bluuebunny/crossref_metadata_2025 huggingface dataset:
The within-person association of relative left frontal activity and vagally mediated heart rate variability not moderated by history of depression
Authors: Ding Yaohui , Allen John J.B.
Published: July 2023

Motivated by the Neurovisceral Integration Model (NVI) of cardiac vagal control, we investigated the relationship between relative left frontal activity (rLFA) and vagally mediated heart rate variability or respiratory sinus arrhythmia (RSA) in 287 participants, half of whom had a history of depression. We hypothesized that there would be a within-person association of rLFA and RSA such that when RSA is lower rLFA would also be lower (Hypothesis I). Moreover, it was hypothesized that this within-subject association would be moderated by a history of depression (Hypothesis II). Metrics of rLFA and RSA were derived from concurrent electroencephalogram and electrocardiogram recordings. The logarithmic difference in EEG alpha power between the homologous right and left electrodes (Ln (Right/Left)) in the frontal region was used to index rLFA. A Hilbert transform was applied to the mean-centered and bandpass-filtered (0.12-.40 Hz) inter-beat interval (IBI) time series to get a fine-grained measure (in the time domain) of RSA. A linearmixed ANOVAmodel with rLFA as the dependent variable and RSA as the main fixed effect found that participants had less rLFA during epochs when they had lower RSA, which was consistent with the prediction from Hypothesis I. Contrary to the prediction from Hypothesis II, the within-person association of RSA and rLFA wasnotmoderated by a history of depression. However, the association between RSA and rLFA varied across the four pairs of frontal electrodes that we examined. Thus, more research is needed to determine the spatial extent of this association, e.g., examining the relationship between source-localized rLFA and RSA.
Hepatocyte-specific disruption of soluble epoxide hydrolase attenuates abdominal aortic aneurysm formation: novel role of the liver in aneurysm pathogenesis
Authors: Kim David , Horimatsu Tetsuo , Ogbi Mourad , Goo Brandee , Shi Hong , Veerapaneni Praneet , Chouhaita Ronnie , Moses Mary , Prasad Rosaria , Benson Tyler W. , Harb Ragheb , Aboud Ghaith , Seller Hunter , Haigh Steve , Fulton David J. , Csányi Gábor , Huo Yuqing , Long Xiaochun , Coffey Philip , Lee Richard , Guha Avirup , Zeldin Darryl , Hwang Sung Hee , Hammock Bruce D. , Weintraub Neal L. , Kim Ha Won
Published: July 2023

Introduction

Inflammation is a key pathogenic feature of abdominal aortic aneurysm (AAA). Soluble epoxide hydrolase (sEH) is a pro-inflammatory enzyme that converts cytochrome P450-derived epoxides of fatty acids to the corresponding diols, and pharmacological inhibition of sEH prevented AAA formation. Both cytochrome P450 enzymes and sEH are highly expressed in the liver. Here, we investigated the role of hepatic sEH in AAA using a selective pharmacological inhibitor of sEH and hepatocyte-specific Ephx2 (which encodes sEH gene) knockout (KO) mice in two models of AAA [angiotensin II (AngII) infusion and calcium chloride (CaCl2) application].

Methods and results

sEH expression and activity were strikingly higher in mouse liver compared with aorta and further increased the context of AAA, in conjunction with elevated expression of the transcription factor Sp1 and the epigenetic regulator Jarid1b, which have been reported to positively regulate sEH expression. Pharmacological sEH inhibition, or liver-specific sEH disruption, achieved by crossing sEH floxed mice with albumin-cre mice, prevented AAA formation in both models, concomitant with reduced expression of hepatic sEH as well as complement factor 3 (C3) and serum amyloid A (SAA), liver-derived factors linked to AAA formation. Moreover, sEH antagonism markedly reduced C3 and SAA protein accumulation in the aortic wall. Co-incubation of liverex vivowith aneurysm-prone aorta resulted in induction of sEH in the liver, concomitant with upregulation of Sp1, Jarid1b, C3 and SAA gene expression, suggesting that the aneurysm-prone aorta secretes factors that activate sEH and downstream inflammatory signaling in the liver. Using an unbiased proteomic approach, we identified a number of dysregulated proteins [e.g.,plastin-2, galectin-3 (gal-3), cathepsin S] released by aneurysm-prone aorta as potential candidate mediators of hepatic sEH induction.

Conclusion

We provide the first direct evidence of the liver’s role in orchestrating AAA via the enzyme sEH. These findings not only provide novel insight into AAA pathogenesis, but they have potentially important implications with regard to developing effective medical therapies for AAA.
Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment
Authors: Díaz-Gay Marcos , Vangara Raviteja , Barnes Mark , Wang Xi , Islam S M Ashiqul , Vermes Ian , Narasimman Nithish Bharadhwaj , Yang Ting , Jiang Zichen , Moody Sarah , Senkin Sergey , Brennan Paul , Stratton Michael R , Alexandrov Ludmil B
Published: July 2023

Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. Here we present SigProfilerAssignment, a desktop and an online computational framework for assigning all types of mutational signatures to individual samples. SigProfilerAssignment is the first tool that allows both analysis of copy-number signatures and probabilistic assignment of signatures to individual somatic mutations. As its computational engine, the tool uses a custom implementation of the forward stagewise algorithm for sparse regression and nonnegative least squares for numerical optimization. Analysis of 2,700 synthetic cancer genomes with and without noise demonstrates that SigProfilerAssignment outperforms four commonly used approaches for assigning mutational signatures. SigProfilerAssignment is freely available athttps://github.com/AlexandrovLab/SigProfilerAssignmentwith a web implementation athttps://cancer.sanger.ac.uk/signatures/assignment/.
Generalizability of foot-placement control strategies during unperturbed and perturbed gait
Authors: Liu Chang , Valero-Cuevas Francisco J. , Finley James M.
Published: July 2023

Control of foot placement is an essential strategy for maintaining balance during walking. During unperturbed, steady-state walking, foot placement can be accurately described as a linear function of the body’s center of mass state at midstance. However, it is uncertain if this mapping from center of mass state to foot placement generalizes to larger perturbations that may be more likely to cause falls. These perturbations may cause balance disturbances and generate reactive control strategies not observed during unperturbed walking. Here, we used unpredictable changes in treadmill speed to assess the generalizability of foot placement mappings identified during unperturbed walking. We found that foot placement mappings generalized poorly from unperturbed to perturbed walking and differed for forward versus backward perturbations. We also used singular value decomposition of the mapping matrix to reveal that people were more sensitive to backward versus forward perturbations. Together, these results indicate that control of foot placement during losses of balance differs from the control strategies used during unperturbed walking. Better characterization of human balance control strategies could improve our understanding of why different neuromotor disorders result in heightened fall risk and inform the design of controllers for balance-assisting devices.
Harnessing the power of whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation
Authors: Cabanes-Creus Marti , Liao Sophia H.Y. , Navarro Renina Gale , Knight Maddison , Nazareth Deborah , Lau Ngee-Soon , Ly Mark , Zhu Erhua , Roca-Pinilla Ramon , Delgado Ricardo Bugallo , Baltazar Grober , Westhaus Adrian , Merjane Jessica , Crawford Michael , McCaughan Geoffrey W. , Unzu Carmen , González-Aseguinolaza Gloria , Alexander Ian E. , Pulitano Carlo , Lisowski Leszek
Published: July 2023

Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in anex situnormothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8-derived variants performed efficiently. This study establishes the use of normothermic liver perfusion as an invaluable preclinical model for evaluating liver-targeted gene therapies and providing guidance for making essential decisions that promote the most effective translational programs.
Petascale Homology Search for Structure Prediction
Authors: Lee Sewon , Kim Gyuri , Karin Eli Levy , Mirdita Milot , Park Sukhwan , Chikhi Rayan , Babaian Artem , Kryshtafovych Andriy , Steinegger Martin
Published: July 2023

The recent CASP15 competition highlighted the critical role of multiple sequence alignments (MSAs) in protein structure prediction, as demonstrated by the success of the top AlphaFold2-based prediction methods. To push the boundaries of MSA utilization, we conducted a petabase-scale search of the Sequence Read Archive (SRA), resulting in gigabytes of aligned homologs for CASP15 targets. These were merged with default MSAs produced by ColabFold-search and provided to ColabFold-predict. By using SRA data, we achieved highly accurate predictions (GDT_TS > 70) for 66% of the non-easy targets, whereas using ColabFold-search default MSAs scored highly in only 52%. Next, we tested the effect of deep homology search and ColabFold’s advanced features, such as more recycles, on prediction accuracy. While SRA homologs were most significant for improving ColabFold’s CASP15 ranking from 11th to 3rd place, other strategies contributed too. We analyze these in the context of existing strategies to improve prediction.
Engineering and Evolution of the Complete Reductive Glycine Pathway inSaccharomyces cerevisiaefor Formate and CO2Assimilation
Authors: Bysani Viswanada R , Alam Ayesha S M , Bar-Even Arren , Machens Fabian
Published: July 2023

Using captured CO2and C1-feedstocks like formate and methanol derived from electrochemical activation of CO2are key solutions for transforming industrial processes towards a circular carbon economy. Engineering formate and CO2-based growth in the biotechnologically relevant yeastSaccharomyces cerevisiaecould boost the emergence of a formate-mediated circular bio-economy. This study adopts a growth-coupled selection scheme for modular implementation of the Reductive Glycine Pathway (RGP) and subsequent Adaptive Laboratory Evolution (ALE) to enable formate and CO2assimilation for biomass formation in yeast. We first constructed a serine biosensor strain and then implemented the serine synthesis module of the RGP into yeast, establishing glycine and serine synthesis from formate and CO2. ALE improved the RGP-dependent growth by 8-fold. 13C-labeling experiments reveal glycine, serine, and pyruvate synthesis via the RGP, demonstrating the complete pathway activity. Further, we reestablished formate and CO2-dependent growth in non-evolved biosensor strains via reverse-engineering a mutation inGDH1identified from ALE. This mutation led to significantly more 13C-formate assimilation than in WT without any selection or overexpression of the RGP. Overall, we demonstrated the activity of the complete RGP, showing evidence for carbon transfer from formate to pyruvate coupled with CO2assimilation.
Exportin-mediated nucleocytoplasmic transport maintains Pch2 homeostasis during meiosis
Authors: Herruzo Esther , Sánchez-Díaz Estefanía , González-Arranz Sara , Santos Beatriz , Carballo Jesús A. , San-Segundo Pedro A.
Published: July 2023

The meiotic recombination checkpoint reinforces the order of events during meiotic prophase I, ensuring the accurate distribution of chromosomes to the gametes. The AAA+ ATPase Pch2 remodels the Hop1 axial protein enabling adequate levels of Hop1-T318 phosphorylation to support the ensuing checkpoint response. While these events are focalized at chromosome axes, the checkpoint activating function of Pch2 relies on its cytoplasmic population. In contrast, forced nuclear accumulation of Pch2 leads to checkpoint inactivation. Here, we reveal the mechanism by which Pch2 travels from the cell nucleus to the cytoplasm to maintain Pch2 cellular homeostasis. Leptomycin B treatment provokes the nuclear accumulation of Pch2, indicating that its nucleocytoplasmic transport is mediated by the Crm1 exportin recognizing proteins containing Nuclear Export Signals (NESs). Consistently, leptomycin B leads to checkpoint inactivation and impaired Hop1 axial localization. Pch2 nucleocytoplasmic traffic is independent of its association with Zip1 and Orc1. We also identify a conserved functional NES in the non-catalytic N-terminal domain of Pch2 that is required for its nucleocytoplasmic traffic and proper checkpoint activity. In sum, we unveil another layer of control of Pch2 function during meiosis involving the nuclear export via the exportin pathway that is crucial to maintain the critical balance of Pch2 distribution among different cellular compartments.
Translation of zinc finger domains induces ribosome collision and Znf598-dependent mRNA decay in vertebrates
Authors: Ishibashi Kota , Shichino Yuichi , Han Peixun , Wakabayashi Kimi , Inada Toshifumi , Kimura Seisuke , Iwasaki Shintaro , Mishima Yuichiro
Published: July 2023

Quality control of translation is crucial for maintaining cellular and organismal homeostasis. Obstacles in translation elongation induce ribosome collision, which is monitored by multiple sensor mechanisms in eukaryotes. The E3 ubiquitin ligase Znf598 recognizes collided ribosomes, triggering ribosome-associated quality control (RQC) to rescue stalled ribosomes and no-go decay (NGD) to degrade stall-prone mRNAs. However, the impact of RQC and NGD on maintaining the translational homeostasis of endogenous mRNAs has remained unclear. In this study, we investigated the endogenous substrate mRNAs of NGD during the maternal-to-zygotic transition (MZT) of zebrafish development. RNA-Seq analysis of zebrafishznf598mutant embryos revealed that Znf598 downregulates mRNAs encoding the C2H2-type zinc finger domain (C2H2-ZF) during the MZT. Reporter assays and disome profiling indicated that ribosomes stall and collide while translating tandem C2H2-ZFs, leading to mRNA degradation by Znf598. We further showed that mRNAs encoding C2H2-ZF were degraded in a ZNF598-dependent manner in HEK293T cells. Our results suggest that NGD maintains the quality of the translatome by mitigating the risk of ribosome collision at the abundantly present C2H2-ZF sequences in the vertebrate genome.
High-resolution map of the Fc-functions mediated by COVID-19 neutralizing antibodies
Authors: Paciello Ida , Maccari Giuseppe , Pantano Elisa , Andreano Emanuele , Rappuoli Rino
Published: July 2023

A growing body of evidence shows that Fc-dependent antibody effector functions play an important role in protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To unravel the mechanisms that drive these responses, we analyzed the phagocytosis and complement deposition mediated by a panel of 482 human monoclonal antibodies (nAbs) neutralizing the original Wuhan virus, expressed as recombinant IgG1. Our study confirmed that nAbs no longer neutralizing SARS-CoV-2 Omicron variants can retain their Fc-functions. Surprisingly, we found that nAbs with the most potent Fc-function recognize the N- terminal domain, followed by those targeting Class 3 epitopes in the receptor binding domain. Interestingly, nAbs direct against the Class 1/2 epitopes in the receptor binding motif, which are the most potent in neutralizing the virus, were the weakest in Fc-functions. The divergent properties of the neutralizing and Fc- function mediating antibodies were confirmed by the use of different B cell germlines and by the observation that Fc-functions of polyclonal sera differ from the profile observed with nAbs, suggesting that not-neutralizing antibodies also contribute to Fc-functions. These data provide a high-resolution picture of the Fc-antibody response to SARS-CoV-2 and suggest that the Fc contribution should be considered for the design of improved vaccines, the selection of therapeutic antibodies and the evaluation of correlates of protection.
Highly pathogenic avian influenza A(H5N1) virus clade 2.3.4.4b in domestic ducks, Indonesia, 2022
Authors: Wibawa Hendra , Wibowo Putut Eko , Supriyadi Arif , Lestari  , Silaban Jessiaman , Fuadi Aziz Ahmad , Fiqri Anna Januar , Handayani Retno Wulan , Irianingsih Sri Handayani , Fahmia Zaza , Mulyawan Herdiyanto , Idris Syafrison , Zainuddin Nuryani
Published: July 2023

Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b viruses were detected and isolated from domestic ducks in South Kalimantan, Indonesia during April 2022. The viruses were genetically similar to clade 2.3.4.4b H5N1 viruses recently detected in East Asia from 2021-2022. Further investigation is necessary to determine the source of virus incursion.
Transposable element insertions are associated with Batesian mimicry in the pantropical butterflyHypolimnas misippus
Authors: Orteu Anna , Kucka Marek , Katili Eunice , Ngumbao Charo , Gordon Ian J. , Ng’iru Ivy , van der Heijden Eva , Talavera Gerard , Warren Ian A. , Collins Steve , ffrench-Constant Richard H. , Martins Dino J. , Chan Yingguang Frank , Jiggins Chris D. , Martin Simon H.
Published: July 2023

Hypolimnas misippusis a Batesian mimic of the toxic African Queen butterfly(Danaus chrysippus). FemaleH. misippusbutterflies use two major wing patterning loci (M and A) to imitate the four colour morphs ofD. chrysippusfound in different regions of Africa. In this study, we examine the evolution of the M locus and identify it as an example of adaptive atavism. This phenomenon involves a morphological reversion to an ancestral character that results in an adaptive phenotype. We show thatH. misippushas re-evolved a wing pattern present in otherHypolimnasspecies for Batesian mimicry of aD. chrysippusmorph. Using haplotagging, a linked-read sequencing technology, we discover two large transposable element (TE) insertions located at the M locus and establish that these insertions are present in the dominant allele responsible for producing the ancestral and mimetic phenotype. By conducting a comparative analysis involving additionalHypolimnasspecies, we demonstrate that the dominant allele is derived. This suggests that the TEs disrupt a cis-regulatory element, leading to the reversion to an ancestral phenotype that is then utilized for Batesian mimicry of a distinct model, a different morph ofD. chrysippus. Our findings present a compelling instance of convergent evolution and adaptive atavism, in which the same pattern element has independently evolved multiple times inHypolimnasbutterflies, repeatedly playing a role in Batesian mimicry of diverse model species.
Sustained hippocampal theta-oscillations reflect experience-dependent learning in backward temporal order memory retrieval
Authors: Jiang Hongjie , Cai Jing , Santos-Pata Diogo , Shi Lei , Zhu Xuanlong , Tong Jiaona , Cai Yudian , Li Chenyang , Wang Rui , Yin Jia , Zhang Shaomin , Kwok Sze Chai
Published: July 2023

Navigating within our neighborhood, learning a set of concepts, or memorizing a story, requires remembering the relationship between individual items that are presented sequentially. Theta activity in the mammalian hippocampus has been related to the encoding and recall of relational structures embedding episodic memories. However, how theta oscillations are involved in retrieving temporal order information in opposing directionality (forward vs backward) has not been characterized. Here, using intracranial recordings from 10 human epileptic patients of both genders with hippocampal electrodes, we tested the patients with a temporal order memory task in which they learned the spatial relationship among individual items arranged along a circular track and were tested on both forward-cued and backward-cued retrieval conditions. We found that sustained high-power oscillatory events in the hippocampal theta (2-8 Hz) band, as quantified by Pepisoderate, were higher for the backward conditions during the later stage but not in the earlier stage. The theta Pepisoderesults are consistent with the behavioral memory performance. In contrast, we observed a stronger effect of forward than backward retrieval for the gamma (30-70 Hz) Pepisoderate irrespective of stages. Our results revealed differential roles of theta vs. gamma oscillations in the retrieval of temporal order and how theta oscillations are specifically implicated in the learning process for efficient retrieval of temporal order memories under opposing directionality.

Significance statement

While the hippocampus is critical to link events into unitary episodes, the effect of repeated experiences, or learning, on these processes is not entirely clear. We discovered that hippocampal theta oscillation in humans is modulated by repeated experiences, which in turn increases the efficacy of backward-cued memory retrieval of temporal order. This study revealed an important physiological signature characterizing the role of experiences and learning in bidirectional temporal memory retrieval.

Journal section

Behavioral/Cognitive
Remodeling of the secretory pathway is coordinated withde novomembrane formation in budding yeast gametogenesis
Authors: Suda Yasuyuki , Tachikawa Hiroyuki , Suda Tomomi , Kurokawa Kazuo , Nakano Akihiko , Irie Kenji
Published: July 2023

Gametogenesis in budding yeast involves a large-scale rearrangement of membrane traffic to allowde novoformation of a membrane, called the prospore membrane (PSM). However, the mechanism underlying this event is not fully elucidated. Here, we show that the number of endoplasmic reticulum exit sites (ERES) per cell fluctuates and switches from decreasing to increasing upon the onset of PSM formation. Reduction in ERES number, presumably accompanying a transient stall in membrane traffic, resulting in the loss of preexisting Golgi apparatus from the cell, was followed by local ERES regeneration, leading to Golgi reassembly in nascent spores. We have revealed that protein phosphatase-1 (PP-1) and its development-specific subunit, Gip1, promote ERES regeneration through Sec16 foci formation. Furthermore,sed4Δ, a mutant with impaired ERES formation, showed defects in PSM growth and spore formation. Thus, ERES regeneration in nascent spores facilitates the segregation of membrane traffic organelles, leading to PSM growth.
Identification of the yeast mannoprotein geneHZY1as a key genetic determinant for yeast-derived haze in beer
Authors: Lacy Keith , Mormando Rita , Smith Jeremy R. , Gibney Patrick A. , Shaner Lance M. , Burns Laura T.
Published: July 2023

With the sustained popularity of hazy IPAs, brewers have explored multiple approaches to maximizing stable haze that will remain in suspension throughout the shelf life of the beer. Our recent investigations into yeast-dependent haze have uncovered specific brewing yeast strains that promote the formation of haze in heavily dry-hopped beer styles. These brewing strains have been termed “haze-positive” and furthermore, the timing of dry hop additions has been found to be another key factor in producing this stable haze. Classical genetics have identified YIL169C (herein referred to asHZY1) as both necessary and sufficient for the haze-positive phenotype in the yeast strain most widely used for Hazy IPAs.HZY1encodes a candidate glycoprotein and our recent findings suggest it is localized to the cell wall through a GPI anchor. Surprisingly, using long-read sequencing data we uncovered extensive genetic variation inHZY1across brewing strains. The haze-positive phenotype correlates with an expansion in the N-terminal serine-rich region. We propose that the Hzy1 glycoprotein is a critical component to yeast-dependent colloidal haze and the genetic variation in this locus contributes the range of haze phenotypes observed across industrial brewing strains.
Regulatory preconditioning for the evolution of C4photosynthesis revealed by low CO2treatment of Arabidopsis thaliana
Authors: Miao Fenfen , Haq Noor UI , Lyu Ming-Ju Amy , Zhu Xin-Guang
Published: July 2023

Low CO2condition was considered a preconditioning or selection pressure for C4evolution. However, it remains elucidated how low CO2condition contribute to the evolutionary assembly of the C4pathway. We conducted a systematic transcriptomics and metabolomics analysis under short-term low CO2condition and found thatArabidopsisgrown under this condition showed increased expression of most genes encoding C4- related enzymes and transporters. Low CO2condition increased NH4+content in leaves; as expected, photorespiratory and ammonia refixing pathways were enhanced. Furthermore, we found that compared to low CO2condition, in vitro treatment with NH4+induced a similar pattern of changes in C4related genes and genes involved in ammonia refixation. This supports that increased expression of C4genes induced by low CO2condition can supply carbon skeleton for ammonia recycling. This study provides new insight into the regulatory preconditioning which may have facilitated the evolution of C4photosynthesis under low atmospheric CO2environments.
Effects of aluminum-salt, CpG and emulsion adjuvants on the stability and immunogenicity of a virus-like particle displaying the SARS-CoV-2 receptor-binding domain (RBD)
Authors: Kumru Ozan S. , Bajoria Sakshi , Kaur Kawaljit , Hickey John M. , Van Slyke Greta , Doering Jennifer , Berman Katherine , Richardson Charles , Lien Hans , Kleanthous Harry , Mantis Nicholas J. , Joshi Sangeeta B. , Volkin David B.
Published: July 2023

Second-generation COVID-19 vaccines with improved immunogenicity (e.g., breadth, duration) and availability (e.g., lower costs, refrigerator stable) are needed to enhance global coverage. In this work, we formulated a clinical-stage SARS-CoV-2 receptor binding domain (RBD) virus-like particle (VLP) vaccine candidate (IVX-411) with widely available adjuvants. Specifically, we assessed thein vitrostorage stability andin vivomouse immunogenicity of IVX-411 formulated with aluminum-salt adjuvants (Alhydrogel™, AH and Adjuphos™, AP), without or with the TLR-9 agonist CpG-1018™ (CpG), and compared these profiles to IVX-411 adjuvanted with an oil-in-water nano-emulsion (AddaVax™, AV). Although IVX-411 bound both AH and AP, lower binding strength of antigen to AP was observed by Langmuir binding isotherms. Interestingly, AH- and AP-adsorbed IVX-411 had similar storage stability profiles as measured by antigen binding assays (competitive ELISAs), but the latter displayed higher pseudovirus neutralizing titers (pNT) in mice, at levels comparable to titers elicited by AV-adjuvanted IVX-411. CpG addition to alum (AP or AH) resulted in a marginal trend of improved pNTs in stressed samples only, yet did not impact the storage stability profiles of IVX-411. In contrast, previous work with AH-formulations of a monomeric RBD antigen showed greatly improved immunogenicity and decreased stability upon CpG addition to alum. At elevated temperatures (25, 37°C), IVX-411 formulated with AH or AP displayed decreasedin vitrostability compared to AV-formulated IVX-411and this rank-ordering correlated within vivoperformance (mouse pNT values). This case study highlights the importance of optimizing antigen-adjuvant interactions to develop low cost, aluminum-salt adjuvanted recombinant subunit vaccine candidates.
Spiking network model of A1 learns temporal filters with frequency preferences
Authors: Roedel Danielle , Brinkman Braden A. W.
Published: July 2023

The sparse coding hypothesis has successfully predicted neural response properties of several sensory brain areas. For example, sparse basis representations of natural images match edge-detecting receptive fields observed in simple cells of primary visual cortex (V1), and sparse representations of natural sounds mimic auditory nerve waveforms. SAILnet, a leaky integrate-and-fire network model (“Sparse and Independently Local network”) has previously been shown to learn simple V1 receptive fields when trained on natural images. Experimental work rewiring visual input to auditory cortex found that auditory neurons developed visual response properties, suggesting that developmental rules may be shared across sensory cortices.

In this work we adapt SAILnet to train it on waveforms of auditory sounds and learn temporal receptive fields (filters), in contrast with previous work that trained SAILnet or other network models on spectrograms. In our model network of primary auditory cortex (A1) neurons receive synaptic current from input neurons who temporally filter the direct sound waveforms. To show the network learns frequency-dependent filters naturally, we do not parametrize the temporal filters, and only restrict the total number of time points in the filters. To make training feasible, we simplify the model to a single input neuron and 768 A1 neurons, and we train the network on “lo-fi” music, whose spectral power is limited to frequencies of∼10, 000 Hz or less, giving a manageable temporal resolution of the stimulus and filters. The learned filters develop distinct frequency preferences, and reconstruction of novel stimuli captures the low-frequency content of signals in reasonable detail, with audio playback capturing clear aspects of the original stimulus. Lastly, our work also has a pedagogical benefit: the learned stimulus features can be played as sounds, which aids in teaching sensory coding to learners with visual impairments who cannot perceive stimulus features learned by V1 models.
Second-order boundaries segment more easily when they are density-defined rather than feature-defined
Authors: DiMattina Christopher
Published: July 2023

Previous studies have demonstrated that density is an important perceptual aspect of textural appearance to which the visual system is highly attuned. Furthermore, it is known that density cues not only influence texture segmentation, but can enable segmentation by themselves, in the absence of other cues. A popular computational model of texture segmentation known as the “Filter-Rectify-Filter” (FRF) model predicts that density should be a second-order cue enabling segmentation. For a compound texture boundary defined by superimposing two single-micropattern density boundaries, a version of the FRF model in which different micropattern-specific channels are analyzed separately by different second-stage filters makes the prediction that segmentation thresholds should be identical in two cases: (1) Compound boundaries with an equal number of micropatterns on each side but different relative proportions of each variety (compound feature boundaries) and (2) Compound boundaries with different numbers of micropatterns on each side, but with each side having an identical number of each variety (compound density boundaries). We directly tested this prediction by comparing segmentation thresholds for second-order compound feature and density boundaries, comprised of two superimposed single-micropattern density boundaries comprised of complementary micropattern pairs differing either in orientation or contrast polarity. In both cases, we observed lower segmentation thresholds for compound density boundaries than compound feature boundaries, with identical results when the compound density boundaries were equated for RMS contrast. In a second experiment, we considered how two varieties of micropatterns summate for compound boundary segmentation. In the case where two single micro-pattern density boundaries are superimposed to form a compound density boundary, we find that the two channels combine via probability summation. By contrast, when they are superimposed to form a compound feature boundary, segmentation performance is worse than for either channel alone. From these findings, we conclude that density segmentation may rely on neural mechanisms different from those which underlie feature segmentation, consistent with recent findings suggesting that density comprises a separate psychophysical ‘channel’.
Krumholzibacteriota and Deltaproteobacteria contain rare genetic potential to liberate carbon from monoaromatic compounds in subsurface coal seams
Authors: Campbell Bronwyn C. , Greenfield Paul , Gong Se , Midgley David J. , Paulsen Ian T. , George Simon C.
Published: July 2023

Biogenic methane in subsurface coal seam environments is produced by diverse consortia of microbes. Although this methane is useful for global energy security, it remains unclear which microbes can liberate carbon from the coal. Most of this carbon is relatively resistant to biodegradation, as it is contained within aromatic rings. Thus, to explore for coal-degrading taxa in the subsurface, this study used coal seam metagenomes to reconstruct important metagenome-assembled genomes (MAGs) using a key genomic marker for the anaerobic degradation of monoaromatic compounds as a guide: the benzoyl-CoA reductase gene (bcrABCD). Three taxa were identified with this genetic potential. The first was a novel taxon from the Krumholzibacteriota phylum, which this study is the first to describe. This Krumholzibacteriota sp. contained a full set of genes for benzoyl-CoA dearomatisation, in addition to other genes for anaerobic catabolism of monoaromatics. Analysis of Krumholzibacteriota MAGs from other environments revealed that this genetic potential may be common within this phylum, and thus they may be important organisms for the liberation of recalcitrant carbon on a global scale. Further, two taxa from the Deltaproteobacteria class were also implicated in monoaromatic degradation; two geographically unrelatedSyntrophorhabdus aromaticivoransMAGs, and a Syntrophaceae sp. MAG. Each of these three taxa are potential rate-limiting organisms for subsurface coal-to-methane biodegradation. Their description here provides an understanding of their function within the coal seam microbiome, and will help inform future efforts in coal bed methane stimulation, anoxic bioremediation of organic pollutants, and assessments of anoxic carbon cycling and emissions.

Importance

Subsurface coal seams are highly anoxic and oligotrophic environments, where the main source of carbon is “locked away” within aromatic rings. Despite these challenges, biogenic methane accumulates within many of these coal seams, which implies that the coal seam microbiome can “unlock” this carbon sourcein situ. For over two decades, researchers have been working to understand which organisms are responsible for these processes. This study provides the first descriptions of these organisms. Here, we report metagenomic insights into the liberation of carbon from aromatic molecules typically found within coal, the degradation pathways involved, and descriptions of the Krumholzibacteriota sp.,Syntrophorhabdus aromaticivorans, and Syntrophaceae sp. that contain this genetic potential. Additionally, this is the first time that the Krumholzibacteriota phylum has been implicated in anaerobic dearomatisation of aromatic hydrocarbons. This potential is identified here in numerous taxa within the phylum from other subsurface environments, implicating Krumholzibacteriota in global-scale carbon-cycling processes.
The Role of Attention in Immersion: The Two–Competitor Model
Authors: Strauss Daniel J. , Francis Alexander L. , Vibell Jonas , Corona–Strauss Farah I.
Published: July 2023

Currently, we face an exponentially increasing interest in immersion, especially sensory–driven immersion, mainly due to the rapid development of ideas and business models centered around a digital virtual universe as well as the increasing availability of affordable immersive technologies for education, communication, and entertainment. However, a clear definition of ‘immersion’, in terms of established neurocognitive concepts and measurable properties, remains elusive, slowing research on the human side of immersive interfaces.

To address this problem, we propose a conceptual, taxonomic model of attention in immersion. We argue (a) modeling immersion theoretically as well as studying immersion experimentally requires a detailed characterization of the role of attention in immersion, even though (b) attention, while necessary, cannot be a sufficient condition for defining immersion. Our broader goal is to characterize immersion in terms that will be compatible with established psychophysiolgical measures that could then in principle be used for the assessment and eventually the optimization of an immersive experience. We start from the perspective that immersion requires the projection of attention to an induced reality, and build on accepted taxonomies of different modes of attention for the development of our two–competitor model. The two–competitor model allows for a quantitative implementation and has an easy graphical interpretation. It helps to highlight the important link between different modes of attention and affect in studying immersion.
What explains the high island endemicity of PhilippineRafflesia? A species distribution modeling analysis of three threatened parasitic plant species and their hosts
Authors: Obico Jasper J.A. , Lapuz R. Sedricke C. , Barcelona Julie F. , Pelser Pieter B.
Published: July 2023

Premise

Rafflesiaare rare holoparasitic plants. In the Philippines, all but one species are found only on single islands. This study aimed to better understand the factors contributing to this distribution pattern. Specifically, we sought to determine whether narrow environmental tolerances of host and/or parasite species might explain their island endemicity.

Methods

We used Maxent species distribution modeling to identify areas with suitable habitat forR. lagascae,R. lobata, andR. speciosaand theirTetrastigmahost species. These analyses were carried out for current climate conditions as well as two future climate change scenarios.

Key results

Whereas species distribution models indicated suitable environmental conditions for theTetrastigmahost species in many parts of the Philippines, considerably fewer areas have suitable conditions for the threeRafflesiaspecies. Some of these areas are found on islands from which they have not been reported. All three species will face significant threats as a result of climate change.

Conclusions

Our results suggest that limited inter-island dispersal abilities and/or specific environmental requirements are likely responsible for the current pattern of island endemicity of the threeRafflesiaspecies, rather than the environmental requirements of theirTetrastigmahost species.
ARCTIC-3D: Automatic Retrieval and ClusTering of Interfaces in Complexes from 3D structural information
Authors: Giulini Marco , Honorato Rodrigo V. , Rivera Jesús L. , Bonvin Alexandre M.J.J.
Published: July 2023

The formation of a stable complex between proteins lies at the core of a wide variety of biological processes and has been the focus of countless experiments. The huge amount of information contained in the protein structural interactome in the Protein Data Bank can now be used to characterise and classify the existing biological interfaces. We here introduce ARCTIC-3D, a fast and user-friendly data mining and clustering software to retrieve data and rationalise the interface information associated with the protein input data. We demonstrate its use by various examples ranging from showing the increased interaction complexity of eukaryotic proteins, 20% of which on average have more than 3 different interfaces compared to only 10% for prokaryotes, to associating different functions to different interfaces. In the context of modelling biomolecular assemblies, we introduce the concept of “recognition entropy”, related to the number of possible interfaces of the components of a protein-protein complex, which we demonstrate to correlate with the modelling difficulty. The identified interface clusters can also be used to generate various combinations of interface-specific restraints for integrative modelling. The ARCTIC-3D software is freely available athttps://github.com/haddocking/arctic3dand can be accessed as a web-service athttps://wenmr.science.uu.nl/arctic-3d
Latent EBV impairs immune cell signaling and enhances the efficacy of anti-CD3 mAb in Type 1 Diabetes
Authors: Delgado Ana Lledo , Preston-Hurlburt Paula , Lim Noha , Sumida Tomokazu S. , Long S. Alice , McNamara James , Serti Elisavet , Higdon Lauren , Herold Kevan C.
Published: July 2023

Teplizumab has been approved for the delay of the onset of type 1 diabetes and may modulate new onset disease. We found that patients who were EBV positive at baseline had a more robust response to drug in two clinical trials and therefore postulated that latent virus has general effects in modifying immune responses. We compared the phenotypes, transcriptomes, and development of peripheral blood cells before and after teplizumab treatment. Higher number of Tregs and partially exhausted CD8+T cells were found in EBV seropositive individuals at the baseline in the TN10 trial and AbATE trial. Single cell transcriptomics and functional assays identified downregulation of the T cell receptor and other signaling pathways before treatment. Impairments in function of adaptive immune cells were enhanced by teplizumab treatment in EBV seropositive individuals. Our data indicate that EBV can impair signaling pathways generally in immune cells, that broadly redirect cell differentiation.
Healthcare Stakeholder Perspectives on a Value Assessment Approach for Duchenne Muscular Dystrophy Therapies
Authors: Fischer Ryan , Furlong Pat , Kennedy Annie , Maynard Kelly , Penrod Marissa , Miller Debra , Laverty Chamindra G. , Lowes Linda , Kuntz Nancy L. , Shieh Perry B. , Kondejewski Jane , Neumann Peter J. , Shafrin Jason , Willke Richard J.
Published: July 2023

BACKGROUND

Traditional value assessment frameworks are challenged in comprehensively assessing the societal value new therapies bring to individuals with rare, progressive, genetic, fatal, neuromuscular diseases such as Duchenne muscular dystrophy (DMD).

OBJECTIVE

To identify how value assessment frameworks may need to be adapted to measure the value to society of DMD therapies.

METHODS

Three groups of stakeholders (patient advocates, clinicians, health economists) participated in semi-structured interviews around the International Society for Pharmacoeconomics and Outcomes Research’s Value Flower, which includes elements of value that can be considered within value assessments of healthcare technologies.

RESULTS

All stakeholders agreed that traditional value assessment frameworks based on the quality-adjusted life year (QALY) are narrow and will undervalue new DMD therapies. All stakeholders expressed some level of concern that use of the QALY as a key metric of value discriminates against patients with severe progressive diseases and disabilities. Some stakeholders saw value in using the QALY for cross-disease comparisons in resource-constrained environments if the methodology was appropriate. All stakeholders recommended considering additional elements of value in decision-making around new DMD therapies. These elements reflect: the economic and humanistic costs incurred by patients, caregivers, and families with Duchenne, such as indirect out-of-pocket costs, lost productivity, and family spillovers; the attributes that are meaningful for individuals with disabilities and high unmet need, such as severity of disease, value of hope, and real option value; and factors that contribute to improvements in population health, such as insurance value, equity, and scientific spillovers.

CONCLUSIONS

These findings highlight the need to expand traditional value assessment frameworks and take a holistic approach that incorporates the perspectives of individuals with Duchenne, caregivers, clinicians, and heath economists when assessing the societal value of new DMD therapies. Broadening value assessment will prevent restricted or delayed access to therapies for individuals with Duchenne.
Unleashing the Power of Language Models in Clinical Settings: A Trailblazing Evaluation Unveiling Novel Test Design
Authors: Li Qian , Tang Kang , Li Sen , Zhang Kaihua , Li Zhantao , Chang Lufan , Li Wenxue , Shen Bingzhi , Ding Jia , Min Xianjun
Published: July 2023

The realm of clinical medicine stands on the brink of a revolutionary breakthrough as large language models (LLMs) emerge as formidable allies, propelled by the prowess of deep learning and a wealth of clinical data. Yet, amidst the disquieting specter of misdiagnoses haunting the halls of medical treatment, LLMs offer a glimmer of hope, poised to reshape the landscape. However, their mettle and medical acumen, particularly in the crucible of real-world professional scenarios replete with intricate logical interconnections, re-main shrouded in uncertainty. To illuminate this uncharted territory, we present an audacious quantitative evaluation method, harnessing the ingenuity of tho-racic surgery questions as the litmus test for LLMs’ medical prowess. These clinical questions covering various diseases were collected, and a test format consisting of multi-choice questions and case analysis was designed based on the Chinese National Senior Health Professional Technical Qualification Examination. Five LLMs of different scales and sources were utilized to answer these questions, and evaluation and feedback were provided by professional thoracic surgeons. Among these models, GPT-4 demonstrated the highest performance with a score of 48.67 out of 100, achieving accuracies of 0.62, 0.27, and 0.63 in single-choice, multi-choice, and case-analysis questions, respectively. However, further improvement is still necessary to meet the passing threshold of the examination. Additionally, this paper analyzes the performance, advantages, disadvantages, and risks of LLMs, and proposes suggestions for improvement, providing valuable insights into the capabilities and limitations of LLMs in the specialized medical domain.