bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engaging dystonia networks with subthalamic stimulation
Authors: Butenko Konstantin , Neudorfer Clemens , Dembek Till A. , Hollunder Barbara , Meyer Garance M. , Li Ningfei , Oxenford Simón , Bahners Bahne H. , Al-Fatly Bassam , Lofredi Roxanne , Gordon Evan M. , Dosenbach Nico U.F. , Ganos Christos , Hallett Mark , Starr Philip A. , Ostrem Jill L. , Wu Yiwen , Zhang ChenCheng , Fox Michael D. , Horn Andreas 
Published: May 2024

AbstractDeep brain stimulation is a viable and efficacious treatment option for dystonia. While the internal pallidum serves as the primary target, more recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its complex surroundings have not been studied in depth. Indeed, multiple historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the exact same target. Therefore, a thorough investigation of the neural substrates underlying effects on dystonia symptoms is warranted.Here, we analyze a multi-center cohort of isolated dystonia patients with subthalamic implantations (N= 58) and relate their stimulation sites to improvement of appendicular and cervical symptoms as well as blepharospasm. Stimulation of the ventral oral posterior nucleus of thalamus and surrounding regions was associated with improvement in cervical dystonia, while stimulation of the dorsolateral STN was associated with improvement in limb dystonia and blepharospasm. This dissociation was also evident for structural connectivity, where the cerebellothalamic, corticospinal and pallidosubthalamic tracts were associated with improvement of cervical dystonia, while hyperdirect and subthalamopallidal pathways were associated with alleviation of limb dystonia and blepharospasm. Importantly, a single well-placed electrode may reach the three optimal target sites. On the level of functional networks, improvement of limb dystonia was correlated with connectivity to the corresponding somatotopic regions in primary motor cortex, while alleviation of cervical dystonia was correlated with connectivity to the recently described ‘action-mode’ network that involves supplementary motor and premotor cortex. Our findings suggest that different types of dystonia symptoms are modulated via distinct networks. Namely, appendicular dystonia and blepharospasm are improved with modulation of the basal ganglia, and, in particular, the subthalamic circuitry, including projections from the primary motor cortex. In contrast, cervical dystonia was more responsive when engaging the cerebello-thalamo-cortical circuit, including direct stimulation of ventral thalamic nuclei.These findings may inform DBS targeting and image-based programming strategies for patient-specific treatment of dystonia.
UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples
Authors: Xie Amy X. , Tansey Wesley , Reznik Ed 
Published: May 2024

AbstractComprehensively studying metabolism requires the measurement of metabolite levels. However, in contrast to the broad availability of gene expression data, metabolites are rarely measured in large molecularly-defined cohorts of tissue samples. To address this basic barrier to metabolic discovery, we propose a Bayesian framework (“UnitedMet”) which leverages the empirical strength of RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. We demonstrate that UnitedMet is equally capable of imputing whole pool sizes as well as the outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying a novel association betweenBAP1and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to combination therapy, and that kidney cancer metastases themselves demonstrate elevated oxidative phosphorylation relative to primary tumors. UnitedMet therefore enables the assessment of metabolic phenotypes in contexts where metabolite measurements were not taken or are otherwise infeasible, opening new avenues for the generation and evaluation of metabolite-centered hypotheses. UnitedMet is open source and publicly available (https://github.com/reznik-lab/UnitedMet).
Comparative analysis of tardigrade locomotion across life stage, species, and pharmacological treatment
Authors: Anderson Emma M. , Houck Sierra G. , Conklin Claire L. , Tucci Katrina L. , Rodas Joseph D. , Mori Kate E. , Armstrong Loriann J. , Illingworth Virginia B. , Lo Te-Wen , Woods Ian G. 
Published: May 2024

AbstractAnimal locomotion requires coordination between the central and peripheral nervous systems, between sensory inputs and motor outputs, and between nerves and muscles. Analysis of locomotion thus provides a comprehensive and sensitive readout of nervous system function and dysfunction. Tardigrades, the smallest known walking animals, coordinate movement of their eight legs with a relatively simple nervous system, and are a promising model for neuronal control of limb-driven locomotion. Here, we developed open-source tools for automated tracking of tardigrade locomotion in an unconstrained two-dimensional environment, for measuring multiple parameters of individual leg movements, and for quantifying interleg coordination. We used these tools to analyze >13,000 complete strides in >100 tardigrades, and identified preferred walking speeds and distinct step coordination patterns associated with those speeds. In addition, the rear legs of tardigrades, although they have distinct anatomy and step kinematics, were nonetheless incorporated into overall patterns of interleg coordination. Finally, comparisons of tardigrade locomotion across lifespan, between species, and between pharmacological treatments suggested that neuronal regulation of high-level aspects of walking (e.g. speed, turns, walking bout initiation) operate independently from circuits controlling individual leg movements and interleg coordination.
Perceptual tri-stability, measured and fitted as emergent from a model for bistable alternations
Authors: Sun Jiaqiu Vince , Jing Zeyu , Rankin James , Rinzel John 
Published: May 2024

AbstractThe human auditory system in attempting to decipher ambiguous sounds appears to resort to perceptual exploration as evidenced by multi-stable perceptual alternations. This phenomenon has been widely investigated via the auditory streaming paradigm, employing ABA_ triplet sequences with much research focused on perceptual bi-stability with the alternate percepts as either a single integrated stream or as two simultaneous distinct streams. We extend this inquiry with experiments and modeling to include tri-stable perception. Here, the segregated percepts may involve a foreground/background distinction. We collected empirical data from participants engaged in a tri-stable auditory task, utilizing this dataset to refine a neural mechanistic model that had successfully reproduced multiple features of auditory bi-stability. Remarkably, the model successfully emulated basic statistical characteristics of tri-stability without substantial modification. This model also allows us to demonstrate a parsimonious approach to account for individual variability by adjusting the parameter of either the noise level or the neural adaptation strength.
Noise Reduction in Resource-Coupled Multi-Module Gene Circuits through Antithetic Feedback Control
Authors: Chakravarty Suchana , Zhang Rong , Tian Xiao-Jun 
Published: May 2024

AbstractGene circuits within the same host cell often experience coupling, stemming from the competition for limited resources during transcriptional and translational processes. This resource competition introduces an additional layer of noise to gene expression. Here we present three multi-module antithetic control strategies: negatively competitive regulation (NCR) controller, alongside local and global controllers, aimed at reducing the gene expression noise within the context of resource competition. Through stochastic simulations and fluctuation-dissipation theorem (FDT) analysis, our findings highlight the superior performance of the NCR antithetic controller in reducing noise levels. Our research provides an effective control strategy for attenuating resource-driven noise and offers insight into the development of robust gene circuits.
Delayed developmental maturation of frontal cortical circuits impacts decision-making
Authors: Mastro Kevin , Lee Wen-Chun , Wang Wengang , Stevens Beth , Sabatini Bernardo L. 
Published: May 2024

AbstractIn humans, frontal cortical circuits mature in parallel with the development of higher cognitive functions over the course of 15-20 years. In mice, behavior and brain structure change rapidly until reaching sexual maturity (∼8 weeks of age). In contrast, the degree to which frontal cortices and the behaviors they support continue to develop in mice after this period is unclear. Here, we uncover age-related changes in the acquisition and execution of a probabilistic reward reinforcement task. Both young and old mice complete a similar number of trials per session, but 16-30-week-old mice obtain higher reward rates than younger mice. The older mice adjust their behavior more readily after failing to receive a reward, suggesting that age-dependent changes to circuits relevant to forming action-outcome associations, such as those in frontal associative cortices (FACs). Indeed, we identified cell-type and input-specific refinements of FAC circuits over the first 24 weeks of age, including protracted reductions in excitatory drive and increases in inhibition onto pyramidal cells. Dampening inhibitory activity in FAC alters behavior in a manner that counteracts the age-related differences. Together, these reveal an extended period of synaptic maturation in FAC that directly impacts age-related changes in decision-making.
A modular strategy for extracellular vesicle-mediated CRISPR-Cas9 delivery through aptamer-based loading and UV-activated cargo release
Authors: Elsharkasy Omnia M. , Hegeman Charlotte V. , Lansweers Ivana , Cotugno Olaf L. , de Groot Ingmar Y. , de Wit Zoë E.M.N.J. , Liang Xiuming , Garcia-Guerra Antonio , Moorman Niels J.A. , Lefferts Juliet , de Voogt Willemijn S. , Gitz-Francois Jerney J. , van Wesel Annet C.W. , El Andaloussi Samir , Schiffelers Raymond M. , Kooijmans Sander A.A. , Mastrobattista Enrico , Vader Pieter , de Jong Olivier G. 
Published: May 2024

AbstractCRISPR-Cas9 gene editing technology offers the potential to permanently repair genes containing pathological mutations. However, efficient intracellular delivery of the Cas9 ribonucleoprotein complex remains one of the major hurdles in its therapeutic application. Extracellular vesicles (EVs) are biological nanosized membrane vesicles released by cells, that play an important role in intercellular communication. Due to their innate capability of intercellular transfer of proteins, RNA, and various other biological cargos, EVs have emerged as a novel promising strategy for the delivery of macromolecular biotherapeutics, including CRISPR-Cas9 ribonucleoproteins. Here, we present a versatile, modular strategy for the loading and delivery of Cas9. We leverage the high affinity binding of MS2 coat proteins (MCPs) fused to EV-enriched proteins to MS2 aptamers incorporated into single guide RNAs (sgRNAs), in combination with a UV-activated photocleavable linker domain, PhoCl. Combined with the Vesicular stomatitis virus G (VSV-G) protein this modular platform enables efficient loading and subsequent delivery of the Cas9 ribonucleoprotein complex, which shows critical dependence on the incorporation and activation of the photocleavable linker domain. As this approach does not require any direct fusion of Cas9 to EV-enriched proteins, we demonstrate that Cas9 can readily be exchanged for other variants, including transcriptional activator dCas9-VPR and adenine base editor ABE8e, as confirmed by various sensitive fluorescent reporter assays. Taken together, we describe a robust and modular strategy for successful Cas9 delivery, which can be applied for CRISPR-Cas9-based genetic engineering as well as transcriptional regulation, underlining the potential of EV-mediated strategies for the treatment of genetic diseases.
Sex-focused analyses of M83 A53T hemizygous mouse model with recombinant human alpha-synuclein preformed fibril injection identifies female resilience to disease progression: A combined magnetic resonance imaging and behavioural study
Authors: Tullo Stephanie , Park Janice , Gallino Daniel , Park Megan , Mar Kristie , Novikov Vladislav , Sandoval Contreras Rodrigo , Patel Raihaan , del Cid-Pellitero Esther , Fon Edward A. , Luo Wen , Shlaifer Irina , Durcan Thomas M. , Prado Marco A.M. , Prado Vania F. , Devenyi Gabriel A. , Chakravarty M. Mallar 
Published: May 2024

AbstractAlpha-synuclein (aSyn) pathology has been extensively studied in mouse models harbouring human mutations. In spite of the known sex differences in age of onset, prevalence and disease presentation in human synucleinopathies, the impact of sex on aSyn propagation has received very little attention. To address this need, we examined sex differences in whole brain signatures of neurodegeneration due to aSyn toxicity in the M83 mouse model using longitudinal magnetic resonance imaging (MRI; T1-weighted; 100 μm3isotropic voxel; acquired −7, 30, 90 and 120 days post-injection [dpi]; n≥8 mice/group/sex/time point). To initiate aSyn spreading, M83 mice were inoculated with recombinant human aSyn preformed fibrils (Hu-PFF) or phosphate buffered saline (PBS) injected in the right dorsal striatum. We observed more aggressive neurodegenerative profiles over time for male M83 Hu-PFF-injected mice when examining voxel-wise trajectories. However, at 90 dpi, we observed widespread patterns of neurodegeneration in the female Hu-PFF-injected mice. These differences were not accompanied with any differences in motor symptom onset between the male and female Hu-PFF-injected mice. However, male Hu-PFF-injected mice reached their humane endpoint sooner. These findings suggest that post-motor symptom onset, even though more accelerated disease trajectories were observed for male Hu-PFF-injected mice, neurodegeneration may appear sooner in female Hu-PFF-injected mice (prior to motor symptomatology). These findings suggest that sex-specific synucleinopathy phenotypes urgently need to be considered to improve our understanding of neuroprotective and neurodegenerative mechanisms.
Structural comparison of protein-RNA homologous interfaces reveals widespread overall conservation contrasted with versatility in polar contacts
Authors: Mahmoudi Ikram , Quignot Chloé , Martins Carla , Andreani Jessica 
Published: May 2024

AbstractProtein-RNA interactions play a critical role in many cellular processes and pathologies. However, experimental determination of protein-RNA structures is still challenging, therefore computational tools are needed for the prediction of protein-RNA interfaces. Although evolutionary pressures can be exploited for structural prediction of protein-protein interfaces, and recent deep learning methods using protein multiple sequence alignments have radically improved the performance of protein-protein interface structural prediction, protein-RNA structural prediction is lagging behind, due to the scarcity of structural data and the flexibility involved in these complexes. To study the evolution of protein-RNA interface structures, we first identified a large and diverse dataset of 2,022 pairs of structurally homologous interfaces (termed structural interologs). We leveraged this unique dataset to analyze the conservation of interface contacts among structural interologs based on the properties of involved amino acids and nucleotides. We uncovered that 73% of distance-based contacts and 68% of apolar contacts are conserved on average, and the strong conservation of these contacts occurs even in distant homologs with sequence identity below 20%. Distance-based contacts are also much more conserved compared to what we had found in a previous study of homologous protein-protein interfaces. In contrast, hydrogen bonds, salt bridges, and π-stacking interactions are very versatile in pairs of protein-RNA interologs, even for close homologs with high interface sequence identity. We found that almost half of the non-conserved distance-based contacts are due to a small proportion of interface residues that no longer belong to the interface in the interolog, a phenomenon we term “interface switching out”. We also examined possible recovery mechanisms for non-conserved hydrogen bonds and salt bridges, uncovering diverse scenarii of switching out, change in amino acid chemical nature, intermolecular and intramolecular compensations. Our findings provide insights for integrating evolutionary signals into predictive protein-RNA structural modeling methods.
Immunogenicity and protective efficacy of an influenza virus-like particle-based SARS-CoV-2 hybrid vaccine candidate in rhesus macaques
Authors: Rahman Sheikh Abdul , Bommireddy Ramireddy , Routhu Nanda Kishore , Lai Lilin , Pack Christopher D. , Ramachandiran Sampath , Suthar Mehul S. , Reddy Shaker J. C. , Selvaraj Periasamy , Amara Rama Rao 
Published: May 2024

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus co-infections present a heightened COVID-19 disease and hospitalization cases. Here, we studied the immunogenicity and efficacy of an influenza-A/PR8 virus-like particle (FluVLP)-based hybrid vaccine candidate displaying GPI-anchored SARS-CoV-2 receptor binding domain fused to GM-CSF and GPI-anchored interleukin-12 (FluVLP-RBD) in rhesus macaques. Animals (n=4/group) received two doses of eitherFluVLP orFluVLP-RBD vaccine four weeks apart and were challenged with SARS-CoV-2 (WA1/2020) infection via intranasal and intratracheal routes. We determined vaccine-induced IgG and neutralizing antibody titers in serum and their association with viral replication in the lower and upper airways (lung, throat, and nose) and lung-associated pathologies.FluVLP-RBD vaccine induced a strong binding IgG in serum against multiple SARS-CoV-2 variants (WA1/2020, Delta and Omicron; BA.1). Both vaccines induced strong influenza A/PR8-specific IgG. Following the SARS-CoV-2 challenge, all four animals in theFluVLP-RBD group showed a profound control of virus replication in all three airway compartments as early as day 2 through day 10 (day of euthanasia). This level of viral control was not observed in theFluVLP group as 2-3 animals exhibited high virus replication in all three airway compartments. The protection in theFluVLP-RBD vaccinated group correlated positively with post challenge neutralizing antibody titer. These results demonstrated that aFluVLP-based hybrid SARS-CoV-2 vaccine induces strong antibody responses against influenza-A/PR8 and multiple SARS-CoV-2 RBD variants and protects from SARS-CoV-2 replication in multiple compartments in macaques. These findings provide important insights for developing multivalent vaccine strategies for respiratory viruses.ImportanceCo-infection with multiple respiratory viruses poses a greater risk than individual infections, especially for individuals with underlying health conditions. Studies in humans consistently demonstrated that simultaneous infection with SARS-CoV-2 and influenza leads to more severe respiratory illness and an increased rate of hospitalization. Therefore, developing hybrid vaccines targeting multiple respiratory viruses is of high importance. The hybrid vaccines also help to reduce the economic and logistic burden associated with vaccine coverage, distribution and storage. Here, we evaluate the immunogenicity and effectiveness of a novel hybrid flu-SARS-CoV-2 vaccine candidate using a nonhuman primate pre-clinical model. Our findings reveal that this vaccine elicits a strong immune response against influenza and SARS-CoV-2 viruses. Importantly, it provides strong protection against SARS-CoV-2 infection and associated pathological conditions.
Rapidly inducible yeast surface display for antibody evolution with OrthoRep
Authors: Paulk Alexandra M. , Williams Rory L. , Liu Chang C. 
Published: May 2024

AbstractWe recently developed ‘autonomous hypermutation yeast surface display’ (AHEAD), a technology that enables the rapid generation of potent and specific antibodies in yeast. AHEAD pairs yeast surface display with an error-prone orthogonal DNA replication system (OrthoRep) to continuously and rapidly mutate surface-displayed antibodies, thereby enabling enrichment for stronger binding variants through repeated rounds of cell growth and fluorescence activated cell sorting (FACS). AHEAD currently utilizes a standard galactose induction system to drive the selective display of antibodies on the yeast surface. However, achieving maximal display levels can require up to 48 hours of induction. Here, we report an updated version of the AHEAD platform that utilizes a synthetic β-estradiol induced gene expression system to regulate the surface display of antibodies and find that induction is notably faster in achieving surface display for both our AHEAD system as well as traditional yeast surface display from nuclear plasmids that do not hypermutate. The updated AHEAD platform was fully functional in repeated rounds of evolution to drive the rapid evolution of antibodies.
The mammary glands of cows abundantly display receptors for circulating avian H5 viruses
Authors: Ríos Carrasco María , Gröne Andrea , van den Brand Judith M.A. , de Vries Robert P. 
Published: May 2024

AbstractInfluenza A viruses (IAV) from the H5N1 2.3.4.4b clade are circulating in dairy farms in the United States of America, and goat infections have also been reported. These ruminants were presumed not to be hosts for IAVs. Previously, IAV-positive mammalian species were hunters and scavengers, possibly getting infected while feeding on infected birds. It is now presumed that H5N1 viruses that circulate in US dairy cattle transmit through a mammary gland route, in contrast to transmission by aerosols via the respiratory tract, although the latter cannot be excluded. The receptor display in the mammary and respiratory tract in cows for IAVs is unknown. Here, we used recombinant HA proteins representing current circulating and classical H5 viruses to determine the distribution of IAV receptors in the respiratory and mammary tract tissues of cows and goats. Most of the sialome of the cow and goat respiratory tract is lined with sialic acid modifications such as N-glycolyl and O-acetyl, which are not bound by IAV. Interestingly, the H5 protein representing the cow isolates bound significantly in the mammary gland, whereas classical H5 proteins failed to do so. Furthermore, whereas the 9-O-acetyl modification is prominent in all tissues tested, the 5-N-glycolyl modification is not, resulting in the display of receptors for avian IAV hemagglutinins. This could explain the high levels of virus found in these tissues and milk, adding supporting data to this possible virus transmission route.