bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-based comparison between the recombinant SARS-CoV-2 XBB and its parental lineages
Authors: Scarpa Fabio , Sanna Daria , Azzena Ilenia , Casu Marco , Cossu Piero , Fiori Pier Luigi , Benvenuto Domenico , Imperia Elena , Giovanetti Marta , Ceccarelli Giancarlo , Cauda Roberto , Cassone Antonio , Pascarella Stefano , Ciccozzi Massimo
Published: December 2022

Recombination is the main contributor to RNA virus evolution, and SARS-CoV-2 during the pandemic produced several recombinants. The most recent SARS-CoV-2 recombinant is the lineage labeled XBB, also known as Gryphon, which arose from BJ.1 and BM. 1.1.1. Here we performed a genome-based survey aimed to compare the new recombinant with its parental lineages that never became dominant. Genetic analyses indicated that the recombinant XBB and its first descendant XBB.1 show an evolutionary condition typical of an evolutionary blind background with no further epidemiologically relevant descendant. Genetic variability and expansion capabilities are slightly higher than parental lineages. Bayesian Skyline Plot indicates that XBB reached its plateau around October 6, 2022 and after an initial rapid growth the viral population size did not further expand, and around November 10, 2022 its levels of genetic variability decreased. Simultaneously with the reduction of the XBB population size, an increase of the genetic variability of its first sub-lineage XBB.1 occurred, that in turn reached the plateau around November 9, 2022 showing a kind of vicariance with its direct progenitors. Structure analysis indicates that the affinity for ACE2 surface in XBB/XBB.1 RBDs is weaker than for BA.2 RBD. In conclusion, nowadays XBB and XBB.1 do not show evidence about a particular danger or high expansion capability. Genome-based monitoring must continue uninterrupted in order to individuate if further mutations can make XBB more dangerous or generate new subvariants with different expansion capability.
Neural distinctiveness and discriminability in regions of the core network representations support associative unitization
Authors: Steinkrauss A. C. , Carpenter C. M. , Tarkenton M. K. , Overman A.A. , Dennis N.A.
Published: December 2022

Previous work has suggested unitized pairs behave as a single unit and more critically, are processed neurally different than those of associative memories. The current works examines the neural differences between unitization and non-unitized memory using fMRI and multivoxel analyses. Specifically, we examined the differences across face-occupation pairings as a function of whether the pairing was viewed as a person performing the given job (unitized binding) or a person saying they knew someone who had a particular job (non-unitized binding). The results show that at encoding, the angular gyrus can discriminate between unitized and non-unitized target trials. Additionally, during encoding, the medial temporal lobe (hippocampus and perirhinal cortex), frontal parietal regions (angular gyrus and medial frontal gyrus) and visual regions (middle occipital cortex) exhibit distinct neural patterns to recollected unitized and non-unitized targets. Furthermore, the medial frontal gyrus and middle occipital cortex show greater neural similarity for recollected unitized trials than those of recollected non-unitized trials. We conclude that visually unitized pairs may enhance unitization in older adults due to greater similarity of trials within the same condition during the encoding process.
QRATER: a collaborative and centralized imaging quality control web-based application
Authors: Fernandez-Lozano Sofia , Dadar Mahsa , Morrison Cassandra , Manera Ana , Andrews Daniel , Rajabli Reza , Madge Victoria , St-Onge Etienne , Shafiee Neda , Livadas Alexandra , Fonov Vladimir , Collins D. Louis ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

Quality control (QC) is an important part of all scientific analysis, including neuroscience. With manual curation considered the gold standard, there remains a lack of available tools that make manual neuroimaging QC accessible, fast, and easy. In this article we present Qrater, a containerized web-based python application that enables viewing and rating of previously generated QC images. A group of raters with varying amounts of experience in QC evaluated Qrater in three different tasks: QC of MRI raw acquisition (10,196 images), QC of non-linear registration to a standard template (10,196 images) and QC of skull segmentation (6,968 images). We measured the proportion of failed images, timing and intra- and inter-rater agreement. Raters spent vastly different amounts of time on each image depending on their experience and the task at hand. QC of MRI raw acquisition was the slowest. While an expert rater needed approximately one minute, trained raters spent 2-6 minutes evaluating an image. The fastest was the curation of a skull segmentation image, where expert raters spent on average 3 seconds per image before assigning a rating. Rating agreement also varied depending on the experience of the raters and the task at hand: trained raters’ inter-rater agreement with the expert’s gold standard ranged from fair to substantial in raw acquisition (Cohen’s chance corrected kappa agreement scores up to 0.72) and from fair to excellent in linear registration (kappa scores up to 0.82), while the experts’ inter-rater agreement of the skull segmentation task was excellent (kappa = 0.83). These results demonstrate that Qrater is a useful asset for QC tasks that rely on manual curation of images.
AFsample: Improving Multimer Prediction with AlphaFold using Aggressive Sampling
Authors: Wallner Björn
Published: December 2022

The AlphaFold neural network model has revolutionized structural molecular biology with unprecedented performance. We demonstrate that by stochastically perturbing the neural network by enabling dropout at inference combined with massive sampling, it is possible to improve the quality of the generated models. We generated around 6,000 models per target compared to 25 default for AF2-multimer, with v1 and v2 multimer network models, with and without templates, and increased the number of recycles within the network. The method was benchmarked in CASP15, and compared to AF2-multimer it improved the average DockQ from 0.41 to 0.55 using identical input and was ranked at the very top in the protein assembly category when compared to all other groups participating in CASP15. The simplicity of the method should facilitate the adaptation by the field, and the method should be useful for anyone interested in modelling multimeric structures, alternate conformations or flexible structures.

Availability

AFsample is available online athttp://wallnerlab.org/AFsample.
Diverse secondary metabolites are expressed in particle-associated and free-living microorganisms of the permanently anoxic Cariaco Basin
Authors: Geller-McGrath David , Mara Paraskevi , Taylor Gordon T. , Suter Elizabeth , Edgcomb Virginia , Pachiadaki Maria
Published: December 2022

Secondary metabolites play essential roles in ecological interactions and nutrient acquisition, and are of interest for their potential uses in medicine and biotechnology. Under laboratory conditions the discovery of new compounds is hindered by low production, high rediscovery rates, and detection evasion. Genome mining for biosynthetic gene clusters (BGCs) is a popular approach to address these limitations, thereby uncovering often cryptic secondary metabolic potential. Marine systems are often underrepresented in bulk genome mining efforts; and habitats with unique physicochemical characteristics such as oxygen-depleted and anoxic water columns remain virtually unexplored regarding BGCs. Here, we use genome mining and differential gene expression analyses to show that redox potential and particle-associated vs. free-living lifestyles both influence the composition and production of secondary metabolites through the stratified water column of the Cariaco Basin, Venezuela. Microbiota, including understudied clades, such as Planctomycetota, encode and express a wide range of secondary metabolites in these anoxic/euxinic waters.
Photovoltaic enzymes by design and evolution
Authors: Bunzel H. Adrian , Smith James A. , Oliver Thomas A. A. , Jones Michael R. , Mulholland Adrian J. , Anderson J. L. Ross
Published: December 2022

The global energy crisis challenges us to develop more efficient strategies for the sustainable production of energy. Given the excellent efficiency of the natural photosynthetic apparatus, biohybrid photovoltaic devices present an attractive solution for solar energy conversion. However, their composition, stability, and complexity can limit their inclusion into photovoltaic devices. Here, we combined computational design and directed evolution to overcome these limitations and create tailor-made photoenzymes. Photo-biocatalysts were designed by introducing photosensitizer binding sites into heme-containing helical bundle proteins. The designed binding sites were specific for the target photosensitizer and readily transplanted into other helical bundles. The best design was highly evolvable and reached nanomolar ligand affinity after mutagenesis and screening. The evolved enzyme generated 2.6 times higher photocurrents than the photosensitizer alone, primarily driven by increased photostability. Evolvability is a unique advantage of our protein-based approach over abiological photovoltaic and will be critical to developing efficient biohybrid systems.

Abstract Figure
Cylicins are a structural component of the sperm calyx being indispensable for male fertility in mice and human
Authors: Schneider Simon , Kovacevic Andjela , Mayer Michelle , Dicke Ann-Kristin , Arévalo Lena , Koser Sophie A. , Hansen Jan N. , Young Samuel , Brenker Christoph , Kliesch Sabine , Wachten Dagmar , Kirfel Gregor , Strünker Timo , Tüttelmann Frank , Schorle Hubert
Published: December 2022

Cylicins are testis-specific proteins, which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2)genes have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cylicins have been localized in the acrosomal region of round spermatids, they resemble a major component of the calyx within the perinuclear theca at the posterior part of mature sperm nuclei. However, the role of Cylicins during spermiogenesis has not yet been investigated. Here, we applied CRISPR/Cas9-mediated gene-editing in zygotes to establishCylc1-andCylc2-deficient mouse lines as a model to study the function of these proteins.Cylc1deficiency resulted in male subfertility, whereasCylc2−/−,Cylc1−/yCylc2+/−, andCylc1−/yCylc2−/−males were infertile. Phenotypical characterization revealed that loss of Cylicins prevents proper calyx assembly during spermiogenesis. This results in decreased epididymal sperm counts, impaired shedding of excess cytoplasm, and severe structural malformations, ultimately resulting in impaired sperm motility. Furthermore, exome sequencing identified an infertile man with a hemizygous variant inCYLC1and a heterozygous variant inCYLC2, displaying morphological abnormalities of the sperm including the absence of the acrosome. Thus, our study highlights the relevance and importance of Cylicins for spermiogenic remodeling and male fertility in human and mouse, and provides the basis for further studies on unraveling the complex molecular interactions between perinuclear theca proteins required during spermiogenesis.
Quantitative modeling of the emergence of macroscopic grid-like representations
Authors: Bin Khalid Ikhwan , Reifenstein Eric T. , Auer Naomi , Kunz Lukas , Kempter Richard
Published: December 2022

Grid cells are neurons in the entorhinal cortex that are thought to perform neural computations in support of spatial navigation. When subjects navigate through spatial environments, grid cells exhibit firing fields that are arranged in a triangular grid pattern. As direct recordings of grid cells from the human brain are only rarely possible, functional magnetic resonance imaging (fMRI) studies proposed and described an indirect measure of entorhinal grid-cell activity, which is quantified as a hexadirectional modulation of fMRI activity as a function of the subject’s movement direction. However, it still remains unclear how the activity of a population of grid cells may exhibit hexadirectional modulation and thus provides the basis for the hexadirectional modulation of entorhinal cortex activity measured with fMRI. Here, we thus performed numerical simulations and analytical calculations to better understand how the aggregated activity of many grid cells may be hexadirectionally modulated. Our simulations implemented three different hypotheses proposing that the hexadirectional modulation occurs because grid cells show head-direction tuning aligned with the grid axes; are subjected to repetition suppression; or exhibit a bias towards a particular grid phase offset. Our simulations suggest that hexadirectional modulation is best explained by the conjunctive grid by head-direction cell hypothesis, which can produce the strongest and most robust hexasymmetry. In contrast, our simulations including previously observed biological properties of grid cells do not provide clear support for the structure-function mapping hypothesis. Our observations on hexadirectional modulation generated by grid-cell adaptation effects and the available data on adaptation properties of grid cells are insufficient to substantiate or refute the repetition suppression hypothesis. Furthermore, we found that the magnitude of the hexadirectional modulation depends considerably on the subject’s navigation pattern. Our results thus indicate that future fMRI studies could be designed to test which of the three hypotheses most likely accounts for the fMRI measure of grid cells. These findings also underline the importance of quantifying the biological properties of single grid cells in humans to further elucidate how hexadirectional modulations of fMRI activity may emerge.
Signal detectability and boldness are not the same: the function of defensive colouration in nudibranchs is distance-dependent
Authors: van den Berg Cedric P. , Endler John A. , Cheney Karen L.
Published: December 2022

Aposematic signals advertise underlying defences in many species. They should be detectable (highly contrasting against the background) and bold (high internal pattern contrast) to enhance predator recognition, learning and memorisation. However, the signalling function of aposematic colour patterns may be distance-dependent: signals may be undetectable from a distance to reduce costs of increased attacks from naïve predators but bold when viewed up close. To test this hypothesis, we quantified the chromatic and achromatic detectability and boldness of colour patterns in 13 nudibranch species that varied in the strength of their chemical defences, in terms of unpalatability and toxicity, using Quantitative Colour Pattern Analysis (QCPA) and data on the visual perception of a triggerfish (Rhinecanthus aculeatus). When viewed from larger distances, there were no differences in detectability and boldness between well-defended and undefended species. However, when viewed at close distances, well-defended species were more detectable and bolder than undefended species. The detectability of defended species decreased more significantly with increased viewing distances compared to boldness but remained relatively consistent over viewing distances for undefended species. We provide evidence for distance-dependent signalling in aposematic nudibranchs and highlight the importance of distinguishing between signal detectability and boldness in studies of aposematism.
Acidovorax temperanspolarizes T17 cells and skews neutrophil maturation to promote lung adenocarcinoma development
Authors: Stone Joshua K. , von Muhlinen Natalia , Zhang Chenran , Robles Ana I. , Vega-Valle Eleazar , Miyanaga Akihiko , Matsumoto Masaru , Greathouse K. Leigh , Cooks Tomer , Trinchieri Giorgio , Harris Curtis C.
Published: December 2022

Dysbiosis, or changes within the microbiome, is a common feature of solid tumors, however whether this dysbiosis directly contributes to tumor development is largely unknown. We previously characterized the lung cancer microbiome and identifiedAcidovorax temperansas enriched in tumors. In this study, we instilledA. temperansin an animal model driven by mutantKrasandTp53alleles. This revealedA. temperansaccelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed toA. temperansdisplayed a mature, pro-tumorigenic genotype with increased cytokine signaling, with a global shift away from IL-1β signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+T cells which polarized to an IL-17A+phenotype detectable in CD4+and γδ populations. T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate dysbiosis promotes tumor growth by modulating inflammation.
The trembling hand unraveled: motor and valuation elements in the neural sources of choice inconsistency
Authors: Kurtz-David Vered , Madar Asaf , Hakim Adam , Palmon Noa , Levy Dino J
Published: December 2022

Extensive evidence shows that humans are inconsistent with their choices. Yet, the neural mechanism underlying this type of choices remains unknown. Here, we aim to show that inconsistent choice is tied to the valuation process, but can also arise from motor errors during task execution. We report the results from three behavioral and neuroimaging studies. Subjects completed a risky-choice task to test their inconsistency levels, followed by two novel tasks, explicitly designed to examine motor output. We recorded mouse trajectories during task execution and designed 34 features to analyze motor dynamics in an exploratory manner. We show that motor dynamics predict inconsistency levels, even when motor output was absent any valuation elements. In the neuroimaging study, we show that inconsistency is associated with value brain circuits, but at the same time, is also related to activity in motor circuits. These findings suggest that (at least) two neural sources of noise contribute to inconsistent choice behavior.
Structure adaptation in Omicron SARS-CoV-2/hACE2: Biophysical origins of evolutionary driving forces
Authors: Hsiao Ya-Wen , Taddese Tseden , Jiménez-Serratos Guadalupe , Bray David J. , Crain Jason
Published: December 2022

Since its emergence, the Covid19 pandemic has been sustained by a series of transmission waves initiated by new variants of the SARS-CoV-2 virus. Some of these arise with higher transmissivity and/or increased disease severity. Here we use molecular dynamics simulations to examine the modulation of the fundamental interactions between the receptor binding domain (RBD) of the spike glycoprotein and the host cell receptor (human angiotensin-converting enzyme 2: hACE2) arising from Omicron variant mutations (BA.1 and BA.2) relative to the original wild type strain. We find significant structural differences in the complexes which overall bring the spike protein and its receptor into closer proximity. These are consistent with and attributed to the higher positive charge on the RBD conferred by BA.1 and BA.2 mutations relative to the wild type. However, further differences between sub-variants BA.1 and BA.2 (which have equivalent RBD charges) are also evident: Mutations affect interdomain interactions between the up-chain and its clockwise neighbor chain, resulting in enhanced flexibility for BA.2. Consequently, additional close contacts arise in BA.2 which include binding to hACE2 by a second spike protein monomer, in addition to the up-chain - a motif not found in BA.1. Finally, the mechanism by which the glycans stabilize the up state of the Spike protein differs for the wild type and the Omicrons. We also found the glycan on N90 of hACE2 turns from inhibiting, to facilitating the binding to Omicron spike protein. These structural and electrostatic differences offer further insight into the mechanisms by which viral mutations modulate host cell binding and provide a biophysical basis for evolutionary driving forces.
Endodermal suberin deposition restricts potassium leakage from roots
Authors: Vestenaa Morten Winther , Husted Søren , Minutello Francesco , Persson Daniel Pergament
Published: December 2022

The endodermis is a checkpoint for ions and water escaping or entering the root. It has been hypothesized that suberin acts as a physical barrier preventing potassium (K) leakage from the stele during translocation, but attempts to support this idea has yielded contradictory results.

We developed a Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS) based element bioimaging method to study K leakage from roots with different suberin deposition, where we show that cesium (Cs) is an excellent tracer for K.

Element bioimaging of roots and total shoot concentrations from variousArabidopsis thalianamutants all showed a positive relationship between suberin deposition and K translocation efficiency. In addition, images from the fully suberized barley (Hordeum vulgare) seminal roots revealed a strongly reduced K leakage compared to less suberized root zones.

Nodal roots form a scattered deposition of suberin towards the phloem in the mature root zone. This incomplete suberin deposition also restrict K leakage efficiently.

Collectively, our findings provide experimental evidence that suberin act as a barrier for K leakage upon root-to-shoot translocation by restricting K movement over the endodermis from the stele to cortex.
Interaction of the mechanosensitive microswimmerParameciumwith obstacles
Authors: Escoubet Nicolas , Brette Romain , Pontani Lea-Laetitia , Prevost Alexis M.
Published: December 2022

In this work, we report investigations of the swimming behavior ofParamecium tetraurelia, a unicellular microorganism, in micro-engineered pools that are decorated with thousands of cylindrical pillars. Two types of contact interactions are measured, either passive scattering ofParameciumalong the obstacle or avoiding reactions, characterized by an initial backward swimming upon contact, followed by a reorientation before resuming forward motion. We find that avoiding reactions are only mechanically triggered about 10% of the time. In addition, we observe that only a third of all avoiding reactions triggered by contact are instantaneous while two thirds are delayed by about 150 ms. These measurements are consistent with a simple electrophysiological model of mechanotransduction composed of a strong transient current followed by a persistent one upon prolonged contact. This is in apparent contrast with previous electrophysiological measurements where immobilized cells were stimulated with thin probes, which showed instantaneous behavioral responses and no persistent current. Our findings highlight the importance of ecologically relevant approaches to unravel the motility of mechanosensitive microorganisms in complex environments.
Cost and benefits of being social: examining the influence of sociality on faecal parasites in free-ranging rhesus macaques
Authors: Pavez-Fox Melissa A. , Escabi-Ruiz Carla M. , Hart Jordan D. A. , Negron-Del Valle Josue E. , Phillips Daniel , Montague Michael J. , Platt Michael L. , Ruiz-Lambides Angelina , Martinez Melween I. ,   Cayo Biobank Research Unit, Higham James P. , Snyder-Mackler Noah , Brent Lauren J.N.
Published: December 2022

Parasites and infectious diseases constitute an important challenge to the health of group-living animals. Social contact and shared space can both increase disease transmission risk, while individual differences in social resources can help prevent infections. For example, high social status individuals and those with more or stronger social relationships may have better immunity and, thus, lower parasitic burden. To test for health trade-offs in the costs and benefits of sociality, we quantified how parasitic load varied with an individual’s social status, as well as with their weak and strong affiliative relationships in a free-ranging population of rhesus macaques (Macaca mulatta). Social resources may also protect against infection under environmentally challenging situations, such as natural disasters. We additionally examined the impact of a major hurricane on the sociality-parasite relationship in this system. We found that both weak and strong proximity partners, but not grooming partners, were associated with lower protozoa infection risk. Social status was not linked to infection risk, even after the hurricane. Overall, our study highlights the buffering against infection that affiliative partners may provide, suggesting individuals can compensate for the health costs of sociality by having partners who tolerate their presence.
Activity Map and Transition Pathways of G Protein Coupled Receptor Revealed by Machine Learning
Authors: Mollaei Parisa , Farimani Amir Barati
Published: December 2022

Approximately, one-third of all FDA-approved drugs target G protein-coupled receptors (GPCRs). However, more knowledge of protein structure-activity correlation is required to improve the efficacy of the drugs targeting GPCRs. In this study, we developed a machine learning (ML) model to predict activation state and activity level of the receptors with high prediction accuracy. Furthermore, we applied this model to thousands of molecular dynamics trajectories to correlate residue-level conformational changes of a GPCR to its activity level. Finally, the most probable transition pathway between activation states of a receptor can be identified by using the state-activity information. In addition, with this model, we can associate the contribution of each amino acid to the activation process. Using this method we will be able to design drugs that mainly target principal amino acids driving the transition between activation states of GPCRs. Our advanced method is generalizable to all GPCR classes and provides mechanistic insight into the activation mechanism in the receptors.
XAP5 CIRCADIAN TIMEKEEPERregulates RNA splicing and the circadian clock via genetically separable pathways
Authors: Zhang (张弘韬) Hongtao , Kumimoto Roderick W. , Anver Shajahan , Harmer Stacey L.
Published: December 2022

The circadian oscillator allows organisms to synchronize their cellular and physiological activities with diurnal environmental changes. In plants, the circadian clock is primarily composed of multiple transcriptional-translational feedback loops. Regulators of post-transcriptional events, such as pre-mRNA splicing factors, are also involved in controlling the pace of the clock. However, in most cases the underlying mechanisms remain unclear. We have previously identifiedXAP5 CIRCADIAN TIMEKEEPER(XCT) as anArabidopsis thalianacircadian clock regulator with uncharacterized molecular functions. Here, we report that XCT physically interacts with components of the spliceosome, including members of the Nineteen Complex (NTC). PacBio Iso-Seq data show thatxctmutants have transcriptome-wide pre-mRNA splicing defects, predominantly aberrant 3’ splice site selection. Expression of a genomic copy ofXCTfully rescues those splicing defects, demonstrating that functionalXCTis important for splicing. Dawn-expressed genes are significantly enriched among those aberrantly spliced inxctmutants, suggesting that the splicing activity ofXCTmay be circadian regulated. Furthermore, we show that loss of function mutations inPRP19AorPRP19B, two homologous core NTC components, suppress the short circadian period phenotype ofxct-2. However, we do not see rescue of the splicing defects of core clock genes inprp19 xctmutants. Therefore, our results suggest thatXCTmay regulate splicing and the clock function through genetically separable pathways.
Beat processing in newborn infants cannot be explained by statistical learning based on transition probabilities
Authors: P. Háden Gábor , Bouwer Fleur L. , Honing Henkjan , Winkler István
Published: December 2022

Newborn infants have been shown to extract temporal regularities from sound sequences, both in the form of learning regular sequential properties, and extracting periodicity in the input, commonly referred to as a beat. However, these two types of regularities are often indistinguishable in isochronous sequences, as both statistical learning and beat perception can be elicited by the regular alternation of accented and unaccented sounds. Here, we manipulated the isochrony of sound sequences in order to disentangle statistical learning from beat perception in sleeping newborn infants in an EEG experiment, as previously done in adults and macaque monkeys. We used a binary accented sequence that induces a beat when presented with isochronous timing, but not when presented with randomly jittered timing. We compared mismatch responses to infrequent deviants falling on either accented or unaccented (i.e., odd and even) positions. Results showed a clear difference between metrical positions in the isochronous sequence, but not in the equivalent jittered sequence. This suggests that beat processing is present in newborns. However, the current paradigm did not show effects of statistical learning, despite previous evidence for this ability in newborns. These results show that statistical learning does not explain beat processing in newborn infants.

Research highlights

Sleeping newborns process musical beat.

Transition probabilities are not enough to explain beat perception in newborn infants.

No evidence of statistical learning (based on transition probabilities) without isochronous stimulation in newborns.

Results converge with previous evidence on beat perception of newborn infants.
A Pilot Survey of Authors’ Experiences with Poor Peer Review Practices
Authors: McCloskey Kyle , Merz Jon F.
Published: December 2022

Objectives

To develop a typology of poor peer review practices (PPRP) and assess researchers’ experiences with PPRP.

Design

Exploratory analysis of cross-sectional internet-based survey.

Participants

We solicited 500 researchers funded by the NIH extramural grants in 2018 by direct email and 600 bioethicists on a bioethics discussion forum (mcw.bioethics). 112 respondents (~10%) completed the survey.

Primary and Secondary Outcomes Measures

The total number of reported PPRP and a five-point scale to assess participants’ views about the effect of PPRP on their ability to disseminate their research.

Results

The mean number of PPRP experienced per author was 12.5 of 28 (44.6%; range 0–27; 95% CI = 11.2–13.8), with fourteen PPRP experienced by 50% or more of the sample. The number of reported PPRP increased with age (P = 0.01) and total number of published peer-reviewed manuscripts (P = 0.02). Authors belonging to underrepresented groups reported more PPRP compared to represented groups (P = 0.05). Most authors viewed the peer review process favorably, with 67% (74/111) of authors responding “sometimes” or “often” to having received insightful peer reviews that improved the quality of their final papers. However, a total of 57% (63/111) of respondents admitted to previously abandoning a manuscript after receiving what they perceived to be unfair peer reviews.

Conclusions

This study introduces a practical list of PPRP and a framework for a typology of PPRP, which could serve as an educational tool for editors and reviewers and further our understanding of poor peer review practices. Future researchers will expand authors’ experiences with constructive or helpful peer review practices.

STRENGTHS AND LIMITATIONS OF THIS STUDY

The sample consisted primarily of experienced researchers from diverse fields, which aided in capturing a wide variety of poor peer review examples.

This survey included a core set of 28 poor peer review practices and allowed respondents to add other practices they had experienced, which helped to generate an extensive list of poor peer review practices.

The generalizability of the prevalence of poor review types and the degree of negative impact on authors should be interpreted with caution due to the low response rate and the potential for response bias.
A Transfer entropy-based methodology to analyze information flow under eyes-open and eyes-closed conditions with a clinical perspective
Authors: Restrepo Juan F. , Mateos Diego M. , Díaz López Juan M.
Published: December 2022

Studying brain dynamics under normal or pathological conditions has proven to be a challenging task, as there is no unified consensus on the best approach. In this article, we present a methodology based on Transfer Entropy to study the information flow between different brain hemispheres in healthy subjects during eyes-open (EO) and eyes-closed (EC) resting states. We used an experimental setup that mimics the technical conditions found in clinical settings and collected data sets from short records of 24 channels electroencephalogram (EEG) at a sampling rate of 65 Hz. Our methodology accounts for interhemispheric and intrahemispheric information flow analysis in both conditions and relies on 4 indexes calculated from the transfer entropy estimations between EEG channels. These indexes provide information on the number, strength, and directionality of active connections. Our results suggest an increase in information transfer in the EC condition for the alpha, beta1, and beta2 frequency bands, but no preferred direction of interhemispheric information movement under either condition. These results are consistent with previously reported studies conducted with denser EEG recordings sampled at a higher rate. In conclusion, our methodology shows a significant difference in the brain’s dynamics of information transfer between EO and EC resting states, which can also be applied to regular clinical sessions.
GβγActivatesPIP2 Hydrolysis by Recruiting and OrientingPLCβon the Membrane Surface
Authors: Falzone Maria E. , MacKinnon Roderick
Published: December 2022

PLCβscatalyze the hydrolysis ofPIP2 into IP3 and DAG.PIP2 regulates the activity of many membrane proteins, while IP3 and DAG lead to increased intracellular Ca2+levels and activate PKC, respectively.PLCβsare regulated by GPCRs through direct interaction withGαqandGβγ. This study addresses the mechanism by whichGβγactivatesPLCβ3. We show thatPLCβ3 functions as a slow Michaelis-Menten enzyme (kcat~2sec−1,KM~0.43mol%) on membrane surfaces. Its partition coefficient (Kx~2.9 * 104) is such that only a small quantity ofPLCβ3 exists in the membrane in the absence ofGβγ. WhenGβγis present, equilibrium binding (Keq~0.009mol%) increasesPLCβ3 in the membrane, increasingVmaxin proportion. Atomic structures on membrane vesicle surfaces show that twoGβγanchorPLCβ3 with its catalytic site oriented toward the membrane surface. This principle of activation explains rapid stimulated catalysis with low background catalysis.
Genomes of the extinct Bachman’s Warbler shows high divergence and no evidence of admixture with other extantVermivoraWarblers
Authors: Wood Andrew W. , Szpiech Zachary A. , Lovette Irby , Smith Brian Tilson , Toews David P. L.
Published: December 2022

Bachman’s Warbler (Vermivora bachmanii) – last sighted in 1988 – is one of the few North American passerines that have gone extinct. Given the extensive ongoing hybridization of its two extant congeners – the Blue-Winged Warbler (V. cyanoptera) and Golden-Winged Warbler (V. chrysoptera) – and shared patterns of plumage variation between Bachman’s Warbler and hybrids between those extant species, it has been suggested that Bachman’s Warbler might have also had a component of hybrid ancestry. Here, we use historic DNA (hDNA) and whole genome sequencing of Bachman’s Warblers collected at the turn of the 20thcentury to address this possibility. We combine these data with genomes of the two extantVermivoraspecies to examine patterns of population differentiation, inbreeding, and gene flow. In contrast to the admixture hypothesis, the genomic evidence is consistent withV. bachmaniibeing a highly divergent, reproductively isolated species, with no evidence of introgression. We show that bothV. bachmaniiandV. chrysopterahave elevated runs of homozygosity compared toV. cyanoptera, consistent with the effects of a small effective population size or population bottlenecks in the former two species. We also found—using population branch statistic estimates of all three species—previously undocumented evidence of lineage-specific evolution inV. chrysopteranear a novel pigmentation gene candidate for warblers,CORIN, which is a known modifier ofASIP, which is in turn involved in melanic throat and mask coloration in this family of birds. Together, these genomic results also highlight how natural history collections are such invaluable repositories of information about extant and extinct species.

Significance

Few common North American passerines have gone extinct. Bachman’s Warbler is, unfortunately, one that has—the last sighting was in 1988. Here we use whole genome historical DNA from museum specimens of Bachman’s warblers collected at the turn of the 20thcentury to learn about the evolution of this species and test whether there was evidence for hybridization and gene flow between it and two extant members of the same genus which, today, hybridize extensively. We find Bachman’s warbler was highly divergent with no evidence of gene flow. We also find evidence of elevated “runs of homozygosity” in both Bachman’s warbler and one of the two extantVermivoraspecies, suggesting the effects of a small population size or population bottlenecks.
Multiplex qPCR assays for detection of two imperiled anuran species,Anaxyrus californicusandSpea hammondii, from environmental DNA
Authors: Rodgers Torrey W. , Lovich Robert E. , Walton James A. , Prince Daniel J. , Gonzalez Bernardo R. , Shaffer H. Bradley , Mock Karen E.
Published: December 2022

We developed a species-specific, quantitative PCR assay multiplex for the detection of two threatened and endangered anuran species, arroyo toad (Anaxyrus californicus)and western spadefoot (Spea hammondii), from environmental DNA (eDNA). Both species have experienced range wide declines over the last century, mostly as a result of habitat loss. Given these declines and their cryptic life histories, improved tools for detecting and monitoring both species are needed. Species-specificity and sensitivity of assays were empirically tested in the lab, and the multiplexed assays were validated with field-collected eDNA samples. Both assays were species-specific, sensitive, and effectively detected the target species from streams, rivers and ponds, although detection was imperfect. These assays provide an efficient and economical tool that will aid in the detection, monitoring, management, and conservation of these at-risk species.
Simulation-guided sloppy DNA probe design for mismatch tolerant hybridization
Authors: Bugga Pallavi , Asthana Vishwaratn , Drezek Rebekah
Published: December 2022

The ability to both sensitively and specifically assess the sequence composition of a nucleic acid strand is an ever-growing field. Designing a detection scheme that can perform this function when the sequence of the target being detected deviates significantly from the canonical sequence however is difficult in part because probe/primer design is based on established Watson-Crick base-pairing rules. We present here a robust and tunable toehold-based exchange probe that can detect a sequence with a variable number of SNPs of unknown identity by inserting a series of controlled, sequential mismatches into the protector seal of the toehold probe, in an effort to make the protector seal “sloppy”. We show that the mismatch tolerant system follows predicted behavior closely even with targets containing up to four mismatches and thermodynamically deviating from the canonical sequence by up to 15 kcal/mole. The system also performs faithfully regardless of the global mismatch position on either the protector seal or target. Lastly, we demonstrate the generalizability of the approach by testing the increasingly sloppy protectors on HIV clinical samples and show that the system is capable of resolving multiple, iteratively mutated sequences derived from numerous HIV sub-populations with remarkable precision.
Spatially distinct phytohormone responses of individualArabidopsis thalianaroot cells to infection and colonization byFusarium oxysporum
Authors: Calabria Jacob , Wang Liu , Rast-Somssich Madlen I. , Chen Hsiang-Wen , Watt Michelle , Persson Staffan , Idnurm Alexander , Somssich Marc
Published: December 2022

Jasmonic acid (JA), ethylene (ET) and salicylic acid (SA) are the three major phytohormones coordinating a plant’s defense response to pathogenic attack. While JA and ET are assumed to primarily control the defense against necrotrophic pathogens, SA-induced defense responses target mainly biotrophic microbes, and can include drastic measures such as programmed cell death as part of the plant’s hypersensitive response (HR).Fusarium oxysporumis a hemibiotrophic fungal pathogen of several plant species, including many important food crops, and the model plant speciesArabidopsis thaliana. Colonization of the plant’s root vascular tissue by the fungus eventually results in wilting and plant death. A general role for JA, ET and SA in combating infection and colonization of the plant byF. oxysporumhas been demonstrated, but their distinct roles and modes of action have so far not been described. Here, using high resolution microscopy with fluorescent marker lines ofA. thalianaroots infected withF. oxysporumwe show that SA acts spatially separate from JA, in a distinct set of root cells immediately neighboring the fungal colonization site. There, SA induces HR to stop the spread of colonization. JA acts in a different, but also clearly defined set of cells, slightly removed from the colonization site, where it initiates a defense response to actively resist the invader. ET is activated in a stretch of cells that covers both, the cells with activated SA and JA signaling, and may be involved in creating these two distinct zones. These results show how the three phytohormones act together, but spatially and functionally separate from each other, to fight this hemibiotrophic pathogen. Such a high-resolution analysis to resolve the plant’s immune response to pathogenic infection on an individual cell level and in intact tissue has so far been lacking.

Graphical Abstract

Colonization of theA.thalianaroot tip byF.oxysporumstrainFo5176 leads to immediate cell death of the colonized and surrounding tissue.

As the colonization front progresses through the vasculature, the cell death front moves along with it through not only the vasculature, but also the surrounding tissues.

WRKY70 positively regulates salicylic acid (SA) biosynthesis in cells immediately adjacent to the colonized tissue, inducing a hypersensitive response (HR), thereby killing off the cells deemed lost to the intruder, establishing the cell death front.

Slightly further removed from the HR zone, WRKY11 induces jasmonate (JA) biosynthesis in cells of the vasculature to launch a defense response aimed at actively repelling the fungus.
Newly repopulated spinal cord microglia exhibit a unique transcriptome and correlate with pain resolution
Authors: Donovan Lauren J. , Bridges Caldwell M. , Nippert Amy R. , Wang Meng , Wu Shaogen , Forman Thomas E. , Haight Elena S. , Huck Nolan A. , Bond Sabrina F. , Jordan Claire E. , Gardner Aysha S. , Nair Ramesh V. , Tawfik Vivianne L.
Published: December 2022

Microglia contribute to the initiation of pain, however, a translationally viable approach addressing how or when to modulate these cells remains elusive. We used a targeted, inducible, genetic microglial depletion strategy at both acute and acute-to-chronic transition phases in the clinically-relevant tibial fracture/casting pain model to determine the contribution of microglia to the initiation and maintenance of pain. We observed complete resolution of pain after transient microglial depletion at the acute-to-chronic phase, which coincided with the timeframe of full repopulation of microglia. These repopulated microglia were morphologically distinct from control microglia, signifying they may exhibit a unique transcriptome. RNA sequencing of repopulated spinal cord microglia identified genes of interest using weighted gene co-expression network analysis (WGCNA). We intersected these genes with a newly-generated single nuclei microglial dataset from human spinal cord dorsal horn and identified human-relevant genes that may ultimately promote pain resolution after injury. This work presents a novel approach to gene discovery in pain and provides comprehensive datasets for the development of future microglial-targeted therapeutics.
Clinically defined mutations inMEN1alter its tumor-suppressive function through increased menin turnover
Authors: Duan Suzann , Sheriff Sulaiman , Elvis-Offiah Uloma B. , Sawyer Travis W. , Sundaresan Sinju , Cierpicki Tomasz , Grembecka Jolanta , Merchant Juanita L.
Published: December 2022

Loss of the tumor suppressor protein menin is a critical event underlying the formation of neuroendocrine tumors (NETs) in hormone-expressing tissues including gastrinomas. While aberrant expression of menin impairs its tumor suppression, few studies explore the structure– function relationship of clinical Multiple Endocrine Neoplasia, type 1 (MEN1) mutations in the absence of a complete loss of heterozygosity at both loci. Here, we determined whether clinicalMEN1mutations render nuclear menin unstable and lead to its functional inactivation. We studied the structural and functional implications of three clinicalMEN1mutations (R516fs, E235K, and A541T) recently identified in a cohort of ten patients with GEP-NETs. We evaluated the subcellular localization and half-lives of these mutated menin variants inMen1-null mouse embryo fibroblast cells and in hormone-expressing human gastric adenocarcinoma and murine enteroendocrine tumor cell lines. Loss of menin function was assessed by cell proliferation and gastrin gene expression assays. Lastly, we evaluated the effect of the small molecule compound MI-503 on stabilizing nuclear menin expression and functionin vitroand in a previously reported mouse model of gastric NET development. Both the R516fs and E235K variants exhibited severe defects in total and subcellular expression of menin, and this was consistent with reduced half-lives of these mutants. Mutated menin variants exhibited loss of function in suppressing tumor cell proliferation and gastrin expression. Treatment with MI-503 rescued nuclear menin expression and attenuated hypergastrinemia and gastric hyperplasia in NET-bearing mice.

Implication

Clinically defined germline and somaticMEN1mutations confer pathogenicity by destabilizing nuclear menin expression.
motifNet: A Neural Network Approach for Learning Functional Sequence Patterns in mRNA
Authors: Deng Kaifeng , Li Zhengchang , Wei Wenqing , Liu Yang
Published: December 2022

We present a new approach for predicting functional sequence patterns in mRNA, known as motifs. These motifs play an important role in understanding the mechanisms of the cell life cycle in clinical research and drug discovery. However, many existing neural network models for mRNA event prediction only take the sequence as input, and do not consider the positional information of the sequence. In contrast, motifNet is a lightweight neural network that uses both the sequence and its positional information as input. This allows for the implicit neural representation of the various motif interaction patterns in human mRNA sequences. The model can then be used to interactively generate motif patterns and the positional effect score in mRNA activities. Additionally, motifNet can identify violations of motif patterns in real human mRNA variants that are associated with disease-related cell dysfunction.