer (ITS1) region and the 16S rRNA gene to profile the mycobiome and microbiome, respectively, we found that while theH. vitripennismycobiome significantly varied across Southern California, the microbiome did not. We also observed a significant difference in both the mycobiome and microbiome between captive and wildH. vitripennis. Finally, we found that the mycobiome, but not the microbiome, was correlated with insecticide-resistance status in wildH. vitripennis. This study serves as a foundational look at theH. vitripennismycobiome and microbiome across Southern California. Future work should explore the putative link between microbes and insecticide-resistance status and investigate whether microbial communities should be considered inH. vitripennismanagement practices.
Ancient methicillin-resistantStaphylococcus aureus: expanding current knowledge using molecular epidemiological characterization of a Swiss legacy collection
Authors: Benvenga Vanni , Cuénod Aline , Purushothaman inithi , Dasen Gottfried , Weisser Maja , Bassetti Stefano , Roloff Tim , Siegemund Martin , Heininger Ulrich , Bielicki Julia , Wehrli Marianne , Friderich Paul , Frei Reno , Widmer Andreas , Herzog Kathrin , Fankhauser Hans , Nolte Oliver , Bodmer Thomas , Risch Martin , Dubuis Olivier , Pranghofer Sigrid , Calligaris-Maibach Romana , Graf Susanne , Tschudin-Sutter Sarah , Perreten Vincent , Seth-Smith Helena M.B , Egli Adrian 
Published: April 2023

AbstractFew methicillin-resistantStaphylococcus aureus(MRSA) from the early years of its global emergence have been sequenced. Knowledge about evolutionary factors promoting the success of specific MRSA multi-locus sequence types (MLSTs) remains scarce. We aimed to characterize a legacy MRSA collection isolated from 1965 to 1987 and compare it against publicly available international and local genomes.We accessed 451 ancient (1965-1987) Swiss MRSA isolates, stored in the Culture Collection of Switzerland. We determined phenotypic antimicrobial resistance (AMR) and performed Illumina short-read sequencing on all isolates and long-read sequencing on a selection with Oxford Nanopore Technology. For context, we included 103 publicly available international genomes from 1960 to 1992 and sequenced 1207 modern Swiss MRSA isolates from 2007 to 2022. We analyzed the core genome (cg)MLST and predicted SCCmeccassette types, AMR, and virulence genes.Among the 451 ancient Swiss MRSA isolates, we found 17 sequence types (STs) of which 11 have been previously described. Two STs were novel combinations of known loci and six isolates carried previously unsubmitted MLST alleles, representing five new STs (ST7843, ST7844, ST7837, ST7839, and ST7842). Most isolates (83% 376/451) represented ST247-MRSA-I isolated in the 1960s, followed by ST7844 (6% 25/451), a novel single locus variant (SLV) of ST239. Analysis by cgMLST indicated that isolates belonging to ST7844-MRSA-III cluster within the diversity of ST239-MRSA-IIII. Early MRSA were predominantly from clonal complex (CC) 8. From 1980 to the end of the 20thcentury we observed that CC22 and CC5 as well as CC8 were present, both locally and internationally.The combined analysis of 1761 ancient and contemporary MRSA isolates across more than 50 years uncovered novel STs and allowed us a glimpse into the lineage flux between Swiss and international MRSA across time.
The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by which LA1011 may Improve the Prognosis of Alzheimer’s Disease
Authors: Roe S. Mark , Török Zsolt , McGown Andrew , Horváth Ibolya , Spencer John , Pázmány Tamás , Vigh László , Prodromou Chrisostomos 
Published: April 2023

AbstractChaperone systems play a major role in the decline of cognition and contribute to neurological pathologies such as Alzheimer’s disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-β (Aβ) plaque formation leads to the hyperphosphorylation of tau by a Hsp90 dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine, LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90 although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. Clinically, this is highly significant, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting.
Harmonizing and aligning M/EEG datasets with covariance-based techniques to enhance predictive regression modeling
Authors: Mellot Apolline , Collas Antoine , Rodrigues Pedro L. C. , Engemann Denis , Gramfort Alexandre 
Published: April 2023

AbstractNeuroscience studies face challenges in gathering large datasets, which limits the use of machine learning (ML) approaches. One possible solution is to incorporate additional data from large public datasets; however, data collected in different contexts often exhibit systematic differences called dataset shifts. Various factors,e.g., site, device type, experimental protocol, or social characteristics, can lead to substantial divergence of brain signals that can hinder the success of ML across datasets. In this work, we focus on dataset shifts in recordings of brain activity using MEG and EEG. State-of-the-art predictive approaches on M/EEG signals classically represent the data by covariance matrices. Model-based dataset alignment methods can leverage the geometry of covariance matrices, leading to three steps: recentering, re-scaling, and rotation correction. This work explains theoretically how differences in brain activity, anatomy, or device configuration lead to certain shifts in data covariances. Using controlled simulations, the different alignment methods are evaluated. Their practical relevance is evaluated for brain age prediction on one MEG dataset (Cam-CAN,n=646) and two EEG datasets (TUAB,n=1385; LEMON,n=213). When the target sample included recordings from the same subjects with a different task among the same dataset, paired rotation correction was essential ((rest-passive) or +0.17 (rest-smt)). When the target dataset included new subjects and a new task, re-centering led to improved performance (for rest-passive,for rest-smt). For generalization to an independent dataset sampled from a different population and recorded with a different device, re-centering was necessary to achieve brain age prediction performance close to within domain prediction performance. This study demonstrates that the generalization of M/EEG-based regression models across datasets can be substantially enhanced by applying domain adaptation procedures that can statistically harmonize diverse datasets.
Abundant capped RNAs are derived from mRNA cleavage at 3’UTR G-Quadruplexes
Authors: Haberman Nejc , Digby Holly , Faraway Rupert , Cheung Rebecca , Jobbins Andrew M , Parr Callum , Yasuzawa Kayoko , Kasukawa Takeya , Yip Chi Wai , Kato Masaki , Takahashi Hazuki , Carninci Piero , Vernia Santiago , Ule Jernej , Sibley Christopher R , Martinez-Sanchez Aida , Lenhard Boris 
Published: April 2023

SummaryThe 3’ untranslated region (3’UTR) plays a crucial role in determining mRNA stability, localisation, translation and degradation. Cap analysis gene expression (CAGE), a method for the detection of capped 5’ ends of mRNAs, additionally reveals a large number of apparently 5’ capped RNAs derived from 3’UTRs. Here we provide the first direct evidence that these 3’UTR-derived RNAs are indeed capped and often more abundant than the corresponding full-length mRNAs. By using a combination of AGO2 enhanced individual nucleotide resolution UV crosslinking and immunoprecipitation (eiCLIP) and CAGE following siRNA knockdowns, we find that these 3’UTR-derived RNAs likely originate from AGO2-mediated cleavage, and most often occur at locations with potential to form RNA-G-quadruplexes and are enriched by RNA-binding protein UPF1. High-resolution imaging and long-read sequencing analysis validates several 3’UTR-derived RNAs, demonstrates their abundance and shows that they tend not to co-localise with the parental mRNAs. We also find that production of 3’UTR-derived RNA could explain the previously reported role of a 3’UTR G-quadruplex in regulating the production of APP protein. Taken together, we provide new insights into the origin and abundance of 3’UTR-derived RNAs, show the utility of CAGE-seq for their quantitative detection, and provide a rich dataset for exploring new biology of a poorly understood new class of RNAs.
Exploration-exploitation mechanisms in recurrent neural networks and human learners in restless bandit problems
Authors: Tuzsus D. , Brands A. , Pappas I. , Peters J. 
Published: April 2023

AbstractA key feature of animal and human decision-making is to balance the exploration of unknown options for information gain (directed exploration) versus selecting known options for immediate reward (exploitation), which is often examined using restless bandit tasks. Recurrent neural network models (RNNs) have recently gained traction in both human and systems neuroscience work on reinforcement learning, due to their ability to show meta-learning of task domains. Here we comprehensively compared the performance of a range of RNN architectures as well as human learners on restless four-armed bandit problems. The best-performing architecture (LSTM network with computation noise) exhibited human-level performance. Computational modeling of behavior first revealed that both human and RNN behavioral data contain signatures of higher-order perseveration, i.e., perseveration beyond the last trial, but this effect was more pronounced in RNNs. In contrast, human learners, but not RNNs, exhibited a positive effect of uncertainty on choice probability (directed exploration). RNN hidden unit dynamics revealed that exploratory choices were associated with a disruption of choice predictive signals during states of low state value, resembling a win-stay-loose-shift strategy, and resonating with previous single unit recording findings in monkey prefrontal cortex. Our results highlight both similarities and differences between exploration behavior as it emerges in meta-learning RNNs, and computational mechanisms identified in cognitive and systems neuroscience work.
Evaluating the interplay between estrous cyclicity and induced seizure susceptibility inScn2aK1422Emice
Authors: Echevarria-Cooper Dennis M. , Kearney Jennifer A. 
Published: April 2023

AbstractPathogenic variants inSCN2Aare associated with a range of neurodevelopmental disorders (NDD).SCN2A-related NDD show wide phenotypic heterogeneity, suggesting that modifying factors must be considered in order to properly elucidate the mechanisms of pathogenic variants. Recently, we characterized neurological phenotypes in a mouse model of the variantSCN2A-p.K1422E. We demonstrated that heterozygousScn2aK1422Efemale mice showed a distinct, reproducible distribution of flurothyl-induced seizure thresholds. Women with epilepsy often show a cyclical pattern of altered seizure susceptibility during specific phases of the menstrual cycle which can be attributed to fluctuations in hormones and corresponding changes in neurosteroid levels. Rodent models have been used extensively to examine the relationship between the estrous (menstrual) cycle, steroid hormones, and seizure susceptibility. However, the effects of the estrous cycle on seizure susceptibility have not been evaluated in the context of an epilepsy-associated genetic variant. To determine whether the estrous cycle affects susceptibility to flurothyl-induced seizures inScn2aK1422Efemale mice, estrous cycle monitoring was performed in mice that had undergone ovariectomy (OVX), sham surgery, or no treatment prior to seizure induction. Removing the influence of circulating sex hormones via OVX did not affect the non-unimodal distribution of flurothyl seizure thresholds observed inScn2aK1422Efemales. Additionally, flurothyl seizure thresholds were not associated with estrous cycle stage in mice that underwent sham surgery or were untreated. These data suggest that variation inScn2aK1422Eflurothyl seizure threshold is not significantly influenced by the estrous cycle and, by extension, fluctuations in ovarian hormones. Interestingly, untreatedScn2aK1422Efemales showed evidence of disrupted estrous cyclicity, an effect not previously described in a genetic epilepsy model. This unexpected result highlights the importance of considering sex specific effects and the estrous cycle in support of more inclusive biomedical research.
A Bacterial Living Therapeutics with Engineered Protein Secretion Circuits To Eliminate Breast Cancer Cells
Authors: Shahid Gozeel Binte , Ahan Recep Erdem , Ostaku Julian , Seker Urartu Ozgur Safak 
Published: April 2023

AbstractCancer therapy can be limited by potential side effects, and bacteria-based living cancer therapeutics have gained scientific interest in recent years. However, the full potential of bacteria as therapeutics has yet to be explored due to engineering challenges. n this study, we present a bacterial device designed to specifically target and eliminate breast cancer cells. We have engineeredEscherichia coli(E. coli) to secrete a Shiga toxin, HlyE, which is a pore-forming protein that binds to HER2 receptors on breast cancer cells. This binding is facilitated by a nanobody expressed on the bacteria’s surface via the Ag43 autotransporter protein system. Our findings demonstrate that the nanobody efficiently binds to HER2+ cells in vitro, and we have utilized the YebF secretion system to secrete HlyE and kill the target cancer cells. Overall, our results highlight the potential of our engineered bacteria as an innovative strategy for breast cancer treatment.
Ventral hippocampal CCK interneurons gate context-reward memory
Authors: Nguyen Robin , Sivakumaran Sanghavy , Lambe Evelyn K. , Kim Jun chul 
Published: April 2023

SUMMARYAssociating contexts with rewards depends on hippocampal circuits, with local inhibitory interneurons positioned to play an important role in shaping activity. Here, we hypothesize that the encoding of context-reward memory requires a ventral hippocampus (vHPC) to nucleus accumbens (NAc) circuit that is gated by CCK interneurons. In a sucrose conditioned place preference (CPP) task, optogenetically inhibiting vHPC-NAc terminals impaired the acquisition of place preference. Transsynaptic rabies tracing revealed vHPC-NAc neurons were monosynaptically innervated by CCK interneurons. Using intersectional genetic targeting of CCK interneurons,ex vivooptogenetic activation of CCK interneurons increased GABAergic transmission onto vHPC-NAc neurons, whilein vivooptogenetic inhibition of CCK interneurons increased cFos in these neurons. Notably, CCK interneuron inhibition during sucrose CPP learning increased time spent in the sucrose-associated location, suggesting enhanced place-reward memory. Our findings reveal a previously unknown hippocampal microcircuit crucial for modulating the strength of contextual reward learning.