bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Digital Surgical Planning and Surgical Guides in the Treatment of Unilateral Condylar Hyperplasia
Authors: Figueroa Alvaro A. , Harmon Kelly A. , Arnold Sydney , Xu Hope , Roy Tulsi , Reid Russell R. , Tragos Christina
Published: October 2023

Unilateral condylar hyperplasia (UCH) results in facial asymmetry, malocclusion, and temporomandibular joint dysfunction. Treatment consists of both surgical and orthodontic intervention. A review was performed for 4 patients with UCH who underwent digital surgical planning (DSP)-assisted condylectomy. All patients were female, aged 14 to 35 years at the time of operation with facial asymmetry and class III malocclusion. None of the patients had prior treatment and all had perioperative orthodontic appliances to provide fixation and postoperative elastic therapy. All patients underwent DSP-guided condylectomy, and intraoperative surgical cutting guides were used for 3 of the patients. All had significant improvement in facial symmetry and occlusion. None had recurrence, and additional intervention has not been required. If UCH is recognized before marked secondary changes in the maxilla, mandible, and occlusion, future orthognathic surgery may be potentially obviated. Craniomaxillofacial surgeons should consider using DSP and surgical guides in the treatment of UCH.
Put It in the Air? Nebulized Opioids in the Emergency Department
Authors: Bailey Abby M. , Weant Kyle A.
Published: October 2023

The emergency department (ED) is a frequent utilizer of alternative routes of medication administration (e.g., intranasal) for a variety of indications. Over the last several years, investigations into the use of medications via the nebulization route have greatly increased, with varying degrees of efficacy identified. This route has multiple theoretical advantages. Medications affecting bronchopulmonary function or secretions can be administered directly to the site of action, possibly utilizing a lower dose and hence minimizing side effects. It is also possible to have a faster onset of action compared with other routes, given the enhanced surface area for absorption. One group of medications that has been explored via this route of administration, and is frequently administered in EDs across the nation, is opioids, most notably fentanyl, hydromorphone, and morphine. However multiple questions exist regarding the implementation of these therapies via this route, including efficacy, dosing, and the functional aspects of medication administration that are more complex than that of more traditional routes. The intent of this review is to explore the supporting literature behind the use of nebulized opioids, most specifically fentanyl, hydromorphone, and morphine, in the ED for the treatment of acute pain presentations and provide the most up-to-date guidance for practitioners.
Microbiological Culture Versus 16S/18S Ribosomal RNA PCR-Sanger Sequencing for Infectious Keratitis: A Three-Arm, Diagnostic Cross-Sectional Study
Authors: Hammoudeh Yasmeen , Suresh Lakshmi , Ong Zun Zheng , Lister Michelle M. , Mohammed Imran , Thomas D. John I. , Cottell Jennifer L. , Holden Jennifer M. , Said Dalia G. , Dua Harminder S. , Jeng Ting Darren Shu
Published: October 2023

Purpose

To compare the diagnostic performance of microbiological culture and 16S/18S polymerase chain reaction (PCR)-Sanger sequencing for infectious keratitis (IK) and to analyse the effect of clinical disease severity on test performance and inter-test concordance.

Design

A three-arm, diagnostic cross-sectional study.

Subjects

We included patients who presented with presumed bacterial/fungal keratitis to the Queen’s Medical Centre, Nottingham, UK, between June 2021 and September 2022.

Methods/interventions

All patients underwent simultaneous culture (either direct or indirect culture, or both) and 16S (pan-bacterial) / 18S (pan-fungal) ribosomal RNA (rRNA) PCR-Sanger sequencing. The bacterial/fungal genus and species identified on culture were confirmed using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. Relevant clinical data were also collected to analyze for any potential clinico-microbiological correlation.

Main outcome measures

Diagnostic yield, test accuracy (including sensitivity and specificity), and inter-test agreement [including percent agreement and Cohen’s kappa (k)].

Results

A total of 81 patients (86 episodes of IK) were included in this study. All organisms identified were of bacterial origin. Diagnostic yields were similar among direct culture (52.3%), indirect culture (50.8%), and PCR (43.1%; p=0.13). The addition of PCR enabled a positive diagnostic yield in 3 (9.7%) direct culture-negative cases. Based on composite reference standard, direct culture had the highest sensitivity (87.5%; 95% CI, 72.4-95.3%), followed by indirect culture (85.4%; 95% CI, 71.6-93.5%) and PCR (73.5%; 95% CI, 59.0- 84.6%), with 100% specificity noted in all tests. Pairwise comparisons showed substantial agreement among the three tests (percent agreement=81.8-86.2%, Cohen’sk=0.67-0.72). Clinico-microbiological correlation demonstrated higher culture-PCR concordance in cases with greater infection severity.

Conclusions

This study highlights a similar diagnostic performance of direct culture, indirect culture and 16S rRNA PCR for bacterial keratitis, with substantial inter-test concordance. PCR serves as a useful diagnostic adjuvant to culture, particularly in culture- negative cases or those with lesser disease severity (where culture-PCR concordance is lower).
Multi-session transcutaneous spinal cord stimulation prevents chloride homeostasis imbalance and the development of spasticity after spinal cord injury in rat
Authors: Malloy Dillon C. , Côté Marie-Pascale
Published: October 2023

Spasticity is a complex and multidimensional disorder that impacts nearly 75% of individuals with spinal cord injury (SCI) and currently lacks adequate treatment options. This sensorimotor condition is burdensome as hyperexcitability of reflex pathways result in exacerbated reflex responses, co-contractions of antagonistic muscles, and involuntary movements. Transcutaneous spinal cord stimulation (tSCS) has become a popular tool in the human SCI research field. The likeliness for this intervention to be successful as a noninvasive anti-spastic therapy after SCI is suggested by a mild and transitory improvement in spastic symptoms following a single stimulation session, but it remains to be determined if repeated tSCS over the course of weeks can produce more profound effects. Despite its popularity, the neuroplasticity induced by tSCS also remains widely unexplored, particularly due to the lack of suitable animal models to investigate this intervention. Thus, the basis of this work was to use tSCS over multiple sessions (multi-session tSCS) in a rat model to target spasticity after SCI and identify the long-term physiological improvements and anatomical neuroplasticity occurring in the spinal cord. Here, we show that multi-session tSCS in rats with an incomplete (severe T9 contusion) SCI (1) decreases hyperreflexia, (2) increases the low frequency-dependent modulation of the H-reflex, (3) prevents potassium-chloride cotransporter isoform 2 (KCC2) membrane downregulation in lumbar motoneurons, and (4) generally augments motor output, i.e., EMG amplitude in response to single pulses of tSCS, particularly in extensor muscles. Together, this work displays that multi-session tSCS can target and diminish spasticity after SCI as an alternative to pharmacological interventions and begins to highlight the underlying neuroplasticity contributing to its success in improving functional recovery.
Reassessment of the risks of climate change for terrestrial ecosystems
Authors: Conradi Timo , Eggli Urs , Kreft Holger , Schweiger Andreas H. , Weigelt Patrick , Higgins Steven I.
Published: October 2023

Forecasting the risks of climate change for species and ecosystems is necessary for developing targeted conservation strategies. Previous risk assessments mapped the exposure of the global land surface to changes in climate1–4However, this procedure is unlikely to robustly identify priority areas for conservation actions because non-linear physiological responses and co-limitation processes ensure that ecological changes will not map perfectly to the forecast climatic changes. Here, we combine ecophysio­logical growth models of 135,153 vascular plant species and plant growth form information to transform ambient and future climatologies into phytoclimates, which describe the ability of climates to support the plant growth forms that characterise terrestrial ecosystems. We forecast that 33% to 68% of the global land surface will experience a significant change in phytoclimate by 2070 under RCP 2.6 and RCP 8.5, respectively. Novel phytoclimates without present-day analogue are forecast to emerge on 0.3-2.2% of the land surface, and 0.1-1.3% of currently realised phytoclimates are forecast to disappear. Notably, the geographic pattern of change, disappearance and novelty of phytoclimates differs markedly from the pattern of analogous trends in climates detected by previous studies1,3,4, thereby defining new priorities for conservation actions and highlighting the limits of using untransformed climate change exposure indices in ecologicaI risk assessments. Our findings suggest that a profound transformation of the biosphere is underway and emphasise the need for a timely adaptation of biodiversity management practices.
Foundation Models Meet Imbalanced Single-Cell Data When Learning Cell Type Annotations
Authors: Alsabbagh Abdel Rahman , de Infante Alberto Maillo Ruiz , Gomez-Cabrero David , Kiani Narsis A. , Khan Sumeer Ahmad , Tegnér Jesper N.
Published: October 2023

With the emergence of single-cell foundation models, an important question arises: how do these models perform when trained on datasets having an imbalance in cell type distribution due to rare cell types or biased sampling? We benchmark three foundation models, scGPT, scBERT, and Geneformer, using skewed single-cell cell-type distribution for cell-type annotation. While all models had reduced performance when challenged with rare cell types, scGPT and scBERT, performed better than Geneformer. Notably, in contrast to scGPT and scBERT, Geneformer uses ordinal positions of the tokenized genes rather than actual raw gene expression values. To mitigate the effect of a skewed distribution, we find that random oversampling, but not random undersampling, improved the performance for all three foundation models. Finally, scGPT, using FlashAttention, has the fastest computational speed, whereas scBERT is more memory-efficient. We conclude that tokenization and data representation are essential areas of research, and new strategies are needed to mitigate the effects of imbalanced learning in single-cell foundation models. Code and data for reproducibility are available athttps://github.com/SabbaghCodes/ImbalancedLearningForSingleCellFoundationModels.
Repertoire-based mapping and time-tracking of helper T cell subsets in scRNA-Seq
Authors: Lukyanov D.K. , Kriukova V.V. , Ladell K. , Shagina I.A. , Staroverov D.B. , Minasian B.E. , Fedosova A.S. , Shelyakin P. , Suchalko O.N. , Komkov A.Y. , Blagodatskikh K.A. , Miners K.L. , Britanova O.V. , Franke A. , Price D.A. , Chudakov D.M.
Published: October 2023

The functional programs selected by CD4+ helper (Th) T cell clones fundamentally determine the architecture of the immune response to distinct challenges. Advances in scRNA-Seq have enhanced our understanding of the diversity of these programs, yet the correspondence between scRNA-Seq clusters and previously characterized Th subsets remains unclear. In this study, we use immune repertoires to position phenotypically sorted Th subsets within scRNA-Seq data from three healthy donors. This approach, termed TCR-Track, and accurately maps Th1, Th1-17, Th17, Th22, Th2a, Th2, Tfh, and Treg subsets, outperforming CITE-Seq-based mapping. Remarkably, the mapping is tightly focused on specific scRNA-Seq clusters despite a four-year interval between the sorting of subsets and the effector CD4+ scRNA-Seq experiment. Thus, while transient T cell plasticity is commonly observed in functionally active T cell populations, TCR-Track reveals high intrinsic program sustainability of Th clones circulating in peripheral blood. Repertoire overlap analysis at the scRNA-Seq level confirms that circulating Th1, Th2, Th2a, Th17, Th22, and Treg subsets are clonally independent. However, a prominent clonal overlap between corresponding clusters indicates that cytotoxic CD4+ T cells differentiate from Th1 clones. More specifically, we demonstrate that sorted CCR10+ Th cells correspond to a specific Th22 scRNA-Seq cluster, while CCR10-CCR6+CXCR3-CCR4+ cells, traditionally sorted as the Th17 subset, represent a mixture ofbona fideTh17 and clonally unrelated CCR10lowTh22 cells, which may have confounded investigators in previous studies. This clear distinction of Th17 and Th22 subsets should influence vaccine and T cell based therapies development. Additionally, we show that SARS-CoV-2 infection is associated with transient IFN type 1 activation of naive CD4+ T cells, and an increased proportion of effector IFN- induced Th cells is associated with a moderate course of the disease but remains low in critical COVID-19 cases. Using integrated scRNA-Seq, TCR-Track, and CITE-Seq data from 122 donors, we provide a comprehensive Th scRNA-Seq reference that should facilitate further investigation of Th subsets in fundamental and clinical studies.
Global transcription regulation revealed from dynamical correlations in time-resolved single-cell RNA-sequencing
Authors: Volteras Dimitris , Shahrezaei Vahid , Thomas Philipp
Published: October 2023

Single-cell transcriptomics reveals significant variations in the transcriptional activity across cells. Yet, it remains challenging to identify mechanisms of transcription dynamics from static snapshots. It is thus still unknown what drives global transcription dynamics in single cells. We present a stochastic model of gene expression with cell size- and cell cycle-dependent rates in growing and dividing cells that harnesses temporal dimensions of single-cell RNA-sequencing through metabolic labelling protocols and cell cycle reporters. We develop a parallel and highly scalable Approximate Bayesian Computation method that corrects for technical variation and accurately quantifies absolute burst frequency, burst size and degradation rate along the cell cycle at a transcriptome-wide scale. Using Bayesian model selection, we reveal scaling between transcription rates and cell size and unveil waves of gene regulation across the cell cycle-dependent transcriptome. Our study shows that stochastic modelling of dynamical correlations identifies global mechanisms of transcription regulation.
Divergent age-dependent conformational rearrangement within Aβ amyloid deposits in APP23, APPPS1, and AppNL-Fmice
Authors: Parvin Farjana , Haglund Samuel , Wegenast-Braun Bettina , Jucker Mathias , Saito Takashi , Saido Takaomi C , Nilsson K Peter R , Nilsson Per , Nyström Sofie , Hammarström Per
Published: October 2023

Amyloid plaques composed of fibrils of misfolded Aβ peptides are pathological hallmarks of Alzheimer’s disease (AD). Aβ fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potency and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aβ fibrils is valuable to understand disease mechanisms. Here, we investigated how Aβ fibril morphologyin situdiffers in Aβ plaque of different mouse models expressing familial mutations in the AβPP gene. We used a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands, Aβ-specific antibodies, and different fluorescence microscopy techniques. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, andAppNL-Fhave different fibril structures depending on AβPP-processing genotype. Co-staining of Aβ-specific antibodies showed that individual plaques from APP23 mice, expressing Swedish mutations (NL) have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact Aβ40 fibrils and the corona region is dominated by diffusely packed Aβ40 fibrils. On the other hand, the APP knock-in mouseAppNL-F, expressing Iberian mutation (F) along with Swedish mutation has tiny, cored plaques consisting mainly of compact Aβ42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age dependent polymorph maturation of plaque cores observed for APP23 and APPPS1 mice >12 months, was minuscule inAppNL-F. These structural studies of amyloid plaquesin situcan map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.

Significance

Alzheimer’s disease (AD) is associated with the formation of deposits in the brain known as Aβ-amyloid plaques. AD can emerge as a sporadic disease or due to familial mutations in genes encoding for Aβ precursor and processing proteins. The Aβ-amyloid found in plaques displays different structures in sporadic AD and in various types of familial AD. We hypothesize that understanding plaque morphology and development is crucial for understanding the initiation and progression of AD. We here compared amyloid structures in three of the most used mouse models of human Aβ-plaque formation. Our findings suggest significant differences in plaque morphologies and structural maturation processes during aging. Our results emphasize that strain-like differences of Aβ-amyloids develop as a function of Aβ precursor protein-processing genetics and age.
Pharmacological enhancement of dopamine neurotransmission does not affect illusory pattern perception
Authors: Smith Elke , Michalski Simon , Knauth Kilian , Tuzsus Deniz , Theis Hendrik , van Eimeren Thilo , Peters Jan
Published: October 2023

Psychotic symptoms and delusional belief have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (n= 48,n= 19 female) in a double-blind placebo-controlled within-subjects design (see preregistration athttps://osf.io/a4k9j/). We predicted individuals on vs. off L-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that L-DOPA compared to placebo increased false alarm rates. Further, L-DOPA did not modulate measures of accuracy, discrimination sensitivity and response bias. In all cases, Bayesian statistics revealed strong evidence in favour of the null hypothesis Future studies should address possible dose-dependent effects and differential effects in healthy vs. clinical samples.
Spectral-based detection of chromatin loops in multiplexed super-resolution FISH data
Authors: Liefsoens Michaël , Földes Timothy , Barbi Maria
Published: October 2023

Involved in mitotic condensation, interaction of transcriptional regulatory elements or isolation of structural domains, understanding loop formation is becoming a paradigm in the deciphering of chromatin architecture and its functional role. Despite the emergence of increasingly powerful genome visualization techniques, the high variability in cell populations and the randomness of conformations still make loop detection a challenge. We introduce a new approach for determining the presence and frequency of loops in a collection of experimental conformations obtained by multiplexed super-resolution imaging. Based on a spectral approach, in conjunction with neural networks, this method offers a powerful tool to detect loops in large experimental data sets, both at the population and single cell level. The method’s performance is confirmed by applying it to recently published experimental data, where it provides a detailed and statistically quantified description of the global architecture of the chromosomal region under study.
PDB NextGen Archive: Centralising Access to Integrated Annotations and Enriched Structural Information by the Worldwide Protein Data Bank
Authors: Choudhary Preeti , Feng Zukang , Berrisford John , Chao Henry , Ikegawa Yasuyo , Peisach Ezra , Piehl Dennis W. , Smith James , Tanweer Ahsan , Varadi Mihaly , Westbrook John D. , Young Jasmine Y. , Patwardhan Ardan , Morris Kyle L. , Hoch Jeffrey C. , Kurisu Genji , Velankar Sameer , Burley Stephen K.
Published: October 2023

The Protein Data Bank (PDB) archive is the global repository for public-domain 3D biomolecular structural information. The archival nature of the PDB presents certain challenges pertaining to updating or adding associated annotations from trusted external biodata resources. While each Worldwide PDB (wwPDB) partner has made best efforts to provide up-to-date external annotations, accessing and integrating information from disparate wwPDB data centers can be an involved process. To address this issue, the wwPDB has established the PDB Next Generation or NextGen Archive, developed to centralize and streamline access to enriched structural annotations from wwPDB partners and trusted external sources. At present, the archive provides mappings between experimentally determined 3D structures of proteins and UniProt amino acid sequences, together with domain annotations from Pfam, SCOP2, and CATH databases, and intra-molecular connectivity information. Since launch, the PDB NextGen Archive has seen substantial user engagement with over 3.5 million data file downloads, ensuring researchers have access to accurate, up-to-date, and easily accessible structural annotations.

Database URL

http://www.wwpdb.org/ftp/pdb-nextgen-archive-site
Non-random polymorphisms near transposable elements facilitate evolution across the genome ofArabidopsis thaliana
Authors: De Kort H. , Ganseman Y. , Deforce D. , Van Nieuwerburgh F.
Published: October 2023

Evolution is a key characteristic of all life on earth, and is achieved mainly through mutation and recombination. To facilitate evolutionary rates in the absence of recombination, increased mutagenesis could provide essential opportunities for evolution. Here, we harness the genomes of 973 wild accessions ofArabidopsis thaliana, a self-fertilizing species characterized by reduced recombination rates, to study the role of transposable elements (TEs) as mutagenic drivers of non-random genetic variation. We found that multiple TE superfamilies accumulate large numbers of genetic variants in gene-rich regions of the genome. Moreover, TEs were enriched in genes underpinning key molecular processes, including fertilization and mRNA cis-splicing, suggesting that TEs generate genetic variation that is fundamental to organismal functioning and reproduction. An excess of common genetic variants (maf>0.4) flanking TEs, despite the extreme degree of self-fertilization, further corroborates the notion that TEs can generate substantial evolutionary potential in the absence of outcrossing. Nevertheless, while other studies point to TE mobilization as a strategy to facilitate adaptive evolution, we find that only a fraction (4.8%) of TE families was linked to genetic variants involved in climate adaptation to a significantly larger extent than background genomic variation, possibly because the high mutation rates near TEs dilute adaptive signals. Overall, all TE superfamilies but one (Gypsy) were significantly associated with evolutionary processes through their association with genes, functional molecular processes, flanking common variants and/or climate adaptation. We conclude that non-random mutations flanking TEs provide substantial evolutionary potential in a self-fertilizing species.
Consistent higher emissions of carbon dioxide, nitrous oxide, and methane during the daytime in reservoirs
Authors: León-Palmero E. , Morales-Baquero R. , Reche I.
Published: October 2023

Greenhouse gas (GHG) emissions from reservoirs are quantitatively relevant for atmospheric climatic forcing. These emissions have large temporal variability, with daily changes accounting for a substantial part of this variability. However, most estimations for GHG fluxes are based on the upscaling of discrete measurements performed during the daytime and, in general, they do not account for nighttime emissions. Here, we explored the daily patterns of CO2, N2O, and diffusive and ebullitive CH4fluxes in two eutrophic reservoirs with contrasted morphometries in two different years. We found a daily pattern for CO2, N2O, and diffusive CH4fluxes with consistent higher emissions during the daytime than during the nighttime, irrespectively of reservoir morphometry. These three diffusive fluxes showed evident daily synchrony suggesting a common driver. The emissions were coupled with the daily solar cycle, wind speed, and water temperature. The daily emissions of the CO2, N2O, and CH4were also positive and significantly related to oxygen saturation. In contrast, we did not find a consistent daily pattern for the ebullitive CH4fluxes, although they represented a significant fraction of the total CH4emitted in these reservoirs. Our study suggests that the daily variability in GHG emissions may be as relevant as the variability at spatial scale or inter-system variability. Therefore, daily ranges should be considered in future GHG budgets to refine temporal trends of GHG emissions from reservoirs.
Landscape structure drives eco-evolution in host-parasite systems
Authors: Deshpande Jhelam N. , Dakos Vasilis , Kaltz Oliver , Fronhofer Emanuel A.
Published: October 2023

Spatial network structure of biological systems drives ecology and evolution by distributing organisms and their genes. The ubiquitous host-parasite systems are no exception. However, past work has largely ignored relevant spatial complexity, hampering the translation of theoretical predictions to real ecosystems. Thus, we develop an eco-evolutionary metapopulation model of host-parasite dynamics where hosts and parasites disperse through realistically complex spatial networks representing major biomes: riverine aquatic and terrestrial. We generate the testable prediction that parasite virulence, or how parasites harm their hosts, is unimodal with dispersal and can reach greater values in aquatic landscapes but saturates to lower values in terrestrial systems. Moreover, we show that kin selection drives virulence evolution. Spatial networks generate characteristic patterns of parasite relatedness which drive differential virulence evolution. Finally, we show that accounting for virulence evolution allows us to predict the distribution of key epidemiological variables (e.g., parasite extinction risks) within spatial networks.
Waveform-based classification of dentate spikes
Authors: Santiago Rodrigo M.M. , Lopes-dos-Santos Vítor , Jones Emily A. Aery , Huang Yadong , Dupret David , Tort Adriano B.L.
Published: October 2023

Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer’s disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.

Author summary

The entorhinal cortex and the dentate gyrus are regions of the brain’s hippocampal formation that play a crucial role in learning and memory. Their synchronous activation generates fast and high-amplitude electrophysiological patterns in the dentate gyrus, called dentate spikes (DSs). However, the functional role of DSs is still poorly understood. A technical limitation for the study of DSs is that their classification into types 1 and 2 is only possible through laminar profiles obtained by multicontact linear probes. In the present work, we propose a method to classify the different types of DSs through their waveforms, thus expanding the investigation of their significance in mnemonic processes by making possible their study in single-site recordings.
Viral protease NIa-Pro increases MEDIATOR SUBUNIT16 cleavage and plant susceptibility to turnip mosaic virus and its aphid vectorMyzus persicae
Authors: Ray Swayamjit , Murad Tyseen , Arena Gabriella D. , Arshad Kanza , Arendsee Zebulun , Herath Venura , Whitham Steven A. , Casteel Clare L.
Published: October 2023

Plant viruses, such turnip mosaic virus (TuMV), both trigger and inhibit host plant defense responses, including defenses that target their insect vectors, such as aphids. TuMV infection and its protein, NIa-Pro (nuclear inclusion protease a), suppress aphid-induced plant defenses, however the mechanisms of this suppression are still largely unknown. In this study, we determined that NIa-Pro’s protease activity is required to increase aphid performance on host plants and that 40 transcripts with predicted NIa-Pro cleavage sequences are regulated in Arabidopsis plants challenged with aphids and/or virus compared to healthy controls. One of the candidates, MEDIATOR 16 (MED16), regulates the transcription of ethylene (ET)/jasmonic acid (JA)-dependent defense responses against necrotrophic pathogens. Using immunoblots, mutants, bioassays, and qRT-PCR, we show that a nuclear localization signal is cleaved from MED16 in virus-infected plants and in the presence of NIa-Pro along with the presence of aphids, suggesting MED16 functions in the nucleus may be impacted. Consistent with this, aphid induction of the MED16-dependent transcript ofPLANT DEFENSIN 1.2 (PDF1.2), was reduced in virus-infected plants and in plants expressing NIa-Pro compared to controls, and NIa-Pro’s protease activity was required for this reduction. Finally, we show performance of both the virus and the aphid vector was enhanced onmed16mutant Arabidopsis compared to controls. Overall, this study demonstrates MED16 regulates defense responses against both the virus and the aphid and provides insights into the mechanism by which TuMV suppresses anti-virus and anti-herbivore defenses.
A deep learning framework for predicting the neutralizing activity of COVID-19 therapeutics and vaccines against evolving SARS-CoV-2 variants
Authors: Matson Robert P. , Comba Isin Y. , Silvert Eli , Niesen Michiel J.M. , Murugadoss Karthik , Padwardhan Dhruti , Suratekar Rohit , Goel Elizabeth-Grace , Poelaert Brittany J. , Wan Kanny , Brimacombe Kyle R. , Venkatakrishnan AJ , Soundararajan Venky
Published: October 2023

Understanding how viral variants evade neutralization is crucial for improving antibody-based treatments, especially with rapidly evolving viruses like SARS-CoV-2. Yet, conventional assays are limited in the face of rapid viral evolution, relying on a narrow set of viral isolates, and falling short in capturing the full spectrum of variants. To address this, we have developed a deep learning approach to predict changes in neutralizing antibody activity of COVID-19 therapeutics and vaccines against emerging viral variants. First, we trained a variational autoencoder (VAE) using all 67,885 unique SARS-CoV-2 spike protein sequences from the NCBI virus (up to October 31, 2022) database to encode spike protein variants into a latent space. Using this VAE and a curated dataset of 7,069in vitroassay data points from the NCATS OpenData Portal, we trained a neural network regression model to predict fold changes in neutralizing activity of 40 COVID-19 therapeutics and vaccines against spike protein sequence variants, relative to their neutralizing activity against the ancestral strain (Wuhan-Hu-1). Our model also employs Bayesian inference to quantify prediction uncertainty, providing more nuanced and informative estimates. To validate the model’s predictive capacity, we assessed its performance on a test set ofin vitroassay data collected up to eight months after the data included in the model training (N = 980). The model accurately predicted fold changes in neutralizing activity for this prospective dataset, with an R2of 0.77. Expanding our methodology to include all available data from NCBI virus and NCATS OpenData Portal up to date, we assessed predicted changes in activity for current COVID-19 monoclonal antibodies and vaccines against newly identified SARS-CoV-2 lineages. Our predictions suggest that current therapeutic and vaccine-induced antibodies will have significantly reduced activity against newer XBB descendants, notably EG.5, FL.1.5.1, and XBB.1.16. Using the model, we were able to primarily attribute the observed predicted loss in activity to the F456L spike mutation found in EG.5 and FL.1.5.1 sequences. Conversely, mRNA-bivalent vaccines are predicted to be less susceptible to the recent BA.2.86 variant compared to new XBB descendants. These findings align closely with recent research, underscoring the potential of deep learning in shaping therapeutic and vaccine strategies for emerging viral variants.
The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway
Authors: Chen Hao , Ferguson Cole J. , Mitchell Dylan C. , Titus Amanda , Paulo Joao A. , Hwang Andrew , Lin Tsen-Hsuan , Yano Hiroko , Gu Wei , Song Sheng-Kwei , Yuede Carla M. , Gygi Steven P. , Bonni Azad , Kim Albert H.
Published: October 2023

Precise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics analysis reveals that the neuronal USP7 interactome is enriched for proteins implicated in neurodevelopmental disorders and specifically identifies the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.
Low booster uptake in cancer patients despite health benefits
Authors: Figueiredo Jane C. , Levy Julia , Choi So Yung , Xu Alexander M. , Merin Noah M. , Hamid Omid , Lemos Tucker , Nguyen Nathalie , Nadri Maimoona , Gonzalez Alma , Mahov Simeon , Darrah Justin M. , Gong Jun , Paquette Ronald L. , Mita Alain C. , Vescio Robert A. , Salvy Sarah J. , Mehmi Inderjit , Hendifar Andrew E. , Natale Ronald , Tourtellotte Warren G. , Krishnan Ramanujan V. , Huynh Carissa A. , Sobhani Kimia , Reckamp Karen L. , Merchant Akil A.
Published: October 2023

Patients with cancer are at increased risk of death from COVID-19 and have reduced immune responses to SARS-CoV2 vaccines, necessitating regular boosters. We performed comprehensive chart reviews, surveys of patients attitudes, serology for SARS-CoV-2 antibodies and T-cell receptor (TCR) β sequencing for cellular responses on a cohort of 982 cancer patients receiving active cancer therapy accrued between November-3-2020 and Mar-31-2023. We found that 92·3% of patients received the primer vaccine, 70·8% received one monovalent booster, but only 30·1% received a bivalent booster. Booster uptake was lower under age 50, and among African American or Hispanic patients. Nearly all patients seroconverted after 2+ booster vaccinations (>99%) and improved cellular responses, demonstrating that repeated boosters could overcome poor response to vaccination. Receipt of booster vaccinations was associated with a lower risk of all-cause mortality (HR=0·61, P=0·024). Booster uptake in high-risk cancer patients remains low and strategies to encourage booster uptake are needed.

Highlights

COVID-19 booster vaccinations increase antibody levels and maintain T-cell responses against SARS-CoV-2 in patients receiving various anti-cancer therapies

Booster vaccinations reduced all-cause mortality in patients

A significant proportion of patients remain unboosted and strategies are needed to encourage patients to be up-to-date with vaccinations
Unveiling the role of local metabolic constraints on the structure and activity of spiking neural networks
Authors: Jaras Ismael , Orchard Marcos , Maldonado Pedro , Vergara Rodrigo
Published: October 2023

Understanding the intricate interplay between neural dynamics and metabolic constraints is crucial for unraveling the mysteries of the brain. Despite the significance of this relationship, specific details concerning the impact of metabolism on neuronal dynamics and neural network architecture remain elusive, creating a notable gap in the existing literature. This study employs an energy-dependent neuron and plasticity model to analyze the role of local metabolic constraints in shaping both the dynamics and structure of Spiking Neural Networks (SNN). Specifically, an energy-dependent version of the leaky integrate-and-fire model is utilized, along with a three-factor learning rule that incorporates postsynaptic available energy as the third factor. These models allow for fine-tuning sensitivity in the presence of energy imbalances. Analytical expressions predicting the network's activity and structure are derived, and a fixed-point analysis reveals the emergence of attractor states characterized by neuronal and synaptic sensitivity to energy imbalances. Analytical findings are validated through numerical simulations using an excitatory-inhibitory network. Furthermore, these simulations enable the study of SNN activity and structure under conditions simulating metabolic impairment. In conclusion, by employing energy-dependent models with adjustable sensitivity to energy imbalances, our study advances the understanding of how metabolic constraints shape SNN dynamics and structure. Moreover, in light of compelling evidence linking neuronal metabolic impairment to neurodegenerative diseases, the incorporation of local metabolic constraints into the investigation of neuronal network structure and activity opens an intriguing avenue for inspiring the development of therapeutic interventions.
A natural cyclic peptide valinomycin enhances plant innate immunity
Authors: Yoo Nayeon , Kang Ji Eun , Kim Da-Ran , Lee Huiwon , Ko Dohee , Kwak Youn-Sig , Chung Eui-Hwan
Published: October 2023

Various natural compounds as alternative agents for the chemical management of plant diseases have long been proposed. Valinomycin, aStreptomyces-derived cyclic peptide, acts as an antifungal agent against several plant pathogenic fungi, includingBotrytis cinerea. Here, we report the novel function of valinomycin, plant immune-boosting. Valinomycin potentiates pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) inArabidopsis, leading to enhanced resistance against bacterial speck disease locally and systemically. Moreover, this plant immune-boosting activity of valinomycin is associated with plant hormonal signaling. Thus, we propose that valinomycin harbors potential as a biocontrol agent suppressing complex pathogen infections, such as bacteria and fungi.
Decoding spatial organization maps and context-specific landscapes of breast cancer and its microenvironment via high-resolution spatial transcriptomic analysis
Authors: Seo Eun Seop , Lee Boram , Hwang Inwoo , Kim Ji-Yeon , Park Kyeongmee , Park Woong-Yang
Published: October 2023

Single-cell RNA transcriptomics has revealed the intricate heterogeneity of both tumors and their microenvironment. However, a notable limitation is its inability to retain spatial context, a crucial aspect of understanding cell identity and function. In this study, we employed imaging-based single-cell spatial transcriptomics to elucidate the tumor and immunological landscapes of two breast cancer samples. By resolving over 400 000 cells per slide, we demonstrated that transcriptional differences lead to structural disparities within and between tumors. Additionally, we observed that the composition of the tumor microenvironment varies depending on its spatial location. Notably, we detected immune cell gradients transitioning from the tumor periphery to its core regions and from tertiary lymphoid structure to immune inflamed regions, in alignment with the specific function of each cell type. This finding facilitated a more precise classification of the tumor immune microenvironment. This study provides a comprehensive dataset for breast cancer researchers and underscores the significance of spatial context in understanding the multifaceted heterogeneity of cancer and its environment.
Structure of PSI-LHCI fromCyanidium caldariumprovides evolutionary insights into conservation and diversity of red-lineage LHCs
Authors: Kato Koji , Hamaguchi Tasuku , Kumazawa Minoru , Nakajima Yoshiki , Ifuku Kentaro , Hirooka Shunsuke , Hirose Yuu , Miyagishima Shin-ya , Suzuki Takehiro , Kawakami Keisuke , Dohmae Naoshi , Yonekura Koji , Shen Jian-Ren , Nagao Ryo
Published: October 2023

Light-harvesting complexes (LHCs) are diversified among photosynthetic organisms, and their structural variety in photosystem I-LHC (PSI-LHCI) supercomplexes has been shown. However, structural and evolutionary correlations of red-lineage LHCs are unknown. Here we determined a 1.92-Å resolution cryo-electron microscopic structure of a PSI-LHCI supercomplex isolated from the red algaCyanidium caldariumRK-1 (NIES-2137) which is an important taxon in the Cyanidiophyceae, and subsequently investigated these correlations through structural comparisons and phylogenetic analysis. The PSI-LHCI structure shows five LHCI subunits together with a PSI-monomer core. The five LHCIs are composed of two Lhcr1s, two Lhcr2s, and one Lhcr3. Phylogenetic analysis of LHCs bound to PSI in red-lineage algae showed clear orthology of LHCs betweenC. caldariumandCyanidioschyzon merolae, whereas no orthologous relationships were found betweenC. caldariumLhcr1–3 and LHCs in other red-lineage PSI-LHCI structures. These findings provide evolutionary insights into conservation and diversity of red-lineage LHCs associated with PSI.
3-O-methyltolcapone and Its Lipophilic Analogues are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity
Authors: Poonsiri Thanalai , dell’Accantera Davide , Loconte Valentina , Casnati Alessandro , Cervoni Laura , Arcovito Alessandro , Benini Stefano , Ferrari Alberto , Cipolloni Marco , Cacioni Elisa , Franco Francesca De , Giacchè Nicola , Rinaldo Serena , Folli Claudia , Sansone Francesco , Berni Rodolfo , Cianci Michele
Published: October 2023

Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine in blood and cerebrospinal fluid. To date, more than 130 TTR point mutations are known to destabilise the TTR tetramer, leading to its extracellular pathological aggregation accumulating in several organs, such as heart, peripheral and autonomic nerves, and leptomeninges. Tolcapone is an FDA-approved drug for Parkinson’s disease that has been repurposed as a TTR stabiliser. We characterised 3-O-methyltolcapone and two newly synthesized lipophilic analogues, which are expected to be protected from the metabolic glucuronidation which is responsible of the lability of tolcapone in the organism. Immunoblotting assays indicated the high degree of TTR stabilisation, coupled with binding selectivity towards TTR in diluted plasma of 3-O-methyltolcapone and its lipophilic analogues. Furthermore,in-vitrotoxicity data showed their several-fold improved neuronal and hepatic safety compared to tolcapone. Calorimetric and structural data showed that both T4 binding sites of TTR are occupied by 3-O-methyltolcapone and its lipophilic analogs, consistent with an effective TTR tetramer stabilisation. Moreover,in-vitropermeability studies showed that the three compounds can effectively cross the blood-brain barrier, which is a prerequisite for the inhibition of TTR amyloidogenesis in the cerebrospinal fluid. Our data demonstrate the relevance of 3-O-methyltolcapone and its lipophilic analogs as potent inhibitors of TTR amyloidogenesis.
NRC immune receptor networks show diversified hierarchical genetic architecture across plant lineages
Authors: Goh Foong-Jing , Huang Ching-Yi , Derevnina Lida , Wu Chih-Hang
Published: October 2023

Plants developed sophisticated immune systems with nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins to repel invading pathogens. The NRC (NLR required for cell death) family includes helper NLRs that form a complex genetic network with multiple sensor NLRs to provide resistance against pathogens of solanaceous plants. However, the evolution and function of NRC networks outside solanaceous plants is currently unknown. We conducted phylogenomic and macroevolutionary analyses comparing NLRs identified from different asterids lineages and found that NRC networks expanded significantly in most lamiids but not in Ericales and campanulids. Using transient expression assays inNicotiana benthamiana, we show that NRC networks are simple in Ericales and campanulids, but are with high complexity in lamiids. Phylogenetic analyses grouped the NRC helper NLRs into three NRC0 subclades that are conserved, and several family-specific NRC subclades of lamiids that show signatures of diversifying selection. Functional analyses revealed that members of the NRC0 subclades are partially interchangeable, whereas family-specific NRC members in lamiids lack interchangeability. Our findings highlight the distinctive evolutionary patterns of the NRC networks in asterids and provide potential insights into transferring disease resistance across plant lineages.