bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating methods for measuring background connectivity in slow event-related functional MRI designs
Authors: Frank Lea E. , Zeithamova Dagmar
Published: December 2022

Resting-state functional MRI (fMRI) is widely used for measuring functional interactions between brain regions, significantly contributing to our understanding of large-scale brain networks and brain-behavior relationships. Furthermore, idiosyncratic patterns of resting-state connections can be leveraged to identify individuals and predict individual differences in clinical symptoms, cognitive abilities, and other individual factors. Idiosyncratic connectivity patters are thought to persist across task states, suggesting task-based fMRI can be similarly leveraged for individual differences analyses. Here, we tested the degree to which functional interactions occurring in the background of a task during slow event-related fMRI parallel or differ from those captured during resting-state fMRI. We compared two approaches for removing task- evoked activity from task-based fMRI: (1) applying a low-pass filter to remove task- related frequencies in the signal, or (2) extracting residuals from a general linear model (GLM) that accounts for task-evoked responses. We found that the organization of large-scale cortical networks and individual’s idiosyncratic connectivity patterns are preserved during task-based fMRI. In contrast, individual differences in connection strength can vary more substantially between rest and task. Compared to low-pass filtering, background connectivity obtained from GLM residuals produced idiosyncratic connectivity patterns and individual differences in connection strength that more resembled rest. However, all background connectivity measures were highly similar when derived from the low-pass filtered signal or GLM residuals, indicating that both methods are suitable for measuring background connectivity. Together, our results highlight new avenues for the analysis of task-based fMRI datasets and the utility of each background connectivity method.
COMPARATIVE RADIOPATHOLOGY OF MALE REPRODUCTIVE ORGANS IN SPRAGUE DAWLEY RATS ADMINISTERED WITHCurcuma longaANDOcimum sanctumAGAINST ACUTE GAMMA IRRADIATION
Authors: Thapru Meikunu , Nair Anirudh A , Hoque Rakibul , Namasudra Mousumi , De Arun Kumar , Pradhan Saktipada , Hansda Rabindra Nath , Mukhopadhayay S. K. , Mondal Samiran
Published: December 2022

Objective

The study was designed to evaluate the deleterious e□ects of acute lethal gamma irradiation on male reproductive organs of Sprague Dawley rats and the radioprotective potential byCurcuma longaandOcimum sanctumin experimental set up.

Methods

25 Male Spraque Dawley rats were taken and randomized into 5 groups (T1, T2, T3, T4, T5). Each group containing 5 animals. The groups were named as Group T1 (Negative Control), Group T2 (irradiation positive control), Group T3 (irradiation andCurcuma longa), Group T4 (irradiation andOcimum sanctum), Group T5 (irradiation,Curcuma longaandOcimum sanctum). The rats in groups T1 and T2 were given a daily dosage of normal saline for 14 days. Group T3 and T4 rats received aqueous extracts ofCurcuma longa(40 mg/kg) andOcimum sanctum(40 mg/kg), respectively, whereas group T5 rats received a combination of aqueous extracts ofCurcuma longa(40 mg/kg) andOcimum sanctum(40 mg/kg) for 14 days. prior to gamma irradiation. Animals of group T2, T3, T4, T5 were irradiated with 10 Gy of γ – radiation on 15th day.

Results

Exposure of animals to 10 Gy gamma radiation resulted in significant decrease in body weight and testicular weight. Histopathological observations revealed testicular degenerative changes in the seminiferous tubules with primary spermatocytes being most affected and epididymis showed decreased spermatids density with cell debris in the lumen. Pretreatment withCurcuma longaat 40mg/kg for 14 days alleviated the radiation induced pathological changes in testis and epididymis.Curcuma longademonstrated much better protective effect in combination withOcimum sanctumin alleviating the radio pathological changes showing the possibility of synergistic effect. However, administration ofOcimum sanctumalone at 40mg/kg for 14 days did not reveal any significant radioprotective property after histomorphological evaluation.

Conclusion

Gamma irradiation of 10 Gy induces severe radio pathological damage to organs of male reproductive system of Spraque Dawley rats. Pre-treatment withCurcuma longaprior to radiotherapy may be effective in preventing radiation-induced damage in the male reproductive organs. Better radioprotection can be achieved with the combination ofCurcuma longaandOcimum sanctumthan using alone.
Regression convolutional neural network models implicate peripheral immune regulatory variants in the predisposition to Alzheimer’s disease
Authors: Ramamurthy Easwaran , Agarwal Snigdha , Toong Noelle , Kaplow Irene M. , Phan BaDoi , Pfenning Andreas R.
Published: December 2022

Alzheimer’s disease (AD) involves aggregation of amyloid β and tau, neuron loss, cognitive decline, and neuroinflammatory responses. Both resident microglia and peripheral immune cells have been associated with the immune component of AD. However, the relative contribution of resident and peripheral immune cell types to AD predisposition has not been thoroughly explored due to their similarity in gene expression and function. To study the effects of AD associated variants oncis-regulatory elements, we train convolutional neural network (CNN) regression models that link genome sequence to cell type-specific levels of open chromatin, a proxy for regulatory element activity. We then usein silicomutagenesis of regulatory sequences to predict the relative impact of candidate variants across these cell types. We develop and apply criteria for evaluating our models and refine our models using massively parallel reporter assay (MPRA) data. Our models identify many AD-associated variants with a greater predicted impact in peripheral cells relative to microglia or neurons but few with greater predicted impact in microglia and neurons. Our results suggest that peripheral immune cells themselves may mediate a component of AD predisposition and support their use as models to study the effects of AD associated variants. We make our library of CNN models and predictions available as a resource for the community to study immune and neurological disorders.
Optical-quality assessment of a miniaturized intraocular telescope
Authors: Nepita Irene , Raimondi Raffaele , Piazza Simonluca , Diaspro Alberto , Vidal-Aroca Faustino , Surdo Salvatore , Romano Mario R.
Published: December 2022

Purpose

Evaluating the optical transmission and geometrical aberrations of an intraocular device, namely, the Small-Incision New Generation Implantable Miniature Telescope (SING IMT™, Samsara Vision), designed to correct age-related macular degeneration.

Methods

Optical transmission in the spectral range 350-750 nm of the implantable optics was recorded with a fiber-optic spectrometer. Geometrical aberrations were studied by measuring the wavefront of a laser beam after passing through the implantable optics and performing an expansion of the measured wavefront into a Zernike polynomial basis. The study was conducted underin-vitroexperimental conditions. A second monofocal intraocular lens (SY60WF, Alcon) was tested and used as reference for assessing the optical quality of the SING IMT™ device.

Results

Spectroscopy measurements revealed that the SING IMT™ and monofocal IOL element feature UV-rejection and blue-rejection capabilities, respectively. Wavefront concavity indicated that the SING IMT™ behaves as a diverging lens with a focal length of approximately -100 mm; Zernike analysis showed that SING IMT™ has negligible coma, trefoil, astigmatism, and spherical aberrations of any order and along any direction.

Conclusions

The SING IMT™ exhibited even optical transmission in the whole visible spectrum and curvature capable of magnifying the retinal images without introducing geometrical aberrations, which proves the feasibility of this device as high-quality optical element for imaging. The rigidity of the compound lens of the SING IMT™ prevents mechanically-induced distortions, an issue encountered with polymeric lenses.

Translational Relevance

Spectrometry andin vitrowavefront analysis provide evidence supporting the new generation miniaturized telescopic intraocular lens as a favorable option to intraocular implant in age-related macular degeneration.
Plant architecture is correlated with variation in cannabinoid concentration and biomass production inCannabis sativa
Authors: Stack George M. , Carlson Craig H. , Toth Jacob A. , Philippe Glenn , Crawford Jamie L. , Hansen Julie L. , Viands Donald R. , Rose Jocelyn K. C. , Smart Lawrence B.
Published: December 2022

Cannabis sativais cultivated for multiple uses including the production of cannabinoids. In developing improved production systems for high-cannabinoid cultivars, scientists and cultivators must consider the optimization of complex and interacting sets of morphological, phenological, and biochemical traits, which have historically been shaped by natural and anthropogenic selection. Determining factors that modulate cannabinoid variation within and among genotypes is fundamental to developing efficient production systems and understanding the ecological significance of cannabinoids. Thirty-two high-cannabinoid hemp cultivars were characterized for traits including flowering date and shoot-tip cannabinoid concentration.

Additionally, a set of plant architecture traits, as well as wet, dry, and stripped inflorescence biomass were measured at harvest. One plant per plot was partitioned post-harvest to quantify intra-plant variation in inflorescence biomass production and cannabinoid concentration. Some cultivars showed intra-plant variation in cannabinoid concentration, while many had a consistent concentration regardless of canopy position. There was both intra- and inter-cultivar variation in architecture that correlated with intra-plant distribution of inflorescence biomass, and concentration of cannabinoids sampled from various positions within a plant. These relationships among morphological and biochemical traits will inform future decisions by cultivators, regulators, and plant breeders as well as our broader understanding of intra-plant variation of specialized biochemicals.

Highlight

In-season hemp plant architecture measurements can predict post-harvest traits related to the distribution of biomass and concentration of cannabinoids.
Single-Cell Transcriptional and Epigenetic Profiles of Male Breast Cancer Nominate Salient Cancer-Specific Enhancers
Authors: Kim Hyunsoo , Wisniewska Kamila , Regner Matthew J. , Spanheimer Philip M. , Franco Hector L.
Published: December 2022

Male breast cancer represents about 1% of all breast cancer diagnoses and, although there are some similarities between male and female breast cancer, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies. To date, most male breast cancers (MBC) are treated according to protocols established for female breast cancer (FBC). Thus, defining the transcriptional and epigenetic landscape of MBC with improved resolution is critical for developing better avenues for therapeutic intervention. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles at single-cell resolution of two treatment naïve MBC tumors processed immediately after surgical resection. These data enable the detection of differentially expressed genes between male and female breast tumors across immune, stromal, and malignant cell types, to highlight several genes that may have therapeutic implications. Notably,MYCtarget genes andmTORC1signaling genes were significantly upregulated in the malignant cells of MBC compared to the female counterparts. To understand how the regulatory landscape of MBC give rise to these male-specific gene expression patterns, we leveraged the scATAC-seq data to systematically link changes in chromatin accessibility to changes in gene expression within each cell type. We observed cancer-specific rewiring of several salient enhancers and posit that these enhancers have a higher regulatory load than lineage specific enhancers. We highlight two examples of previously unannotated cancer-cell specific enhancers ofANXA2andPRDX4gene expression and show evidence for super-enhancer regulation ofLAMB3andCD47in male breast cancer cells. Overall, this dataset annotates clinically relevant regulatory networks in male breast tumors, providing a useful resource that expands our current understanding of the gene expression programs that underlie the biology of MBC.
Mathematical modeling of mechanosensing and contact-dependent motility coordination inMyxococcus xanthus
Authors: Chen Yirui , Chen Jing
Published: December 2022

Sensing and responding to mechanical cues in the environment are important for the survival and propagation of bacteria. A ‘social’ bacterium,Myxococcus xanthus, which exhibits periodic cell reversals, modulates its reversal frequency in response to environmental mechanical cues, such as substrate stiffness and cell-cell contact. InM. xanthuspopulations, the cell-cell contact-dependent reversal control is particularly important for formation of complex multicellular patterns and structures during the cooperative ‘social’ behaviors. Here we hypothesize that the gliding motility machinery ofM. xanthuscan sense the environmental mechanical cues during force generation and modulate the timing and frequency of cell reversal through signaling the cell’s reversal control pathway. To examine our hypothesis, we extend an existing mathematical model for periodic polarity switching (which mediates periodic cell reversal) inM. xanthus, and incorporate the experimentally suggested (i) intracellular dynamics of the gliding motors and (ii) interactions between the gliding motors and reversal regulators. The model results suggest the proper mode of interaction between the gliding motors and reversal regulators that can generate the observed increase of cell reversal frequency on stiffer substrates. Furthermore, the selected model predicts a cell reversal response to cell-cell contact, which is sufficient for generating the rippling wave, an important multicellular pattern inM. xanthuspopulations. Our model highlights a potential role of the gliding machinery ofM. xanthusas a ‘mechanosensor’ that transduces mechanical cues into a reversal control signal.
Alpha suppression during prehension indicates neural motor drive inhibition
Authors: Ortiz Oscar , Kuruganti Usha , Chester Victoria , Wilson Adam , Blustein Daniel
Published: December 2022

Changes in alpha band activity (8-12 Hz) have been shown to indicate the inhibition of engagement of brain regions during cognitive tasks, reflecting real-time cognitive load. Despite this, its feasibility to be used in a more dynamic environment with ongoing motor corrections has not been studied. This research used electroencephalography (EEG) to explore how different brain regions are engaged during a simple grasp and lift task where unexpected changes to the object’s properties are introduced. To our knowledge, this is the first study to show alpha activity changes related to motor error correction occur only in motor-related areas (i.e. central areas), but not in error processing areas (ie. fronto-parietal network). This suggests that oscillations over motor areas could reflect inhibition of motor drive related to motor error correction, thus being a potential cortical electrophysiological biomarker for the process, and not solely as a proxy for cognitive demands. This observation is particularly relevant in scenarios where these signals are used to evaluate high cognitive demands co-occurring with high levels of motor errors and corrections, such as prosthesis use. The establishment of electrophysiological biomarkers of mental resource allocation during movement and cognition can help identify indicators of mental workload and motor drive, which may be useful for improving brain-machine interfaces.

New and Noteworthy

This research expands on previous fMRI literature by demonstrating that alpha band suppression, an EEG metric with high temporal resolution, occurs over the primary sensorimotor area during error correction of hand movements. This furthers our understanding of alpha suppression beyond processes related to cognitive demands by highlighting how motor control also influences this frequency band. Recognizing that alpha band activity is modulated by both motor and cognitive processes is important in situations where high cognitive demands can lead to a high level of movement errors. Interpretations of such modulation are often attributed only to cognitive demands, whereas a motor process may also play a factor. Furthermore, alpha suppression could be used as a biomarker for error correction with applications in human machine interfaces, such as neuroprostheses.
Transcriptomic and DNA methylation modifications during fruit ripening and in response to ABA treatment in sweet cherry
Authors: Kuhn Nathalie , Arellano Macarena , Ponce Claudio , Hodar Christian , Correa Francisco , Multari Salvatore , Martens Stefan , Carrera Esther , Donoso José Manuel , Meisel Lee A.
Published: December 2022

Abscisic acid (ABA) plays a key role in the ripening process of non-climacteric fruits, triggering pigment production, fruit softening, and sugar accumulation. Transcriptomic studies show that ABA modifies the expression of several ripening-related genes, but to date, the epigenetic approach has not been utilized to characterize the role of ABA during this process. Therefore, this work aimed to perform transcriptomic and DNA methylation analyses of fruit samples treated with ABA during the fruit ripening process in the non-climacteric sweet cherry model. RNA-seq analyses revealed an overrepresentation of transcripts annotated in functional categories related to ABA response, secondary metabolism, and sugar synthesis. In contrast, Whole Genome Bisulfite Sequencing (WGBS) revealed DNA hypomethylation in the 5’UTR region of genes related to carotene catabolism. Genes encoding xyloglucan enzymes were regulated transcriptionally and epigenetically during ripening. ABA treatment enhanced color development and ripening. GO analysis of DEGs in the RNA-seq of the ABA treatment revealed expression variations in genes encoding members of the Aux/IAA and ARF families. In the WGBS, genes encoding enzymes of the cytokinin biosynthesis had differential DNA methylation after the ABA treatment. Our work shows the genetic factors modulated by ABA at the genetic and epigenetic levels during non-climacteric ripening.
Investigating the conformational landscape of AlphaFold2-predicted protein kinase structures
Authors: Al-Masri Carmen , Trozzi Francesco , Patek Marcel , Cichońska Anna , Ravikumar Balaguru , Rahman Rayees
Published: December 2022

Protein kinases are a family of signalling proteins, crucial for maintaining cellular homeostasis. When dysregulated, kinases drive the pathogenesis of several diseases, and are thus one of the largest target categories for drug discovery. Kinase activity is tightly controlled by switching through several active and inactive conformations in their catalytic domain. Kinase inhibitors have been designed to engage kinases in specific conformational states, where each conformation presents a unique physico-chemical environment for therapeutic intervention. Thus, modeling kinases across conformations can enable the design of novel and optimally selective kinase drugs. Due to the recent success of AlphaFold2 in accurately predicting the 3D structure of proteins based on sequence, we investigated the conformational landscape of protein kinases as modeled by AlphaFold2. We observed that AlphaFold2 is able to model several kinase conformations across the kinome, however, certain conformations are only observed in specific kinase families. Furthermore, we show that the per residue predicted local distance difference test can capture information describing conformational dynamics of kinases. Finally, we evaluated the docking performance of AlphaFold2 kinase structures for enriching known ligands. Taken together, we see an opportunity to leverage AlphaFold2 models for structure-based drug discovery against kinases across several pharmacologically relevant conformational states.
Realtime observation of ATP-driven single B12molecule translocation through BtuCD-F
Authors: Zhu Lingwei , Kim Jinrang , Leng Kun , Ramos John E. , Kinz-Thompson Colin D. , Karpowich Nathan K. , Gonzalez Ruben L. , Hunt John F.
Published: December 2022

ATP-BindingCassette (ABC) Transporters use ATP binding and hydrolysis to power transmembrane transport of chemically diverse substrates. Current knowledge of their mechanism comes primarily from static structures of stable intermediates along the transport cycle. Recently, single-molecule fluorescence resonance energy transfer (smFRET) measurements have generated insight into the functional dynamics of transmembrane transporters, but studies to date lack direct information on the physical movement of the transport substrate. Here, we report development of an smFRET system that exploits fluorescence quenching by vitamin B12to track its location in real time during ATP-driven transport by nanodisc-reconstitutedE. coliBtuCD-F, an extensively studied type II ABC importer. Our data demonstrate that transmembrane translocation of B12is driven by two sequential high-energy conformational changes that are inaccessible to standard structural methods because they are inherently transient. The first moves B12from the periplasm into the transmembrane domain of the transporter; notably, this reaction is driven by hydrolysis of a single ATP molecule, in contrast to the mechanism established for several other ABC Transporter families in which ATP-binding drives the mechanochemical power-stroke prior to hydrolysis. The second mediates B12release on the opposite side of the transporter, and it is driven by formation of a hyper-stable complex between BtuCD and BtuF. Hydrolysis of a second single ATP molecule is then required to dissociate BtuCD from the BtuF substrate-binding protein to enable it to bind B12and initiate another round of transport. Our experiments have visualized substrate translocation in real-time at a single-molecule level and provided unprecedented information on the mechanism and dynamics of a paradigmatic transmembrane transport process.
Cell-Sized Lipid Vesicles as Artificial Antigen-Presenting Cells for Antigen-Specific T Cell Activation
Authors: Chen Jui-Yi , Agrawal Sudhanshu , Yi Hsiu-Ping , Vallejo Derek , Agrawal Anshu , Lee Abraham
Published: December 2022

In this study, efficient T cell activation is demonstrated using cell-sized artificial antigen-presenting cells (aAPCs) with protein-conjugated bilayer lipid membranes that mimic biological cell membranes. The highly uniform aAPCs are generated by a facile method based on standard droplet microfluidic devices. These aAPCs are able to activate the T cells in peripheral blood mononuclear cells (PBMCs), showing a 28-fold increase in IFNγ secretion, a 233-fold increase in antigen-specific CD8 T cells expansion, and a 16-fold increase of CD4 T cell expansion. The aAPCs do not require repetitive boosting or additional stimulants and can function at a relatively low aAPC-to-T cell ratio (1-to-17). The research presents strong evidence that the surface fluidity and size of the aAPCs are critical to the effective formation of immune synapses essential for T cell activation. The findings demonstrate that the microfluidic-generated aAPCs can be instrumental in investigating the physiological conditions and mechanisms for T cell activation. Finally, this method demonstrates the feasibility of customizable aAPCs for a cost-effective off-the-shelf approach to immunotherapy.
Ovule cell wall composition is a maternal determinant of grain size in barley
Authors: Yang Xiujuan , Wilkinson Laura G. , Aubert Matthew K. , Houston Kelly , Shirley Neil J. , Tucker Matthew R.
Published: December 2022

In cereal species, seed and grain size is influenced by growth of the ovule integuments (seed coat), the spikelet hull (lemma and palea) and the filial endosperm. It has remained unclear whether a highly conserved ovule tissue, the nucellus, has any impact on grain size.

Immunolabelling revealed that the barley nucellus comprises two distinct cell types that differ in terms of cell wall homogalacturonan (HG) accumulation. Transcriptional profiling of the nucellus identified two pectin methylesterase genes,OVULE PECTIN MODIFIER 1(OPM1) andOPM2, which are expressed in the ovule but absent from the seed.

Ovules from anopm1 opm2mutant, and plants expressing an ovule-specific pectin methylesterase inhibitor (PMEI), exhibit reduced HG accumulation. This results in changes to ovule cell size and shape, and ovules that are longer than wild-type controls. At grain maturity, this is manifested as significantly longer grain.

These findings indicate that cell wall composition during ovule development acts to limit ovule and seed growth. The investigation of ovule PME and PMEI activity reveals an unexpected role of maternal tissues in controlling grain growth prior to fertilisation, one that has been lacking from models exploring improvements in grain size.
Type I Interferon Signaling on Antigen-Presenting Cells Blunts Cell-Mediated Immunity TowardListeria monocytogenes
Authors: Morrow Zachary T. , Sauer John-Demian
Published: December 2022

Listeria monocytogenesis a facultative intracellular pathogen that has been used for decades to understand mechanisms of bacterial pathogenesis and both innate and adaptive immunity.L. monocytogenesis a potent activator of CD8+T-cell mediated immunity. Yet how the innate immune response to infection modulates CD8+T-cell responses is incompletely understood. Here, we utilize an attenuatedL. monocytogenesvaccine platform to understand the impact of two innate immune pathways, type I interferon and inflammasomes, on CD8+T-cell responses using a combination of mutant mice and genetically engineeredL. monocytogenes. IFNAR−/−mice had the most robust T-cell response, while Caspase-1−/−mice were not different from WT. We uncover a role for inflammasomes in the absence of type I interferon as Caspase-1−/−/IFNAR−/−mice had fewer T-cells than IFNAR−/−. IFNAR−/−had more than twice as many memory precursors, promoting enhanced protection from rechallenge. Importantly, increased memory precursor T-cell abundance did not come at the expense of short-lived effectors. Vaccines genetically modified to induce lower type I interferon production yielded enhanced T-cell responses. Deficits from type I interferon signaling are dendritic cell-intrinsic, rather than acting on T-cells, as IFNAR−/−dendritic cells induced two-fold more T-cell proliferation than WT inex vivoT-cell proliferation assays. Thus, modulating type I IFN signaling during vaccination may lead to more potent T-cell-based vaccines. Importantly, this suggests innate immune signaling significantly impacts the CD8+T-cell response and suggests CD8+T-cell quantity and quality are important factors to consider during rational vaccine design.
Crystal structure and solution state of the C-terminal head region of the narmovirus receptor binding protein
Authors: Stelfox Alice J. , Oguntuyo Kasopefoluwa Y. , Rissanen Ilona , Harlos Karl , Rambo Robert , Lee Benhur , Bowden Thomas A.
Published: December 2022

Increased viral surveillance has led to the isolation and identification of numerous uncharacterized paramyxoviruses, rapidly expanding our understanding of paramyxoviral diversity beyond the bounds of known genera. Despite this diversity, a key feature that unites paramyxoviruses is the presence of a receptor-binding protein, RBP, which facilitates host-cell attachment and plays a fundamental role in determining host-range. Here, we study the RBP presented on the surface of rodent-borne paramyxoviruses Mossman and Nariva (MosV and NarV, respectively), viruses that constitute founding members of the recently definedNarmovirusgenus within theParamyxoviridaefamily. Crystallographic analysis of the C-terminal head region of the dimeric MosV and NarV RBPs demonstrates that while these glycoproteins retain the canonical six-bladed β-propeller fold found in other paramyxoviral RBPs, they lack the structural motifs associated with established paramyxovirus host-cell receptor entry pathways. Consistent with MosV-RBP and NarV-RBP undergoing a distinct entry pathway from other characterized paramyxoviruses, structure-based phylogenetic analysis demonstrates that these six-bladed β-propeller head domains form a singular structural class that is distinct from other paramyxoviral RBPs. Additionally, using an integrated crystallographic and small angle X-ray scattering analysis, we confirm that MosV-RBP and NarV-RBP form homodimeric arrangements that are distinct from those adopted by other paramyxovirus RBPs. Altogether, this investigation provides a molecular-level blueprint of the narmovirus RBP that broadens our understanding of the structural space and functional diversity available to paramyxovirus RBPs.

Importance

Genetically diverse paramyxoviruses are united in their presentation of a receptor-binding protein (RBP), which works in concert with the fusion protein to facilitate host-cell entry. The C-terminal head region of the paramyxoviral RBP, a primary determinant of host-cell tropism and inter-species transmission potential, forms structurally distinct classes dependent upon protein and glycan receptor specificity. Here, we reveal the architecture of the C-terminal head region of the RBPs from Nariva virus (NarV) and Mossman virus (MosV), two archetypal rodent-borne paramyxoviruses within the recently established genusNarmovirus, familyParamyxoviridae. Our analysis reveals that while narmoviruses retain the general architectural features associated with paramyxoviral RBPs, namely a six-bladed β-propeller fold, they lack the structural motifs associated with known receptor-mediated host-cell entry pathways. This investigation indicates that the RBPs of narmoviruses exhibit pathobiological features that are distinct from those of other paramyxoviruses.
Divisively normalized neuronal processing of uncertain visual feedback for visuomotor learning
Authors: Makino Yuto , Hayashi Takuji , Nozaki Daichi
Published: December 2022

When encountering a visual error during a reaching movement, the motor system improves the motor command for the subsequent trial. The degree of improvement is well-known to be degraded with visual error uncertainty, which is considered evidence that the motor system optimally estimates the error. However, it remains unclear how such statistical computation is accomplished. Here, we propose an alternative motor learning scheme implemented with a divisive normalization (DN) mechanism. This scheme assumes that when an uncertain visual error is provided by multiple cursors, the motor system processes the error conveyed by each cursor and integrates the information using DN. The DN scheme can reproduce the patterns of learning response when 1, 2, or 3 cursors are concurrently displayed and predict how the increase in the visual error uncertainty degrades the learning response. Our proposed scheme provides a novel view of how the motor learning system updates the motor command according to uncertain visual error information.
Time scales of human mpox transmission in the Netherlands
Authors: Miura Fuminari , Backer Jantien A. , van Rijckevorsel Gini , Bavalia Roisin , Raven Stijn , Petrignani Mariska , Ainslie Kylie E. C. , Wallinga Jacco ,   the Dutch Mpox Response Team
Published: December 2022

Mpox has spread rapidly to many countries in non-endemic regions. After reviewing detailed exposure histories of 109 pairs of mpox cases in the Netherlands, we identified 34 pairs where transmission was likely and the infectee reported a single potential infector with a mean serial interval of 10.1 days (95% CI: 6.6–14.7 days). Pre-symptomatic transmission may have occurred in five out of eighteen pairs. These findings emphasize that precaution remains key, regardless of the presence of recognizable symptoms of mpox.
Detection of Left Ventricular Systolic Dysfunction from Single-Lead Electrocardiography Adapted for Wearable Devices
Authors: Khunte Akshay , Sangha Veer , Oikonomou Evangelos K , Dhingra Lovedeep S , Aminorroaya Arya , Mortazavi Bobak J , Coppi Andreas , Krumholz Harlan M , Khera Rohan
Published: December 2022

Artificial intelligence (AI) can detect left ventricular systolic dysfunction (LVSD) from electrocardiograms (ECGs). Wearable devices could allow for broad AI-based screening but frequently obtain noisy ECGs. We report a novel strategy that automates the detection of hidden cardiovascular diseases, such as LVSD, adapted for noisy single-lead ECGs obtained on wearable and portable devices. Overall, 385,601 ECGs were used for development of a standard and noise-adapted model. For the noise-adapted model, ECGs were augmented during training with random gaussian noise within four distinct frequency ranges, each emulating real-world noise sources. Both models performed comparably on clean ECGs with an AUROC of 0.90. The noise-adapted model performed significantly better on the same test set augmented with four distinct real-world noise recordings at multiple signal-to-noise ratios (SNRs), including noise isolated from a portable device ECG. The standard and noise-adapted models had an AUROC of 0.72 and 0.87, respectively when evaluated on ECGs augmented with portable ECG device noise at an SNR of 0.5. This approach represents a novel strategy for the development of wearable adapted tools from clinical ECG repositories.
The kinematics of 3D arm movements in sub-acute stroke: impaired inter-joint coordination caused by both weakness and flexor synergy intrusion
Authors: Avni Inbar , Arac Ahmet , Binyamin-Netser Reut , Kramer Shilo , Krakauer John W. , Shmuelof Lior
Published: December 2022

It has long been of interest to characterize the components that generate the motor control abnormalities in the arm after stroke. One approach has been to decompose the hemiparesis phenotype into negative signs, such as weakness, and positive signs, such as intrusion of synergies. Here, we sought to identify the contributions of weakness and the flexor synergy to motor function and impairment, as defined by kinematic and clinical scales, respectively, in sub-acute stroke using two 3D arm tasks that differed in their requirement for elbow extension. Thirty-three sub-acute post-stroke participants and sixteen healthy controls performed a cup-to-mouth task, requiring shoulder and elbow flexion (within flexor synergy), and a reaching task, requiring shoulder flexion and elbow extension (out of flexor synergy). Using markerless 3D pose-estimation, we analyzed upper limb kinematics to assess overall task performance and intrusion of pathological synergies. Weakness was measured using a grip dynamometer. Performance in both tasks was impaired to a similar degree in the stroke participants compared to controls. Subsequent analysis of coordination patterns between the elbow and the shoulder joints revealed intrusion of synergies in the reaching task based on the time spent within a flexion-flexion pattern (flexor synergy proportion) and the correlation between shoulder and elbow angles when the shoulder was flexing (flexion synergy strength). Regression analysis indicated that the significant predictors of poor task performance were weakness and flexor synergy intrusion. Notably, the Fugl-Meyer Assessment was abnormal even when just weakness caused the impairment, which means that caution is required when using this scale to quantify synergies. We conclude that both weakness and synergy intrusion contribute to impaired coordination of the elbow and shoulder joints in the sub-acute post-stroke period. This study shows that careful kinematic analysis of naturalistic movements is required to better characterize the components of upper limb impairment after stroke.
The developmental basis for scaling of mammalian tooth size
Authors: Christensen Mona M. , Hallikas Outi , Roy Rishi Das , Väänänen Vilma , Stenberg Otto E. , Häkkinen Teemu J. , François Jean-Christophe , Asher Robert J. , Klein Ophir D. , Holzenberger Martin , Jernvall Jukka
Published: December 2022

When evolution leads to differences in body size, organs generally scale along. A well-known example of the tight relationship between organ and body size is the scaling of mammalian molar teeth. To investigate how teeth scale during development and evolution, we compared molar development in mouse and rat from initiation through final size. Whereas the linear dimensions of the rat first lower molar are twice that of the mouse molar, their shapes are largely the same. We found that scaling of the molars starts early, and that the rat molar is patterned equally as fast but in a larger size than the mouse molar. Using transcriptomics, we discovered that a known regulator of body size, insulin-like growth factor 1 (Igf1), is more highly expressed in the rat molars compared to the mouse molars.Ex vivoandin vivomouse models demonstrated that modulation of the IGF pathway reproduces several aspects of the observed scaling process. Furthermore, analysis of IGF1-treated mouse molars and computational modeling indicate that IGF signaling scales teeth by simultaneously enhancing growth and by inhibiting the cusp patterning program, thereby providing a relatively simple mechanism for scaling teeth during development and evolution. Finally, comparative data from shrews to elephants suggest that this scaling mechanism regulates the minimum tooth size possible, as well as the patterning potential of large teeth.
Investigating the genetic diversity of H5 avian influenza in the UK 2020-2022
Authors: Byrne Alexander MP , James Joe , Mollett Benjamin C , Meyer Stephanie M , Lewis Thomas , Czepiel Magdalena , Seekings Amanda H , Mahmood Sahar , Thomas Saumya S , Ross Craig S , Byrne Dominic JF , McMenamy Michael J , Bailie Valerie , Lemon Ken , Hansen Rowena DE , Falchieri Marco , Lewis Nicola S , Reid Scott M , Brown Ian H , Banyard Ashley C
Published: December 2022

Since 2020, the UK and Europe, have experienced annual epizootics of high pathogenicity avian influenza virus (HPAIV). The first during autumn/winter 2020/21 involved the detected with six H5Nx subtypes although H5N8 HPAIV dominated in the UK. Whilst genetic assessment of the H5N8 HPAIVs within the UK demonstrated relative homogeneity, there was a background of other genotypes circulating at a lower degree with different neuraminidase and internal genes. Following a small number of summer detections of H5N1 in wild birds over the summer of 2021, autumn/winter 2021/22 saw another European H5 HPAIV epizootic, that has dwarfed the prior epizootic. This second epizootic was dominated almost exclusively by H5N1 HPAIV, although six distinct genotypes were defined. We have used genetic analysis to evaluate the emergence of different genotypes and proposed reassortment events that have been observed. The existing data suggests that the H5N1 circulating in Europe during late 2020, continued to circulate in wild birds throughout 2021, with minimal adaptation, but has then gone on to reassort with AIVs in the wild bird population. We have undertaken an in-depth genetic assessment of H5 HPAIVs detected in the UK, over the last two winter seasons and demonstrate the utility of in-depth genetic analyses in defining the diversity of H5 HPAIVs circulating in avian species, the potential for zoonotic risk and whether incidents of lateral spread can be defined over independent incursion of infection from wild birds. Key supporting data for mitigation activities.

Importance

High pathogenicity avian influenza virus (HPAIV) outbreaks devastate avian species across all sectors having both economic and ecological impacts through mortalities in poultry and wild birds, respectively. These viruses can also represent a significant zoonotic risk. Since 2020, the UK has experienced two successive outbreaks of H5 HPAIV. Whilst H5N8 HPAIV was predominant during the 2020/21 outbreak, other H5 subtypes were also detected. The following year there was a shift in subtype dominance to H5N1 HPAIV, but multiple H5N1 genotypes were detected. Through thorough utilisation of whole-genome sequencing, it was possible to track and characterise the genetic evolution of these H5 HPAIVs in UK poultry and wild birds. This has enabled us to assess the risk posed by these viruses at the poultry:wild bird and the avian:human interface and to investigate potential lateral spread between infected premises, a key factor in understanding threat to the commercial sector.
Contextual and temporal regulation of fear memory consolidation in the basolateral amygdala complex
Authors: Leake Jessica , Cardona Luisa Saavedra , Westbrook R. Frederick , Holmes Nathan M.
Published: December 2022

It is widely accepted that fear memories are consolidated through protein synthesis-dependent changes in the basolateral amygdala complex (BLA). However, recent studies show that protein synthesis isnotrequired to consolidate the memory of a new dangerous experience when it is similar to a prior experience. Here, we examined whether the protein synthesis requirement for consolidation of the new experience varies with its spatial and temporal distance from the prior experience. In each experiment, rats were conditioned to fear a stimulus (S1, e.g., light) across its pairings with shock in stage 1; and a second stimulus (S2, e.g., tone) that preceded additional S1-shock pairings (S2-S1-shock) in stage 2. The latter stage was followed by a BLA infusion of a protein synthesis inhibitor, cycloheximide or vehicle. Finally, rats were tested for fear to S2. Critically, protein synthesis in the BLA wasnotrequired to consolidate fear to S2 when the two training stages occurred 48 hours apart and in the same context;wasrequired when the two training stages were separated by a 14-day delay or occurred in different contexts; but wasagain notrequired when rats were re-exposed to S1 or shock after the delay or in the different context. Thus, protein synthesis in the BLA is not always required to consolidate a new fear memory. Instead, this requirement is determined by the degree of similarity between present and past experiences, the time and place in which those experiences occur, as well as reminders of the past experience.

Significance Statement

Protein synthesis in the basolateral amygdala complex (BLA) isnotrequired to consolidate the memory of a new dangerous experience when it is similar to a prior experience. This study is significant in showing that: 1) when the new, similar experience occurs after a delay or in a different context, the protein synthesis requirement for its consolidation is reinstated; and 2) the effects of the delay and context shift are reversed by reminding animals of their prior experience. Thus, the neural mechanisms underlying memory consolidation are dynamically regulated by similarity/dissimilarity between present and past experiences, the time and place in which those experiences occur, as well as reminders of the past experience.
Cytokinin synthesis and export from symbiotic root nodules coordinates shoot growth with nitrogen fixation
Authors: Chen Yumeng , Liu Jie , Lin Jieshun , Roswanjaya Yuda Purwana , Nadzieja Marcin , Buron Flavien , Kohlen Wouter , Geisler Markus , Stougaard Jens , Reid Dugald
Published: December 2022

Development of symbiotic root nodules is a cytokinin-dependent process that is critical to nitrogen acquisition in legumes. The extent and manner in which root nodules contribute to whole-plant cytokinin and nitrogen supply signalling is unknown.

Using a combination of genetic, biochemical and physiological approaches, we characterised the role of cytokinin synthesis, export and perception in coordination of symbiotic nodule development and shoot growth in the legumeLotus japonicus.

LjPup1encodes a plasma membrane localised cytokinin exporter with isopentenyladenine (iP) andtrans-Zeatin (tZ) export capacity.LjPup1shows a distinct nodule-specific expression pattern with greatest transcript levels detected in mature nodules. Mutants accumulate more isopentenyladenine riboside (iPR) in nodule tissues and demonstrate hallmarks of reduced cytokinin signalling. Despite normal nodule numbers and function, shoot growth is markedly reduced inLjpup1mutants, as well as in mutants impaired in tZ biosynthesis.

We found symbiotic root nodules contribute to shoot growth via export of active cytokinins. A cytokinin exporter in the purine permease family thus contributes to long-distance cytokinin homeostasis regulating plant development.
Spatial single-cell mass spectrometry defines zonation of the hepatocyte proteome
Authors: Rosenberger Florian A. , Thielert Marvin , Strauss Maximilian T. , Ammar Constantin , Mädler Sophia C. , Schweizer Lisa , Metousis Andreas , Skowronek Patricia , Wahle Maria , Gote-Schniering Janine , Semenova Anna , Schiller Herbert B. , Rodriguez Edwin , Nordmann Thierry M. , Mund Andreas , Mann Matthias
Published: December 2022

Single-cell proteomics by mass spectrometry (MS) is emerging as a powerful and unbiased method for the characterization of biological heterogeneity. So far, it has been limited to cultured cells, whereas an expansion of the method to complex tissues would greatly enhance biological insights. Here we describe single-cell Deep Visual Proteomics (scDVP), a technology that integrates high-content imaging, laser microdissection and multiplexed MS. scDVP resolves the context-dependent, spatial proteome of murine hepatocytes at a current depth of 1,700 proteins from a slice of a cell. Half of the proteome was differentially regulated in a spatial manner, with protein levels changing dramatically in proximity to the central vein. We applied machine learning to proteome classes and images, which subsequently inferred the spatial proteome from imaging data alone. scDVP is applicable to healthy and diseased tissues and complements other spatial proteomics or spatial omics technologies.
Visual homogeneity computations in the brain enable solving property-based visual tasks
Authors: Jacob Georgin , Pramod R. T. , Arun S. P.
Published: December 2022

Most visual tasks involve looking for specific object features. But we also often perform property-based tasks where we look for specific property in an image, such as finding an odd item, deciding if two items are same, or if an object has symmetry. How do we solve such tasks? These tasks do not fit into standard models of decision making because their underlying feature space and decision process is unclear. Using well-known principles governing multiple object representations, we show that displays with repeating elements can be distinguished from heterogeneous displays using a property we define as visual homogeneity. In behavior, visual homogeneity predicted response times on visual search, same-different and symmetry tasks. Brain imaging during visual search and symmetry tasks revealed that visual homogeneity was localized to a region in the object-selective cortex. Thus, property-based visual tasks are solved in a localized region in the brain by computing visual homogeneity.

SIGNIFICANCE STATEMENT

Most visual tasks involve looking for specific features, like finding a face in a crowd. But we also often look for a particular image property – such as finding an odd item, deciding if two items are same, or judging if an object is symmetric. How does our brain solve these disparate tasks? Here, we show that these tasks can all be solved using a simple computation over object representations in higher visual cortex, which we define as visual homogeneity.