bluuebunny/crossref_metadata_2025 huggingface dataset:
Bivalent COVID-19 mRNA booster vaccination (BA.1 or BA.4/BA.5) increases neutralization of matched Omicron variants
Authors: Springer David N. , Bauer Michael , Medits Iris , Camp Jeremy V. , Aberle Stephan W. , Burtscher Clemens , Höltl Eva , Weseslindtner Lukas , Stiasny Karin , Aberle Judith H.
Published: April 2023

We report SARS-CoV-2 neutralizing antibody titers in sera of triple-vaccinated individuals who received a booster dose of an original monovalent or a bivalent BA.1- or BA.4/BA.5-adapted vaccine, or had a breakthrough infection with Omicron variants BA.1, BA.2 or BA.4/BA.5. A bivalent BA.4/BA.5 booster or Omicron-breakthrough infection induced increased Omicron-neutralization titers compared with the monovalent booster. The XBB.1.5 variant effectively evaded neutralizing-antibody responses elicited by current vaccines and/or infection with previous variants.
A novel mutation in EROS (CYBC1) causes Chronic Granulomatous Disease
Authors: Mortimer Paige M , Nichols Esme , Thomas Joe , Shanbhag Rachna , Singh Neha , Coomber Eve L , Malik Talat H , Pickering Matthew C , Randzavola Lyra , Rae William , Bhattad Sagar , Thomas David C
Published: April 2023

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterised by opportunistic infection and sterile granulomatous inflammation. CGD is caused by a failure of reactive oxygen species (ROS) production by the phagocyte NADPH oxidase. Mutations in the genes encoding phagocyte NADPH oxidase subunits cause CGD. We and others have described a novel form of CGD (CGD5) secondary to lack of EROS (CYBC1), a highly selective chaperone for gp91phox. EROS-deficient cells express minimal levels of gp91phoxand its binding partner p22phox, but EROS also controls the expression of other proteins such as P2×7. The full nature of CGD5 is currently unknown. We describe a homozygous frameshift mutation inCYBC1leading to CGD. Individuals who are heterozygous for this mutation are found in South Asian populations (allele frequency = 0.00006545), thus it is not a private mutation. Therefore, it is likely to be the underlying cause of other cases of CGD.
A TNF-IL-1 circuit controlsYersiniawithin intestinal granulomas
Authors: Matsuda Rina , Daniel Sorobetea , Zhang Jenna , Peterson Stefan T. , Grayczyk James P. , Herrmann Beatrice , Yost Winslow , O’Neill Rosemary , Bohrer Andrea C. , Lanza Matthew , Assenmacher Charles-Antoine , Mayer-Barber Katrin D. , Shin Sunny , Brodsky Igor E.
Published: April 2023

Monocytes restrictYersiniainfection within intestinal granulomas. Here, we report that monocyte-intrinsic TNF signaling drives production of IL-1 that signals to non-hematopoietic cells to control intestinalYersiniainfection within granulomas.

Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens.Yersinia pseudotuberculosiscolonizes the intestinal mucosa and induces recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas that control the bacterial infection. Inflammatory monocytes are essential for control and clearance ofYersiniawithin intestinal pyogranulomas, but how monocytes mediateYersiniarestriction is poorly understood. Here, we demonstrate that TNF signaling in monocytes is required for bacterial containment following entericYersiniainfection. We further show that monocyte-intrinsic TNFR1 signaling drives production of monocyte-derived interleukin-1 (IL-1), which signals through IL-1 receptor on non-hematopoietic cells to enable pyogranuloma-mediated control ofYersiniainfection. Altogether, our work reveals a monocyte-intrinsic TNF-IL-1 collaborative circuit as a crucial driver of intestinal granuloma function, and defines the cellular target of TNF signaling that restricts intestinalYersiniainfection.
Two distinct stimulus-locked EEG signatures reliably encode domain-general confidence during decision formation
Authors: Kopčanová Martina , Ince Robin A. A. , Benwell Christopher S. Y.
Published: April 2023

Decision confidence, an internal estimate of how accurate our choices are, is essential for metacognitive self-evaluation and guides behaviour. However, it can be suboptimal and hence understanding the underlying neurocomputational mechanisms is crucial. To do so, it is essential to establish the extent to which both behavioural and neurophysiological measures of metacognition are reliable over time and shared across cognitive domains. The evidence regarding domain-generality of metacognition has been mixed, while the test-retest reliability of the most widely used metacognitive measures has not been reported. Here, in human participants of both sexes, we examined behavioural and electroencephalographic (EEG) measures of metacognition across two tasks that engage distinct cognitive domains – visual perception and semantic memory. The test-retest reliability of all measures was additionally tested across two experimental sessions. The results revealed a dissociation between metacognitive bias and efficiency, whereby only metacognitive bias showed strong test-retest reliability and domain-generality whilst metacognitive efficiency (measured by M-ratio) was neither reliable nor domain-general. Hence, overall confidence calibration (i.e., metacognitive bias) is a stable trait-like characteristic underpinned by domain-general mechanisms whilst metacognitive efficiency may rely on more domain-specific computations. Additionally, we found two distinct stimulus-locked EEG signatures related to the trial-by-trial fluctuations in confidence ratings during decision formation. A late event-related potential was reliably linked to confidence across cognitive domains, while evoked spectral power predicted confidence most reliably in the semantic knowledge domain. Establishing the reliability and domain-generality of neural predictors of confidence represents an important step in advancing our understanding of the mechanisms underlying self-evaluation.

Significance Statement

Understanding the mechanisms underlying metacognition is essential for addressing deficits in self-evaluation. Open questions exist regarding the domain-generality and reliability of both behavioural and neural measures of metacognition. We show that metacognitive bias is reliable across cognitive domains and time, whereas the most adopted measure of metacognitive efficiency is domain-specific and shows poor test-retest reliability. Hence, more reliable measures of metacognition, tailored to specific domains, are needed. We further show that decision confidence is linked to two EEG signatures: late event-related potentials and evoked alpha/beta spectral power. While the former predicts confidence in both perception and semantic knowledge domains, the latter is only reliably linked to knowledge confidence. These findings provide crucial insights into the computations underlying metacognition across domains.
scDEED: a statistical method for detecting dubious 2D single-cell embeddings and optimizing t-SNE and UMAP hyperparameters
Authors: Xia Lucy , Lee Christy , Li Jingyi Jessica
Published: April 2023

Two-dimensional (2D) embedding methods are crucial for single-cell data visualization. Popular methods such as t-SNE and UMAP are commonly used for visualizing cell clusters; however, it is well known that t-SNE and UMAP’s 2D embedding might not reliably inform the similarities among cell clusters. Motivated by this challenge, we developed a statistical method, scDEED, for detecting dubious cell embeddings output by any 2D-embedding method. By calculating a reliability score for every cell embedding, scDEED identifies the cell embeddings with low reliability scores as dubious and those with high reliability scores as trustworthy. Moreover, by minimizing the number of dubious cell embeddings, scDEED provides intuitive guidance for optimizing the hyperparameters of an embedding method. Applied to multiple scRNA-seq datasets, scDEED demonstrates its effectiveness for detecting dubious cell embeddings and optimizing the hyperparameters of t-SNE and UMAP.
Immediate effects of light on circadian eclosion and locomotor activity depend on distinct sensory input pathways
Authors: Bidell Daniel , Feige Natalie-Danielle , Triphan Tilman , Müller Claudia , Pauls Dennis , Helfrich-Förster Charlotte , Selcho Mareike
Published: April 2023

Animals need to be able to sharpen circadian behavioural output in the adaptation to the variable environment. Light is the main entraining signal of the circadian clock, but can also directly increase alertness, locomotor activity, body temperature and heart rate in diurnal animals including humans. Thus, immediate effects of light can enhance or even overwrite circadian output and thereby mask circadian behaviour.

InDrosophila melanogaster, immediate light effects are most evident as a lights-on response in two well described behavioural rhythms of the fly – the emergence rhythm of the adult insect from the pupa, called eclosion, and the diurnal rhythm of locomotor activity. Here, we show that the immediate effect of light on rhythmic eclosion depends on the R8 photoreceptor cells of the compound eyes, while the light response of locomotor activity is triggered by different light detecting cells and organs, that seem to compensate for the loss of each other.
Development of genomic resources for cattails (Typha), a globally important macrophyte genus
Authors: Aleman Alberto , Dorken Marcel E. , Shafer Aaron B. A. , Patel Tulsi , Volkova Polina A. , Freeland Joanna R.
Published: April 2023

1. Background

A critical knowledge gap in freshwater plants research is the lack of genetic tools necessary to answer fundamental questions about their demographic histories, adaptation, and phylogenetic relationships. One example of this isTypha, a global genus of freshwater plants foundational to wetlands that is also becoming an increasingly problematic biological invader in numerous regions worldwide; while important insights have been discovered for this genus, existing markers are insufficient to answer fundamental questions about their demographic histories, adaptation, and phylogenetic relationships, to identify introduced and hybrid lineages, and to examine patterns of hybridisation and introgression.

2. Methods

We optimised a library preparation and data processing protocol to develop genome–wide nuclear and plastid resources for studying the evolutionary history, genetic structure and diversity, hybridisation, local adaptation, invasiveness, and geographic expansion dynamics ofTypha.

3. Main results

We sequenced 140Typhasamples and identified ∼120K nuclear SNPs that differentiateT. angustifolia,T. domingensisandT. latifoliaand retrieved their plastome sequences. We observed genetic introgression among the three species.

4. Conclusions

Following a fast, straightforward, and cost–efficient genomic library preparation protocol, we produced a suite of genome–wide resources to facilitate investigations into the taxonomy and population genetics ofTyphaand to advance the genomic understanding of wetland plants.

5. Contributions

The protocol described, the updated chromosome–level genome assembly ofT. latifolia, the catalogue of species-specific SNPs, and the chloroplast sequences produced in this study comprise permanent resources that can be applied to study the genetic composition of multiple populations and hybrid zones and will be incorporated into future studies ofTypha,an ecologically important and globally invasive macrophyte.
The Healthcare Access and Delivery Survey: Turkiye Earthquake response
Authors: Rahman Najeeb , İnanç Balkan İlker
Published: April 2023

Background

Conducting rapid health assessments during large-scale disasters can present significant challenges. While responding to key humanitarian needs is a priority, assessing and understanding gaps and areas for strengthening are vital in ensuring a comprehensive and equitable response.

Aim

To utilise the perspectives of healthcare workers responding to the Turkiye earthquake 2023, as a means of assessing humanitarian health response gaps.

Design and setting

Observational, descriptive, prospective study design in Turkiye.

Method

Online survey tool using a Likert-type scale, aligned with minimum standards of humanitarian health response themes, in both English and Turkish distributed by healthcare organisations and academic networks to a convenience sample of health workers responding to the earthquake.

Results

45 respondents with perspectives demonstrating general limitations across all humanitarian health themes, with particular gaps in:

Coordination and response timeliness

Reporting and surveillance

Mental health, palliative care and sexual and reproductive health

Conclusion

Using a survey tool to assess health worker perspective is feasible and provides rapid insights into humanitarian response efforts. Such data can be added to other assessment information to build a more comprehensive picture of needs while engaging with a key stakeholder group, and can support service providers to address gaps and strengthen response actions.
A major myna problem; invasive predator removal benefits female survival and population growth of a translocated island endemic
Authors: Brown Thomas J. , Hellicar Max , Accouche Wilna , van der Woude Jildou , Dugdale Hannah , Komdeur Jan , Richardson David S.
Published: April 2023

Invasive predators are a major driver of extinctions and continue to threaten native populations worldwide. Island eradications of (mostly mammalian) invasive predators have facilitated the (re)establishment of numerous island-endemic populations. Other invasive taxa, such as some predatory birds, could pose a more persistent threat due to their ability to fly and actively re-invade even remote and isolated islands. However, the impact of invasive predatory birds has been largely overlooked. We report on a novel sex-specific impact of an invasive-nest predator, the common myna (Acridotheres tristis), on a reintroduced population of Seychelles warblers (Acrocephalus sechellensis); translocated from Cousin Island to Denis Island in 2004. Regular post-translocation monitoring revealed that female mortality was 20% higher than males, leading to a 60–70% male-biased population sex-ratio between 2005–2015. This was attributed to mynas inflicting severe injuries to incubating female warblers while attempting to prey upon eggs in their nests. These effects likely contributed to the slower-than-expected population growth observed (relative to previous translocations of Seychelles warblers to other islands) over the same period. An eradication programme beginning in 2011 removed all mynas from Denis by 2015. Subsequently, we observed a balancing of sex-specific survival and the population sex-ratio of Seychelles warblers and, consequently, accelerated population growth. This study demonstrates the importance of assessing the threat posed by all invasive taxa (not just mammals) to island conservation. Furthermore, we show how extended monitoring is needed to identify problems, and develop solutions, post-translocation.
Nonlinear sensitivity to acoustic context is a stable feature of neuronal responses to complex sounds in auditory cortex of awake mice
Authors: Akritas Marios , Armstrong Alex G. , Lebert Jules M. , Meyer Arne F. , Sahani Maneesh , Linden Jennifer F.
Published: April 2023

The perceptual salience of a sound depends on the acoustic context in which it appears, and can vary on a timescale of milliseconds. At the level of single neurons in the auditory cortex, spectrotemporal tuning for particular sounds is shaped by a similarly fast and systematic nonlinear sensitivity to acoustic context. Does this neuronal context sensitivity “drift” over time in awake animals, or is it a stable feature of sound representation in the auditory cortex? We used chronically implanted tetrode arrays in awake mice to measure the electrophysiological responses of auditory cortical neurons to spectrotemporally complex, rapidly varying sounds across many days. For each neuron in each recording session, we applied the nonlinear-linear “context model” to estimate both a principal (spectrotemporal) receptive ﬁeld and a “contextual gain ﬁeld” describing the neuron’s nonlinear sensitivity to acoustic context. We then quantiﬁed the stability of these ﬁelds within and across days, using spike waveforms to match neurons recorded in multiple sessions. Contextual gain ﬁelds of auditory cortical neurons in awake mice were remarkably stable across many days of recording, and comparable in stability to principal receptive ﬁelds. Interestingly, there were small but signiﬁcant effects of changes in locomotion or pupil size on the ability of the context model to ﬁt temporal fluctuations in the neuronal response.

We conclude that both spectrotemporal tuning and nonlinear sensitivity to acoustic context are stable features of neuronal sound representation in the awake auditory cortex, which can be modulated by behavioral state.
Superior colliculus cell types bidirectionally modulate choice activity in frontal cortex
Authors: Thomas Alyse , Yang Weiguo , Wang Catherine , Tipparaju Sri Laasya , Chen Guang , Sullivan Brennan , Swiekatowski Kylie , Tatam Mahima , Gerfen Charles , Li Nuo
Published: April 2023

Action selection occurs through competition between potential choice options. Neural correlates of choice competition are observed across frontal cortex and downstream superior colliculus (SC) during decision-making, yet how these regions interact to mediate choice competition remains unresolved. Here we report that cell types within SC can bidirectionally modulate choice competition and drive choice activity in frontal cortex. In the mouse, topographically matched regions of frontal cortex and SC formed a descending motor pathway for directional licking and a re-entrant loop via the thalamus. During decision-making, distinct neuronal populations in both frontal cortex and SC encoded opposing lick directions and exhibited push-pull dynamics. SC GABAergic neurons encoded ipsilateral choice and glutamatergic neurons encoded contralateral choice, and activating or suppressing these cell types could bidirectionally drive push-pull choice activity in frontal cortex. These results thus identify SC as a major locus to modulate choice competition within the broader action selection network.
Functional divergences of natural variations ofTaNAM-A1controlling leaf senescence initiation during wheat grain filling
Authors: Zhou Longxi , Shen Chuncai , Teng Wan , He Xue , Zhao Xueqiang , Jing Yanfu , Huang Zhixiong , Tong Yiping
Published: April 2023

Leaf senescence is an essential physiological process related to grain yield potential and nutritional quality. Green leaf duration (GLD) after anthesis directly reflects the leaf senescence process and exhibits large genotypic differences in common wheat; however, the underlying gene regulatory mechanism is still lacking up to now. Here, we reportTaNAM-A1as the causal gene of major lociqGLD-6Afor GLD during grain filling by map-based cloning. The role of TaNAM-A1 in regulating leaf senescence, spike length, and grain size was proved by transgenic assay and TILLING mutants analyses. Furthermore, the functional divergences amongTaNAM-A1three haplotypes were systematically evaluated. Wheat varieties withTaNAM-A1d(containing two mutations in CDS ofTaNAM-A1) had longer GLD and advantages in yield-related traits than those with the wild typeTaNAM-A1a. All three haplotypes were functional in transactivating the expression of genes involved in macromolecular degradation and mineral nutrient remobilization, with TaNAM-A1a the strongest activity and TaNAM-A1d the weakest. TaNAM-A1 modulates the expression ofTaNAC016-3AandTaNAC-S-7Ato trigger senescence initiation. TaNAC016-3A enhances TaNAM-A1 transcriptional activation ability by protein-protein interaction. Our study provides new insights into fine-tuning the leaf functional period and grain yield formation for wheat breeding under different geographical climatic conditions.
Automated whole-organ histological imaging assisted with ultraviolet-excited sectioning tomography and deep learning
Authors: Kang Lei , Yu Wentao , Zhang Yan , Wong Terence T. W.
Published: April 2023

Three-dimensional (3D) histopathology involves the microscopic examination of a specimen, which plays a vital role in studying tissue’s 3D structures and the signs of diseases. However, acquiring high-quality histological images of a whole organ is extremely time-consuming (e.g., several weeks) and laborious, as the organ has to be sectioned into hundreds or thousands of slices for imaging. Besides, the acquired images are required to undergo a complicated image registration process for 3D reconstruction. Here, by incorporating a recently developed vibratome-assisted block-face imaging technique with deep learning, we developed a pipeline termed HistoTRUST that can rapidly and automatically generate subcellular whole organ’s virtual hematoxylin and eosin (H&E) stained histological images which can be reconstructed into 3D by simple image stacking (i.e., without registration). The performance and robustness of HistoTRUST have been successfully validated by imaging all vital mouse organs (brain, liver, kidney, heart, lung, and spleen) within 1–3 days depending on the size. The generated 3D dataset has the same color tune as the traditional H&E stained histological images. Therefore, the virtual H&E stained images can be directly analyzed by pathologists. HistoTRUST has a high potential to serve as a new standard in providing 3D histology for research or clinical applications.
Competitive performance and superior noise robustness of a non-negative deep convolutional spiking network
Authors: Rotermund David , Garcia-Ortiz Alberto , Pawelzik Klaus R.
Published: April 2023

Networks of spiking neurons promise to combine energy efficiency with high performance. However, spiking models that match the performance of current state-of-the-art networks while requiring moderate computational resources are still lacking. Here we present an alternative framework to deep convolutional networks (CNNs), the ”Spike by Spike” network (SbS), together with an efficient backpropagation algorithm. SbS implements networks based on non-negative matrix factorisation (NNMF), but uses discrete events as signals instead of real values. On clean data, the performance of CNNs is matched by both NNMF-based networks and SbS. SbS are found to be most robust when the data is corrupted by noise, specially when this noise was not seen before.
A DRG genetic toolkit reveals molecular, morphological, and functional diversity of somatosensory neuron subtypes
Authors: Qi Lijun , Iskols Michael , Shi David , Reddy Pranav , Walker Christopher , Lezgiyeva Karina , Voisin Tiphaine , Pawlak Mathias , Kuchroo Vijay K. , Chiu Isaac , Ginty David D. , Sharma Nikhil
Published: April 2023

Mechanical and thermal stimuli acting on the skin are detected by morphologically and physiologically distinct sensory neurons of the dorsal root ganglia (DRG). Achieving a holistic view of how this diverse neuronal population relays sensory information from the skin to the central nervous system (CNS) has been challenging with existing tools. Here, we used transcriptomic datasets of the mouse DRG to guide development and curation of a genetic toolkit to interrogate transcriptionally defined DRG neuron subtypes. Morphological analysis revealed unique cutaneous axon arborization areas and branching patterns of each subtype. Physiological analysis showed that subtypes exhibit distinct thresholds and ranges of responses to mechanical and/or thermal stimuli. The somatosensory neuron toolbox thus enables comprehensive phenotyping of most principal sensory neuron subtypes. Moreover, our findings support a population coding scheme in which the activation thresholds of morphologically and physiologically distinct cutaneous DRG neuron subtypes tile multiple dimensions of stimulus space.
Frontal-midline theta and posterior alpha oscillations index early processing of spatial representations during active navigation
Authors: Du Yu Karen , Liang Mingli , McAvan Andrew S. , Wilson Robert C. , Ekstrom Arne D.
Published: April 2023

Previous research has demonstrated that humans combine multiple sources of spatial information such as self-motion and landmark cues, while navigating through an environment. However, it is unclear whether this involves comparing multiple representations obtained from different sources during navigation (parallel hypothesis) or building a representation first based on self-motion cues and then combining with landmarks later (serial hypothesis). We tested these two hypotheses (parallel vs. serial) in an active navigation task using wireless mobile scalp EEG recordings. Participants walked through an immersive virtual hallway with or without conflicts between self-motion and landmarks (i.e., intersections) and pointed toward the starting position of the hallway. We employed the oscillatory signals recorded during mobile wireless scalp EEG as means of identifying when participant representations based on self-motion vs. landmark cues might have first emerged. We found that path segments, including intersections present early during navigation, were more strongly associated with later pointing error, regardless of when they appeared during encoding. We also found that there was sufficient information contained within the frontal-midline theta and posterior alpha oscillatory signals in the earliest segments of navigation involving intersections to decode condition (i.e., conflicting vs. not conflicting). Together, these findings suggest that intersections play a pivotal role in the early development of spatial representations, suggesting that memory representations for the geometry of walked paths likely develop early during navigation, in support of the parallel hypothesis.
Drug combinations proposed by machine learning on genes/proteins to improve the efficacy of Tecovirimat in the treatment of Monkeypox: A Systematic Review and Network Meta-analysis
Authors: Boush Mahnaz , Kiaei Ali A. , Safaei Danial , Abadijou Sadegh , Salari Nader , Mohammadi Masoud
Published: April 2023

Background

The World Health Organization (WHO) describes Monkeypox as a viral zoonosis, or an animal-to-human virus transmission, with symptoms comparable to those of past smallpox patients but clinically less severe. This study’s objective is to assess the results of previous investigations on the best drug combinations for treating Monkeypox.

Method

The pharmacological combinations used to treat monkeypox sickness have been researched in two stages for this systematic review and network meta-analysis. To begin with, a certain machine learning technique is used to extract the medication combinations from the researched articles offered on science databases, including Scopus, PubMed, Web of Science (ISI), Science Direct, Embase, and Google Scholar. Second, the tested medicine combinations will have been proven.

Results

The results of this study show that the p-value between the proposed drug combination and Monkeypox for scenarios 1 to 5 were 0.108, 0.042, 0.023, 0.018, and 0.015, respectively. Scenarioiis the combination of the firstisuggested drugs for treating Monkeypox. This has led to a 720 percent increase in the proposed drug combination’s efficacy in treating Monkeypox.

Conclusion

The suggested drug combination decreases the p-value between MonkeyPox and the genes as potential targets for Monkeypox progression, which leads to an improvement in the treatment of Monkeypox. Therefore, using the right combination of drugs is important in improving the community’s health and reducing per capita treatment costs.
IL-15 priming alters IFN-γ regulation in murine NK cells
Authors: Cimpean Maria , Keppel Molly P. , Gainullina Anastasiia , Fan Changxu , Schedler Nathan C. , Swain Amanda , Kolicheski Ana , Shapiro Hannah , Young Howard A. , Wang Ting , Artyomov Maxim N. , Cooper Megan A.
Published: April 2023

Natural killer (NK) effector functions can be triggered by inflammatory cytokines and engagement of activating receptors. NK cell production of IFN-γ, an important immunoregulatory cytokine, exhibits activation-specific IFN-γ regulation. Resting murine NK cells exhibit activation-specific metabolic requirements for IFN-γ production, which are reversed for activating receptor-mediated stimulation following IL-15 priming. While both cytokine and activating receptor stimulation leads to similar IFN-γ protein production, only cytokine stimulation upregulatesIfngtranscript, suggesting that protein production is translationally regulated after receptor stimulation. Based on these differences in IFN-γ regulation, we hypothesized that ex vivo IL-15 priming of murine NK cells allows a switch to IFN-γ transcription upon activating receptor engagement. Transcriptional analysis of primed NK cells compared to naïve cells or cells cultured with low-dose IL-15 demonstrated that primed cells strongly upregulatedIfngtranscript following activating receptor stimulation. This was not due to chromatin accessibility changes in theIfnglocus or changes in ITAM signaling, but was associated with a distinct transcriptional signature induced by ITAM stimulation of primed compared to naïve NK cells. Transcriptional analyses identified a common signature of c-Myc (Myc) targets associated withIfngtranscription. While Myc marked NK cells capable ofIfngtranscription, Myc itself was not required forIfngtranscription using a genetic model of Myc deletion. This work highlights altered regulatory networks in IL-15 primed cells, resulting in distinct gene expression patterns and IFN-γ regulation in response to activating receptor stimulation.
Localized estimation of electromagnetic sources underlying event-related fields using recurrent neural networks
Authors: O’Reilly Jamie A. , Zhu Judy D. , Sowman Paul F.
Published: April 2023

Objective

To use a recurrent neural network (RNN) to reconstruct neural activity responsible for generating noninvasively measured electromagnetic signals.

Approach

Output weights of an RNN were fixed as the lead field matrix from volumetric source space computed using the boundary element method with co-registered structural magnetic resonance images and magnetoencephalography (MEG). Initially, the network was trained to minimize mean-squared-error loss between its outputs and MEG signals, causing activations in the penultimate layer to converge towards putative neural source activations. Subsequently, L1 regularization was applied to the final hidden layer, and the model was fine-tuned, causing it to favour more focused activations. Estimated source signals were then obtained from the outputs of the last hidden layer. We developed and validated this approach with simulations before applying it to real MEG data, comparing performance with three existing methods: beamformers, minimum-norm estimate, and dynamical statistical parametric mapping.

Main results

The proposed method had higher output signal-to-noise ratios than the others and comparable correlation and error between estimated and simulated sources. Reconstructed MEG signals were also equal or superior to the other methods in terms of their similarity to ground-truth. When applied to MEG data recorded during an auditory roving oddball experiment, source signals estimated with the RNN were generally consistent with expectations from the literature and qualitatively smoother and more reasonable-looking than estimates from the other methods.

Significance

This work builds on recent developments of RNNs for modelling event-related neural responses by incorporating biophysical constraints from the forward model, thus taking a significant step towards greater biological realism and introducing the possibility of exploring how input manipulations may influence localized neural activity.
Temporal variability can promote migration between habitats
Authors: Jaggi Harman , Steinsaltz David , Tuljapurkar Shripad
Published: April 2023

Understanding the conditions that promote the evolution of migration is important in ecology and evolution. When environments are fixed and there is one most favorable site, migration to other sites lowers overall growth rate and is not favored. Here we ask, can environmental variability favor migration when there is one best site on average? Previous work suggests that the answer is yes, but a general and precise answer remained elusive. Here we establish new, rigorous inequalities to show (and use simulations to illustrate) how stochastic growth rate can increase with migration when fitness (dis)advantages fluctuate over time across sites. The effect of migration between sites on the overall stochastic growth rate depends on the difference in expected growth rates and the variance of the fluctuating difference in growth rates. When fluctuations (variance) are large, a population can benefit from bursts of higher growth in sites that are worse on average. Such bursts become more probable as the between-site variance increases. Our results apply to many (≥ 2) sites, and reveal an interplay between the length of paths between sites, the average differences in site-specific growth rates, and the size of fluctuations. Our findings have implications for evolutionary biology as they provide conditions for departure from the reduction principle, and for ecological dynamics: even when there are superior sites in a sea of poor habitats, variability and habitat quality across space determine the importance of migration.
Mechanism of the Covalent Inhibition of Human Transmembrane Protease Serine 2 as an Original Antiviral Strategy
Authors: Spinello Angelo , D’Anna Luisa , Bignon Emmanuelle , Miclot Tom , Grandemange Stéphanie , Terenzi Alessio , Barone Giampaolo , Barbault Florent , Monari Antonio
Published: April 2023

The Transmembrane Protease Serine 2 (TMPRSS2) is a human enzyme which is involved in the maturation and post-translation of different proteins. In addition of being overexpressed in cancer cells, TMPRSS2 plays a further fundamental role in favoring viral infections by allowing the fusion of the virus envelope and the cellular membrane, notably in SARS-CoV-2. In this contribution we resort to multiscale molecular modeling to unravel the structural and dynamical features of TMPRSS2 and its interaction with a model lipid bilayer. Furthermore, we shed light into the mechanism of action of a potential inhibitor (Nafamostat), determining the free-energy profile associated with the inhibition reaction, and showing the facile poisoning of the enzyme. Our study, while providing the first atomistically resolved mechanism of TMPRSS2 inhibition, is also fundamental in furnishing a solid framework for further rational design targeting transmembrane proteases in a host-directed antiviral strategy.

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Mechanistic characterization of aDrosophilamodel of paraneoplastic nephrotic syndrome
Authors: Xu Jun , Liu Ying , Chen Weihang , Shun Li Joshua Shing , Comjean Aram , Hu Yanhui , Perrimon Norbert
Published: April 2023

Paraneoplastic syndromes occur in cancer patients and originate from dysfunction of organs at a distance from the tumor or its metastasis. A wide range of organs can be affected in paraneoplastic syndromes; however, the pathological mechanisms by which tumors influence host organs are poorly understood. Recent studies in the fly uncovered that tumor secreted factors target host organs, leading to pathological effects. In this study, using aDrosophilagut tumor model, we characterized a mechanism of tumor-induced kidney dysfunction. Specifically, we found that Pvf1, a PDGF/VEGF signaling ligand, secreted by gut tumors activates the PvR/JNK/Jra signaling pathway in the principal cells of the kidney, leading to mis-expression of renal genes and paraneoplastic renal syndrome-like phenotypes. Our study describes a novel mechanism by which gut tumors perturb the function of the kidney, which might be of clinical relevance for the treatment of paraneoplastic syndromes.
State-dependent role of interhemispheric pathway for motor recovery in primates
Authors: Mitsuhashi Masahiro , Yamaguchi Reona , Kawasaki Toshinari , Ueno Satoko , Sun Yiping , Isa Kaoru , Takahashi Jun , Kobayashi Kenta , Onoe Hirotaka , Takahashi Ryosuke , Isa Tadashi
Published: April 2023

Whether and how the interhemispheric pathway is involved in post-injury motor recovery is controversial. Unidirectional chemogenetic blockade of the interhemispheric pathway from the contralesional to ipsilesional premotor cortex impaired dexterous hand movements during the early recovery stage after lesioning the lateral corticospinal tract in macaques. Furthermore, electrocorticographical recording showed that the low frequency band activity of the ipsilesional premotor cortex around the movement onset was decreased by the blockade during the early recovery stage, while it was increased by blockade during the intact state and the late recovery stage. These results demonstrate that the action of the interhemispheric pathway changed from inhibition to facilitation, leading to the involvement of the ipsilesional sensorimotor cortex in hand movements during the early recovery stage. The present study offers new insights into the state-dependent role of the interhemispheric pathway and a therapeutic target in the early recovery stage after lesioning of the corticospinal tract.
Male nurses’ adaptation experiences after turnover to community institutions in Korea
Authors: Kim Ja-Sook , Kim Suhyun , Chung Hyang-In Cho
Published: April 2023

We aimed to develop a substantive theory according to the associations between adaptation experience-related factors identified in male nurses after turnover to community institutions. From April through August 2019, data were collected through direct observations and in-depth interviews of 22 male nurse participants who were recruited purposively and analyzed simultaneously with the method proposed by Strauss and Corbin. Furthermore, 29 subcategories were derived from 11 categories, including: (1) leaving the clinical sector and changing jobs, (2) shaking while settling, (3) characteristics of the new job, (4) personal disposition, (5) support system, (6) finding my place, (7) solidifying my place, (8) demonstrating my professional competence, (9) stable settlement in my place, (10) preparing for a better future, and (11) still confused. The core category was identified as “putting down roots in another place for myself.” The verification of this theory in this study’s results indicates a need for research into the evaluation and development of professional development programs and related policies to provide support to male nurses who are pursuing opportunities in community institutions to maintain their nursing identity and further their efforts for developing a nursing specialty. Keywords: nurses, male, turnover, adaptation, grounded theory, qualitative research
Computation of Expected Epidemic Duration
Authors: González Alejandro Alarcón , Pérez Guillermo A.
Published: April 2023

This paper discusses the mean duration of a closed epidemic modeled by a discrete-time Markov chain. We develop a methodology for the efficient computation of the quantity of interest. The Markov chain model in consideration is bivariate, and is formally handled. We derive explicit terms for the probability to transition from one state to another, and prove that the chain is absorbing. The computation of the mean duration is translated to the computation of the expected hitting times to the set of absorbing states. We use the theory of absorbing Markov chains to derive a matrix formulation that gives way to an efficient algorithm to solve for the expected hitting times. This approach is instantiated in the form of a concrete algorithm, which is further optimized by using dynamic programming. Finally, we have implemented the method and tested it against the use of simulations to estimate mean durations.
A multiplexed RT-PCR Assay for Nanopore Whole Genome Sequencing of Tilapia lake virus (TiLV)
Authors: Delamare-Deboutteville Jerome , Meemetta Watcharachai , Pimsannil Khaettareeya , Sangpo Pattiya , Gan Han Ming , Mohan Chadag Vishnumurthy , Dong Ha Thanh , Senapin Saengchan
Published: April 2023

Tilapia lake virus (TiLV) is a highly contagious viral pathogen that affects tilapia, a globally significant and affordable source of fish protein. To prevent the introduction and spread of TiLV and its impact, there is an urgent need for increased surveillance, improved biosecurity measures, and continuous development of effective diagnostic and rapid sequencing methods. In this study, we have developed a multiplexed RT-PCR assay that can amplify all ten complete genomic segments of TiLV from various sources of isolation. The amplicons generated using this approach were immediately subjected to real-time sequencing on the Nanopore system. By using this approach, we have recovered and assembled 10 TiLV genomes from total RNA extracted from naturally TiLV-infected tilapia fish, concentrated tilapia rearing water, and cell culture. Our phylogenetic analysis, consisting of more than 36 TiLV genomes from both newly sequenced and publicly available TiLV genomes, provides new insights into the high genetic diversity of TiLV. This work is an essential steppingstone towards integrating rapid and real-time Nanopore-based amplicon sequencing into routine genomic surveillance of TiLV, as well as future vaccine development.
Rapid dissemination of host-metabolism-manipulating transposon-like entities via integrative and conjugative elements
Authors: Colombi Elena , Bertels Frederic , Doulcier Guilhem , McConnell Ellen , Pichugina Tatyana , Sohn Kee Hoon , Straub Christina , McCann Honour , Rainey Paul B.
Published: April 2023

Integrative and conjugative elements (ICEs) are self-transmissible mobile elements that transfer functional genetic units across broad phylogenetic distances. Accessory genes shuttled by ICEs can make significant contributions to bacterial fitness, yet ICEs that carry accessory genes encoding functions other than antimicrobial resistance remain poorly characterized.

Recent observation of the rapid acquisition of ICEs in a pandemic lineage ofPseudomonas syringaepv.actinidaeled to investigation of the structural and functional diversity of these elements among a diverse array ofP. syringae. Fifty-three unique ICE types were identified across multiple phylogroups. These ICEs display distinct evolutionary histories compared to their bacterial hosts, are highly recombinogenic, exhibit a conserved structure and are punctuated by hotspots of accessory gene integration. Many carry a 16 kb transposon-like entity (Tn6212) that shows little polymorphism indicating recent dissemination. Deletion of Tn6212did not alter pathogen growthin planta, but mutants displayed significant fitness defects when grown on TCA cycle intermediates. These were largely attributable to a single LysR regulator. RNA-seq analysis of a set of nested Tn6212deletions confirmed a central role of LysR in enhanced expression of more than 300 genes and down-regulation of genes controlling expression of energetically demanding loci. Together the transcriptional data indicate a major role for Tn6212in manipulation of bacterial metabolism with primary effects on RNA degradation, protein synthesis and potential diversion of ATP to growth.
Latent Representations in Hippocampal Network Model Co-Evolve with Behavioral Exploration of Task Structure
Authors: Cone Ian , Clopath Claudia
Published: April 2023

Real-life behavioral tasks are often complex and depend on abstract combinations of sensory stimuli and internal logic. To successfully learn these tasks, animals must pair actions or decisions to the task’s complex structure. The hippocampus has been shown to contain fields which represent complex environmental and task variables, including place, lap, evidence accumulation, etc. Altogether, these representations have been hypothesized to form a “cognitive map” which encodes the complex real-world structure underlying behavior. However, it is still unclear how biophysical plasticity mechanisms at the single cell level can lead to the population-wide evolution of task-relevant maps. In this work we present a biophysically plausible model comprised of a recurrent hippocampal network and an action network, in which the latent representational structure co-evolves with behavior in a task-dependent manner. We demonstrate that the network develops latent structures that are needed for solving the task and does not integrate latent structures which do not support task learning. We show that, in agreement with experimental data, cue-dependent “splitters” can only be induced at the single cell level if the task requires a split representation to solve. Finally, our model makes specific predictions on how biases in behavior result from experimentally testable biases in the underlying latent representation.
Introduction of Barnase/Barstar in soybean produces a rescuable male sterility system for hybrid breeding
Authors: Szeluga Nicole , Baldrich Patricia , DelPercio Ryan , Meyers Blake C. , Frank Margaret H.
Published: April 2023

Hybrid breeding for increased vigor has been used for over a century to boost agricultural outputs without requiring higher inputs. While this approach has led to some of the most substantial gains in crop productivity, breeding barriers have fundamentally limited soybean (Glycine max) from reaping the benefits of hybrid vigor. Soybean makes inconspicuous flowers that self-fertilize before opening, and thus are not readily amenable to outcrossing. In this study, we demonstrate that the Barnase/Barstar male sterility/male rescue system can be used in soybean to produce hybrid seeds. By expressing the cytotoxic ribonuclease, Barnase, under a tapetum-specific promoter in soybean anthers, we are able to completely block pollen maturation, creating male-sterile plants. We show that fertility can be rescued in the F1 generation of these Barnase-expressing lines when they are crossed with pollen from plants that express the Barnase inhibitor, Barstar. Importantly, we found that the successful rescue of male fertility is dependent on the relative dosage of Barnase and Barstar. When Barnase and Barstar were expressed under the same tapetum-specific promoter, the F1 offspring remained male-sterile. When we expressed Barstar under a relatively stronger promoter than Barnase, we were able to achieve a successful rescue of male fertility in the F1 generation. This work demonstrates the successful implementation of a biotechnology approach to produce fertile hybrid offspring in soybean.
daf-42is an evolutionarily young gene essential for dauer development inCaenorhabditis elegans
Authors: Lim Daisy S. , Kim Jun , Kim Wonjoo , Kim Nari , Lee Sang-Hee , Lee Daehan , Lee Junho
Published: April 2023

Under adverse environmental conditions, nematodes arrest into dauer, an alternative developmental stage for diapause. Dauer endures unfavorable environments and interacts with host animals to access favorable environments, thus playing a critical role in survival. Here, we report that inCaenorhabditis elegans,daf-42is essential for development into the dauer stage, as the null mutant ofdaf-42exhibited a “no viable dauer” phenotype in which no viable dauers were obtained in any dauer-inducing conditions. Long-term time lapse microscopy of synchonized larvae revealed thatdaf-42is involved in developmental changes from the pre-dauer L2d stage to the dauer stage.daf-42encodes large, disordered proteins of various sizes that are expressed in and secreted from the seam cells within a narrow time window shortly before the molt into dauer stage. Transcriptome analysis showed that the transcription of genes involved in larval physiology and dauer metabolism are highly affected by thedaf-42 mutation. Contrary to the notion that essential genes that control the life and death of an organism may well be conserved across diverse species,daf-42is an evolutionarily young gene conserved only in theCaenorhabditisgenus. Our study shows that dauer formation is a vital process that is controlled not only by conserved genes but also by newly emerged genes, providing important insights into evolutionary mechanisms.