bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal affectation in Huntington’s disease mouse models concurs with a local innate immune response
Authors: Arroba Ana I. , Gallardo-Orihuela Andrea , Cano-Cano Fátima , Martín-Loro Francisco , González-Montelongo María del Carmen , Hervás-Corpión Irati , de la Villa Pedro , Ramón-Marco Lucía , Gómez-Jaramillo Laura , Valor Luis M.
Published: January 2023

Huntington’s disease (HD) is a devastating disorder caused by aberrant expansion of CAG repeats in theHTTgene. Striatal dysfunction has been widely studied in HD mouse models. However, cumulative evidence indicates that the retina can also be functionally altered with consequences for visual function and circadian rhythms. The retina is the most exposed part of the central nervous system that can be used for monitoring the health status of patients using noninvasive techniques. To establish the retina as an appropriate tissue for HD studies, we linked the retinal alterations with those in the inner brain. We confirmed the malfunction of the R6/1 retinas, which underwent a rearrangement of their transcriptome as extensive as in the striatum, indicating a profound retinal affectation in HD. Tissue-enriched genes were downregulated in both areas, but a neuroinflammation signature was specifically induced in the R6/1 retina due to glial activation that was reminiscent of the situation in HD patient’s brains. These phenomena were confirmed in the zQ175 strain, and were accompanied by a differential impairment of the autophagy system between both tissues. Overall, these results demonstrated the suitability of the mouse retina as a research model for HD.
Vision-Based Collective Motion: A Locust-Inspired Reductionist Model
Authors: Krongauz David L. , Ayali Amir , Kaminka Gal A.
Published: January 2023

Naturally occurring collective motion is a fascinating phenomenon in which swarming individuals aggregate and coordinate their motion. Many theoretical models of swarming assume idealized, perfect perceptual capabilities, and ignore the underlying perception processes, particularly for agents relying on visual perception. Specifically, biological vision in many swarming animals, such as locusts, utilizes monocular non-stereoscopic vision, which prevents perfect acquisition of distances and velocities. Moreover, swarming peers can visually occlude each other, further introducing estimation errors. In this study, we explore necessary conditions for the emergence of ordered collective motion under restricted conditions, using non-stereoscopic, monocular vision. We present a model of vision-based of collective motion for locust-like agents: elongated shape, omni-directional visual sensor parallel to the horizontal plane, and lacking stereoscopic depth perception. The model addresses (i) the non-stereoscopic estimation of distance and velocity, (ii) the presence of occlusions in the visual field. We consider and compare three strategies that an agent may use to interpret partially-occluded visual information at the cost of the computational complexity required for the visual perception processes. Computer-simulated experiments conducted in various geometrical environments (toroidal, corridor, and ring-shaped arenas) demonstrate that the models can result in an ordered or near-ordered state. At the same time, they differ in the rate at which order is achieved. Moreover, the results are sensitive to the elongation of the agents. Experiments in geometrically constrained environments reveal differences between the models and elucidate possible tradeoffs in using them to control swarming agents. These suggest avenues for further study in biology and robotics.

Author summary

Swarm collective motion is a wide-ranging phenomenon in nature, with applications in multi-agent, multi-robot systems. In most natural swarming species, individuals rely on monocular, non-stereoscopic vision as the key sensory modality for their interactions. For example, the migratory locust (locusta migratoria) displays large swarms of individuals, moving in alignment and relying solely on non-stereoscopic visual perception. Inspired by these locust swarms, we have developed a monocular, non-stereoscopic vision-based model that achieves synchronized motion in a swarm of two-dimensional agents, even with inaccurate estimates of distances and velocities, particularly in the presence of occlusions. We explore three general strategies for handling occlusions, which differ in the requirements they place on the complexity of the visual perception process. We show that strategies may reach a highly ordered motion state but differ in their convergence rate.
Elevation of NAD+ by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery
Authors: Metcalfe Mariajose , David Brian T. , Langley Brett C. , Hill Caitlin E.
Published: January 2023

Spinal cord injury (SCI)-induced tissue damage spreads to neighboring spared cells in the hours, days and weeks following injury leading to exacerbation of tissue damage and functional deficits. Among the biochemical changes is the rapid reduction of cellular nicotinamide adenine dinucleotide (NAD+), an essential coenzyme for energy metabolism and an essential cofactor for non-redox NAD+-dependent enzymes with critical functions in sensing and repairing damaged tissue. NAD+depletion propagates tissue damage. Augmenting NAD+by exogenous application of NAD+, its synthesizing enzymes or its cellular precursors mitigates tissue damage. Among the NAD+precursors, nicotinamide riboside (NR) appears to be particularly well-suited for clinical translation. It safely and effectively augments cellular NAD+synthesis in a variety of species, including rats and humans, and in a variety of preclinical models, elicits tissue protection. Evidence of NR’s efficacy in the context of SCI repair, however, is currently lacking. These studies tested the hypothesis that administration of NR can effectively enhance NAD+in the injured spinal cord and that augmenting spinal cord NAD+protects spinal cord tissue from injury and leads to improvements in locomotor recovery. The results show that intraperitoneal administration of NR (500 mg/kg), administered four days prior to and two weeks following a mid-thoracic contusion-SCI injury, doubles spinal cord NAD+levels in Long-Evans rats. NR administration preserves spinal cord tissue after injury including neurons and axons, as determined by gray and white matter sparing, and enhances motor function, as assessed by the BBB subscore and missteps on the horizontal ladderwalk. Collectively, the findings demonstrate that administration of the NAD+precursor, NR, to elevate NAD+within the injured spinal cord mitigates the tissue damage and functional decline that occurs following SCI.

HIGHLIGHTS

Nicotinamide Riboside augments spinal cord nicotinamide adenine dinucleotide (NAD+).

Elevating NAD+protects spinal cord tissue from spinal cord injury (SCI).

Elevating NAD+enhances motor recovery following SCI.
Conserved cis-acting motifs and localization of transcripts and proteins ofMFT2in barley and rice
Authors: Utsugi Shigeko , Kawahigashi Hiroyuki , Tagiri Akemi , Kikuchi Rie , Mishina Kohei , Morishige Hiromi , Nakamura Shingo
Published: January 2023

MFTis an important regulator of seed dormancy in flowering plants. A natural mutation in the A-box motif in the promoter of wheat (Triticum aestivum) MFT2on chromosome 3A (TaMFT2-3A) has been used to prevent pre-harvest sprouting (PHS) in wheat cultivars in East Asia. Previous research usingin situhybridization showed thatTaMFT2-3Ais primarily expressed in the seed scutellum. In this study, we analyzed the localization of transcripts and encoded proteins for theTaMFT2homologs from barley (Hordeum vulgare) and rice (Oryza sativa), HvMFT2andOsMFT2, respectively. RNAin situhybridization showed that, like the wheat genes, the rice and barley homologs are primarily expressed in the scutellum, indicating that these threeMFT2genes have a common expression pattern during seed development. Analysis of thecis-acting regulatory elements of their promoter sequences showed that the threeMFT2promoters share eight seed-specificcis-acting RY motifs, which are binding sites for B3-domain transcription factors of the AFL-B3 and VIVIPAROUS1/ABI3-LIKE (VAL) families. In addition, we detected tandemly repeated and partially overlapping A-box motifs in the promoters ofHvMFT2, TaMFT2-3B, andTaMFT2-3D, possibly explaining why the natural allele ofTaMFT2-3Ahas been employed in breeding. We generated transgenic rice plants expressing nuclear-localized green fluorescent protein (NLS-2xGFP) and OsMFT2-GFP under the control of a 3-kb fragment of theOsMFT2promoter. Immunohistochemical staining using anti-GFP antibodies mainly detected GFP in the scutellum and scutellar epithelium, which is an important tissue for initiating germination upon seed hydration. We confirmed these results by confocal microscopy of GFP fluorescence in seeds. Our results suggest thatMFT2expression in rice, barley, and wheat might be regulated by a similar network of transcription factors through multi-RY motifs in theMFT2promoters, with possible roles in scutellar epithelium development.
Oligodendrocyte dynamics dictate individual performance outcomes of working memory training in mice
Authors: Shimizu Takahiro , Nayar Stuart G , Swire Matthew , Jiang Yi , Grist Matthew , Kaller Malte , Baptista Cassandra Sampaio , Bannerman David M , Johansen-Berg Heidi , Ogasawara Katsutoshi , Tohyama Koujiro , Li Huiliang , Richardson William D
Published: January 2023

Motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursors (OLPs). We asked whether OL production is also required for non-motor learning and cognition, using T-maze and radial arm maze tasks that tax spatial working memory. Maze training stimulated OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation; myelin sheath formation was also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination inMyrfconditional-knockout mice strongly impaired training-induced improvements in maze performance. Remarkably, there was a strong positive correlation between working memory performance of individual mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+neurons in the mPFC, underscoring the key role of OL lineage cells in cognitive performance.
Data stochasticity and model parametrisation impact the performance of species distribution models: insights from a simulation study
Authors: Lambert Charlotte , Virgili Auriane
Published: January 2023

Species distribution models (SDM) are widely used to describe and explain how species relate to their environment, and predict their spatial distributions. As such, they are the cornerstone of most of spatial planning efforts worldwide. SDM can be implemented with wide array of data types (presence-only, presence-absence, count…), which can either be point- or areal-based, and use a wide array of environmental conditions as predictor variables. The choice of the sampling type as well as the resolution of environmental conditions to be used are recognized as of crucial importance, yet we lack any quantification of the effects these decisions may have on SDM reliability. In the present work, we fill this gap with an unprecedented simulation procedure. We simulated 100 possible distributions of two different virtual species in two different regions. Species distribution were modelled using either segment- or areal-based sampling and five different spatial resolutions of environmental conditions. The SDM performances were inspected by statistical metrics, model composition, shapes of relationships and prediction quality. We provided clear evidence of stochasticity in the modelling process (particularly in the shapes of relationships): two dataset from the same survey, species and region could yield different results. Sampling type had stronger effects than spatial resolution on the final model relevance. The effect of coarsening the resolution was directly related to the resistance of the spatial features to changes of scale: SDM failed to adequately identify spatial distributions when the spatial features targeted by the species were diluted by resolution coarsening. These results have important implications for the SDM community, backing up some commonly accepted choices, but also by highlighting some up-to-now unexpected features of SDM (stochasticity). As a whole, this work calls for carefully weighted decisions in implementing models, and for caution in interpreting results.

Abstract Figure
Lemur gut microeukaryotic community variation is not associated with host phylogeny, diet, or habitat
Authors: Donohue Mariah E. , Hert Zoe L. , Karrick Carly E. , Rowe Amanda K. , Wright Patricia C. , Randriamanandaza Lovasoa J. , Zakamanana François , Nomenjanahary Stela , Everson Kathryn M. , Weisrock David W.
Published: January 2023

Gut prokaryotic (GP) community variation is often associated with host evolutionary and ecological variables; whether these factors drive variation in other gut taxa remains largely untested. We present a one-to-one comparison of GP (16S rRNA metabarcoding) and microeukaryotic (GME) (18S rRNA metabarcoding) community patterning among 12 species of lemurs. Lemurs were sampled from dry forests and rainforests of southeastern Madagascar and display a range of phylogenetic and ecological diversity. We found that while lemur GPs vary with host taxonomy, diet, and habitat, GMEs have no association with these factors. As a mechanism, we suggest purifying selection purges microbes with negative and commensal associations, while positive selection promotes the persistence of beneficial microbes. It is therefore likely that a greater proportion of GMEs comprise taxa with commensal, transient, and parasitic symbioses compared with GPs, many of which are mutualists. Our study reveals different microbial taxa are shaped by unique selective pressures.
A tessellated lymphoid network provides whole-body T cell surveillance in zebrafish
Authors: Robertson Tanner F. , Hou Yiran , Shen Simone , Rindy Julie , Sauer John-Demian , Dinh Huy Q , Huttenlocher Anna
Published: January 2023

Homeostatic trafficking to lymph nodes allows T cells to efficiently survey the host for cognate antigen. Non-mammalian jawed vertebrates lack lymph nodes but maintain similarly diverse T cell pools. Here, we exploitin vivoimaging of transparent zebrafish to investigate how T cells organize and survey for antigen in an animal devoid of lymph nodes. We find that naïve-like T cells in zebrafish organize into a previously undescribed whole-body lymphoid network that supports streaming migration and coordinated trafficking through the host. This network has the cellular hallmarks of a mammalian lymph node, including naïve T cells and CCR7-ligand expressing non-hematopoietic cells, and facilitates rapid collective migration. During infection, T cells transition to a random walk that supports antigen presenting cell interactions and subsequent activation. Our results reveal that T cells can toggle between collective migration and individual random walks to prioritize either large-scale trafficking or antigen searchin situ. This novel lymphoid network thus facilitates whole-body T cell trafficking and antigen surveillance in the absence of a lymph node system.

Significance Statement

In mammals, lymph nodes play a critical role in the initiation of adaptive immune responses by providing a dedicated place for T cells to scan antigen-presenting cells. Birds, reptiles, amphibians, and fish all maintain diverse repertoires of T cells but lack lymph nodes, raising questions about how adaptive immunity functions in lower jawed vertebrates. Here, we describe a novel network of lymphocytes in zebrafish that supports whole-body T cell trafficking and provides a site for antigen search, mirroring the function of mammalian lymph nodes. Within this network, T cells can prioritize large-scale trafficking or antigen scanning by toggling between two distinct modes of migration. This network provides valuable insights into the evolution of adaptive immunity.
Molecular Logic of Synaptic Diversity BetweenDrosophilaTonic and Phasic Motoneurons
Authors: Jetti Suresh K. , Crane Andrés B. , Akbergenova Yulia , Aponte-Santiago Nicole A. , Cunningham Karen L. , Whittaker Charles A. , Littleton J. Troy
Published: January 2023

Although neuronal subtypes display unique synaptic organization and function, the underlying transcriptional differences that establish these features is poorly understood. To identify molecular pathways that contribute to synaptic diversity, single neuron PatchSeq RNA profiling was performed onDrosophilatonic and phasic glutamatergic motoneurons. Tonic motoneurons form weaker facilitating synapses onto single muscles, while phasic motoneurons form stronger depressing synapses onto multiple muscles. Super-resolution microscopy andin vivoimaging demonstrated synaptic active zones in phasic motoneurons are more compact and display enhanced Ca2+influx compared to their tonic counterparts. Genetic analysis identified unique synaptic properties that mapped onto gene expression differences for several cellular pathways, including distinct signaling ligands, post-translational modifications and intracellular Ca2+buffers. These findings provide insights into how unique transcriptomes drive functional and morphological differences between neuronal subtypes.
A predicted amphipathic helix contributes to the efficient S-acylation of theArabidopsis thalianaCalcineurin B-like protein 2
Authors: Wyganowski Thomas , Beckmann Linda , Batistič Oliver
Published: January 2023

Membrane targeting of the Calcineurin B-like (CBL) calcium sensor proteins through protein S-acylation is crucial for various processes in plants, like nutrient uptake, plant development, and response to abiotic and biotic stresses. Certain CBLs target specifically to the vacuolar membrane, but which factors contribute to this particular localization and to the lipid modification efficiency are not yet known. Here, we examined the structural features of the N-terminus ofArabidopsis thalianaCBL2 and show that the lipid-modified cysteines are integrated within a predicted amphipathic helix. Mutations of amino acids, which contribute to the formation of this specific domain, affect S-acylation efficiency, membrane binding and function of CBL2. Interestingly, overexpression of the protein S-acyl transferase (PAT) 10 can compensate for the binding deficiency of a CBL2 mutant variant, which harbours a helix breaker mutation. This indicates that helix formation is rather involved in the S-acylation mechanism and is less important for membrane binding. Moreover, the introduction of basic residues resulted in a partial shift of the protein from the vacuolar to the plasma membrane, indicating that the underrepresentation of positively charged amino acids contributes to the vacuolar targeting specificity. Overall, our data suggest that helix formation is potentially an initial step in the S-acylation process and provides a deeper understanding of the mechanistic interplay between PATs and tonoplast targeted CBLs.
HiCLift: A fast and efficient tool for converting chromatin interaction data between genome assemblies
Authors: Wang Xiaotao , Yue Feng
Published: January 2023

Motivation

With the continuous effort to improve the quality of human reference genome and the generation of more and more personal genomes, the conversion of genomic coordinates between genome assemblies is critical in many integrative and comparative studies. While tools have been developed for such task for linear genome signals such as ChIP-Seq, no tool exists to convert genome assemblies for chromatin interaction data, despite the importance of three-dimensional (3D) genome organization in gene regulation and disease.

Results

Here, we present HiCLift, a fast and efficient tool that can convert the genomic coordinates of chromatin contacts such as Hi-C and Micro-C from one assembly to another, including the latest T2T genome. Comparing with the strategy of directly re-mapping raw reads to a different genome, HiCLift runs on average 42 times faster (hours vs. days), while outputs nearly identical contact matrices. More importantly, as HiCLift does not need to re-map the raw reads, it can directly convert human patient sample data, where the raw sequencing reads are sometimes hard to acquire or not available.

Availability

HiCLift is publicly available athttps://github.com/XiaoTaoWang/HiCLift.
Nitrogen-limitation independent control ofglnA(glutamine synthetase) expression inEscherichia coliby urea, several amino acids, and post-transcriptional regulation
Authors: Urs Karthik , Zimmern Philippe E. , Reitzer Larry
Published: January 2023

The expression ofglnA(ammonia-assimilating glutamine synthetase) is high for uropathogenicE. coligrown in urine. BecauseglnAis part of an operon that codes for regulators of the nitrogen-regulated (Ntr) response, highglnAexpression has been interpreted to suggest nitrogen limitation, which is unexpected because of the high urinary ammonia concentration and the extremely rapid bacterial growth. We present evidence thatglnAexpression does not result from nitrogen limitation. First, in the presence of ammonia, urea induced expression ofglnAfrom the cAMP receptor protein (Crp)- dependentglnAp1promoter, which circumvents control from the nitrogen-regulatedglnAp2promoter. This urea effect onglnAexpression has not been previously described. Second, the most abundant amino acids in urine inhibited GS activity, based on reversal of the inhibition by glutamate and glutamine, and increasedglnAexpression. The relevance of these inhibitory amino acids in natural environments has not been previously demonstrated. Third, neither urea nor the inhibitory amino acids induced other Ntr genes, i.e., highglnAexpression can be independent of other Ntr genes. Finally, the urea-dependent induction did not result in GlnA synthesis because of a previously undescribed translational control. We conclude thatglnAexpression in urea-containing environments does not imply growth rate-limiting nitrogen restriction and is consistent with rapid growth of uropathogenicE. coli.

Significance

Urinary tract infections (UTIs), often caused byE. coli, frequently become resistant to antibiotic treatment. Expressed metabolic genes during an infection could guide development of urgently-needed alternate or adjunct therapies.glnA(glutamine synthetase) is expressed during growth in urine, which implies growth-restricting nitrogen limitation. We show thatglnAexpression results from urinary amino acids that inhibit GlnA activity and urea, but not from nitrogen limitation. Urinary components will vary greatly between individuals which suggests corresponding variations inglnAexpression. GlnA may be a metabolic vulnerability during UTIs, which may depend on a variable urinary composition.glnAexpression may be important in a complex host-pathogen interaction, but may not be a good therapeutic target.
HIV-PULSE: A long-read sequencing assay for high-throughput near full-length HIV-1 proviral genome characterization
Authors: Lambrechts Laurens , Bonine Noah , Verstraeten Rita , Pardons Marion , Noppe Ytse , Rutsaert Sofie , Van Nieuwerburgh Filip , Van Criekinge Wim , Cole Basiel , Vandekerckhove Linos
Published: January 2023

A deep understanding of the composition of the HIV-1 reservoir is necessary for the development of targeted therapies and the evaluation of curative efforts. However, current near full-length (NFL) HIV-1 proviral genome sequencing assays are based on labor-intensive and costly principles of repeated PCRs at limiting dilution, restricting their scalability. To address this, we developed a high-throughput, long-read sequencing assay called HIV-PULSE (HIVProviralUMI-mediatedLong-readSequencing). This assay uses unique molecular identifiers (UMIs) to tag individual HIV-1 genomes, allowing for the omission of the limiting dilution step and enabling long-range PCR amplification of many NFL genomes in a single PCR reaction, while simultaneously overcoming poor single-read accuracy. We optimized the assay using HIV-infected cell lines and then applied it to blood samples from 18 individuals living with HIV on antiretroviral therapy, yielding a total of 1,308 distinct HIV-1 genomes. Benchmarking against the widely applied Full-Length Individual Proviral Sequencing assay revealed similar sensitivity (11% vs 18%) and overall good concordance, though at a significantly higher throughput. In conclusion, HIV-PULSE is a cost-efficient and scalable assay that allows for the characterization of the HIV-1 proviral landscape, making it an attractive method to study the HIV-1 reservoir composition and dynamics.
Spatial transcriptomics reveals unique gene expression changes in different brain regions after sleep deprivation
Authors: Vanrobaeys Yann , Peterson Zeru J. , Walsh Emily. N. , Chatterjee Snehajyoti , Lin Li-Chun , Lyons Lisa C. , Nickl-Jockschat Thomas , Abel Ted
Published: January 2023

Sleep deprivation has far-reaching consequences on the brain and behavior, impacting memory, attention, and metabolism. Previous research has focused on gene expression changes in individual brain regions, such as the hippocampus or cortex. Therefore, it is unclear how uniformly or heterogeneously sleep loss affects the brain. Here, we use spatial transcriptomics to define the impact of a brief period of sleep deprivation across the brain. We find that sleep deprivation induced pronounced differences in gene expression across the brain, with the greatest changes in the hippocampus, neocortex, hypothalamus, and thalamus. Both the differentially expressed genes and the direction of regulation differed markedly across regions. Importantly, we developed bioinformatic tools to register tissue sections and gene expression data into a common anatomical space, allowing a brain-wide comparison of gene expression patterns between samples. Our results suggest that distinct molecular mechanisms acting in discrete brain regions underlie the biological effects of sleep deprivation.

Graphical Abstract

Highlights

Spatial transcriptomics using the Visium platform reveals the transcriptional signature across the brain, recapitulating the anatomy of the mouse brain

Sleep deprivation induces transcriptomic changes unique to each brain region

The hippocampus is the brain region impacted the most by acute sleep deprivation, with most differentially regulated genes significantly downregulated

The neocortex exhibits layer-specific changes in gene expression, with most differentially regulated genes significantly upregulated

Registration of spatial transcriptomic data to a common anatomical reference space (Allen Common Coordinate Framework) allows statistical analysis of gene expression across regions of the brain and for multi-sample analysis
Hierarchical Deviant Processing in Auditory Cortex of Awake Mice
Authors: Luo Dan , Liu Ji , Auksztulewicz Ryszard , Wing Yip Tony Ka , Kanold Patrick O. , Schnupp Jan W.
Published: January 2023

Detecting patterns, and noticing unexpected pattern changes, in the environment is a vital aspect of sensory processing. Adaptation and prediction error responses are two components of neural processing related to these tasks, and previous studies in the auditory system in rodents show that these two components are partially dissociable in terms of the topography and latency of neural responses to sensory deviants. However, many previous studies have focused on repetitions of single stimuli, such as pure tones, which have limited ecological validity. In this study, we tested whether the auditory cortical activity shows adaptation to repetition of more complex sound patterns (bisyllabic pairs). Specifically, we compared neural responses to violations of sequences based on single stimulus probability only, against responses to more complex violations based on stimulus order. We employed an auditory oddball paradigm and monitored the auditory cortex (ACtx) activity of awake mice (N=8) using wide-field calcium imaging. We found that cortical responses were sensitive both to single stimulus probabilities and to more global stimulus patterns, as mismatch signals were elicited following both substitution deviants and transposition deviants. Notably, A2 area elicited larger mismatch signaling to those deviants than primary ACtx (A1), which suggests a hierarchical gradient of prediction error signaling in the auditory cortex. Such a hierarchical gradient was observed for late but not early peaks of calcium transients to deviants, suggesting that the late part of the deviant response may reflect prediction error signaling in response to more complex sensory pattern violations.
Genome wide clustering on integrated chromatin states and Micro-C contacts reveals chromatin interaction signatures
Authors: Sexton Corinne E. , Han Mira V.
Published: January 2023

Chromatin states based on various histone modifications are a common annotation for genomes, and have been shown to correspond to regulatory functions such as enhancers and transcription start sites. With the advent of Hi-C and other chromatin conformation capture technologies, we now have the ability to analyze 3-dimensional physical interactions of chromatin regions, in addition to the 1-dimensional regulatory annotation, but methods to integrate this information are lacking. We present a framework for integrating the chromatin state of interacting regions into a numeric vector through the contact-weighted sum of chromatin states. Unsupervised clustering on integrated chromatin states and Micro-C contacts reveals common patterns of chromatin interaction which we call chromatin interaction signatures. Our results indicate that most chromatin interaction signatures are found in all four cell types investigated here. Between 12-40% of the regions change chromatin interaction signatures between the cell types despite maintaining chromatin state, hinting at the dynamic nature of chromatin conformation. Although regions with similar chromatin states are often in contact as expected, subcategories of enhancers and transcription start sites have distinct chromatin interaction signatures that are associated with gene expression. The integrated information on the chromatin states that the region is in contact with adds another layer of annotation beyond chromatin state or Hi-C contact separately. In summary, we present the first set of chromatin interaction signatures for the human genome that provides an integrated view of the complex dynamics of concurrent change occurring in chromatin state and in chromatin interaction.
Cyclic and pseudo-cyclic electron pathways play antagonistic roles during nitrogen deficiency inChlamydomonas reinhardtii
Authors: Dao Ousmane , Burlacot Adrien , Buchert Felix , Bertrand Marie , Auroy Pascaline , Stoffel Carolyne , Irby Jacob , Hippler Michael , Peltier Gilles , Li-Beisson Yonghua
Published: January 2023

Nitrogen (N) scarcity is a frequently encountered situation that constrains global biomass productivity. In response to N deficiency, cell division stops and photosynthetic electron transfer is downregulated, while carbon storage is enhanced. However, the molecular mechanism downregulating photosynthesis during N deficiency and its relationship with carbon storage are not fully understood. The Proton Gradient Regulator-like 1 (PGRL1) controlling cyclic electron flow (CEF) and Flavodiiron proteins involved in pseudo-(CEF) are major players in the acclimation of photosynthesis. To determine the role of PGRL1 or FLV in photosynthesis under N deficiency, we measured photosynthetic electron transfer, oxygen gas exchange and carbon storage inChlamydomonas pgrl1andflvBknockout mutants. Under N deficiency,pgrl1maintains higher net photosynthesis and O2photoreduction rates, whileflvBshows a similar response compared to control strains. Cytochromeb6fand PSI are maintained at a higher abundance inpgrl1. The photosynthetic activity offlvBandpgrl1 flvBdouble mutants decreases in response to N deficiency similar to the control strains. Furthermore, the preservation of photosynthetic activity inpgrl1is accompanied by an increased accumulation of triacylglycerol depending on the genetic background. Taken together, our results suggest that in the absence of PGRL1-controlled CEF, FLV-mediated PCEF maintains net photosynthesis at a high level and that CEF and PCEF play antagonistic roles during N deficiency. It further illustrates how nutrient status and genetic makeup of a strain can affect the regulation of photosynthetic energy conversion in relation to carbon storage and provides new strategies for improving lipid productivity in algae.

Significance statement

Nitrogen (N) deficiency, an often-encountered phenomenon in nature, results in growth arrest, downregulation of photosynthesis and massive carbon storage in microalgae. However, more mechanistic insights involved in tuning photosynthetic electron transfer during N deficiency are required. Here, we provide evidence that a well-conserved protein in chlorophytes, the Proton Gradient Regulator-like 1 (PGRL1), is a key regulator of photosynthesis during N deficiency. In its absence, cells exhibited sustained photosynthesis thanks to the Flavodiiron (FLV) proteins. We propose that both PGRL1 and FLV, by having antagonistic roles in N deficiency, manage the redox landscape, carbon storage and biomass production. Our work revolves around the current paradigm of photosynthesis regulation during N deficiency and provides a new framework for improving biomass production and carbon storage in microalgae for biotechnological purposes.
Microbial community-based bacterial protein from soybean-processing wastewater as a value-added alternative fish feed ingredient for Asian sea bass (Lates calcarifer)
Authors: Santillan Ezequiel , Yasumaru Fanny , Vethathirri Ramanujam Srinivasan , Thi Sara Swa , Hoon Hui Yi , Pek Sian Diana Chan , Wuertz Stefan
Published: January 2023

As the global demand for food increases, aquaculture plays a key role as the fastest growing animal protein sector. However, existing aquafeeds contain protein ingredients that are not sustainable under current production systems. We evaluated the use of microbial community-based single cell protein (SCP), produced from soybean processing wastewater, as a partial fishmeal protein substitute in juvenile Asian seabass (Lates calcarifer). A 24-day feeding trial was conducted with a control fishmeal diet and a 50% fishmeal replacement with microbial community-based SCP as an experimental group, in triplicate tanks containing 20 fish each. Both diets met the protein, essential amino acids (except for lysine), and fat requirements for juvenile Asian sea bass. The microbial composition of the SCP was dominated by the generaAcidipropionibacteriumandPropioniciclava, which have potential as probiotics and producers of valuable metabolites. The growth performance in terms of percent weight gain, feed conversion ratio (FCR), specific growth rate (SGR), and survival were not significantly different between groups after 24 days. The experimental group had less variability in terms of weight gain and FCR than the control group. Overall, microbial community-based protein produced from soybean processing wastewater has potential as a value-added feed ingredient for sustainable aquaculture feeds.
AUTOMATIC EXTRACTION OF ACTIN NETWORKS IN PLANTS
Authors: Hembrow Jordan , Deeks Michael J. , Richards David M.
Published: January 2023

Abstract

The actin cytoskeleton is essential in eukaryotes, not least in the plant kingdom where it plays key roles in cell expansion, cell division, environmental responses and pathogen defence. Yet, the precise structure-function relationships of properties of the actin network in plants are still to be unravelled, including details of how the network configuration depends upon cell type, tissue type and developmental stage. Part of the problem lies in the difficulty of extracting high-quality, three-dimensional, quantitative measures of actin network features from microscopy data. To address this problem, we have developed DRAGoN, a novel image analysis algorithm that can automatically extract the actin network across a range of cell types, providing seventeen different quantitative measures that describe the network at a local level. Using this algorithm, we then studied a number of cases inArabidopsis thaliana, including several different tissues, a variety of actin-affected mutants, and cells responding to powdery mildew. In many cases we found statistically-significant differences in actin network properties. In addition to these results, our algorithm is designed to be easily adaptable to other tissues, mutants and plants, and so will be a valuable asset for the study and future biological engineering of the actin cytoskeleton in globally-important crops.
A robust normalized local filter to estimate compositional heterogeneity directly from cryo-EM maps
Authors: Forsberg Bjoern O. , Shah Pranav N.M. , Burt Alister
Published: January 2023

Cryo electron microscopy (cryo-EM) is used by biological research to visualize biomolecular complexes in 3D, but the heterogeneity of cryo-EM reconstructions is not easily estimated. Current processing paradigms nevertheless exert great effort to reduce flexibility and heterogeneity to improve the quality of the reconstruction. Clustering algorithms are typically employed to identify populations of data with reduced variability, but lack assessment of remaining heterogeneity. We have developed a fast and simple algorithm based on spatial filtering to estimate the heterogeneity of a reconstruction. In the absence of flexibility, this estimate approximates macromolecular component occupancy. We show that our implementation can derive reliable input parameters automatically, that the resulting estimate is accurate, and the reconstruction can be modified accordingly to emulate altered constituent occupancy, which may benefit conventionally employed maximum-likelihood classification methods. Here, we demonstrate the utility of this method for cryo-EM map interpretation, quantification, and particle-image signal subtraction.
Towards stability of dynamic FC estimates in neuroimaging and electrophysiology: solutions and limits
Authors: Alonso Sonsoles , Vidaurre Diego
Published: January 2023

Time-varying functional connectivity methods are used to map the spatiotemporal organization of brain activity. However, their estimation can be unstable, in the sense that different runs of the inference may yield different solutions. But to draw meaningful relations to behaviour, estimates must be robust and reproducible. Here, we propose two solutions using the Hidden Markov Model (HMM) as a descriptive model of time-varying FC. The first, best-ranked HMM, involves running the inference multiple times and selecting the best model based on a quantitative measure combining fitness and model complexity. The second, hierarchical clustered HMM, generates stable aggregated state timeseries by applying hierarchical clustering to the state timeseries obtained from multiple runs. Experimental results on fMRI and MEG data demonstrate that these approaches substantially improve the stability of time-varying FC estimations. Overall, hierarchical clustered HMM is preferred when the inference variability is high, while the best-ranked HMM performs better otherwise.
Validation and characterization of a viral antisense transcript with Northern blot analysis and qRT-PCR
Authors: Kara Mehmet
Published: January 2023

The transcription of mammalian genomes has been shown to possess an intriguing complexity and numerous novel RNA molecules have been identified in the last 10-15 years. Viruses with large DNA genomes, especially herpesviruses, are also shown to generate many different RNA species and some of them may function as long non-coding RNAs. Viral genomes harbor several genes within close proximity to each other and can generate multigenic transcripts in addition to commonly observed antisense transcription. It is essential to study the biological roles of these transcripts aside from the protein-coding counterparts. A transcriptionally complex locus can be studied with a combination of methods. Generally, quantitative PCR assays are very commonly used for expression analyses of the transcripts of interest. Here an example from a gammaherpesvirus is discussed in more detail. A recently developed method, for the resolution of complicated transcriptomes for viral genomes, elucidated multiple antisense transcripts from ORF63-64 locus in murine gammaherpesvirus 68 (MHV68). In order to identify the roles of these new transcripts, quantitative PCR assays may not be enough alone and should be supported by alternative methods such as Northern blots. A more detailed transcriptional map of the locus of interest is useful to design experimental strategies and perform functional studies.
Mechanistic Basis for Enhanced Strigolactone Sensitivity in KAI2 Triple Mutant
Authors: Sobecks Briana L. , Chen Jiming , Shukla Diwakar
Published: January 2023

Striga hermonthicais a parasitic weed that destroys billions of dollars’ worth of staple crops every year. Its rapid proliferation stems from an enhanced ability to metabolize strigolactones (SLs), plant hormones that direct root branching and shoot growth.Striga’sSL receptor,ShHTL7, bears more similarity to the staple crop karrikin receptor KAI2 than to SL receptor D14, though KAI2 variants in plants likeArabidopsis thalianashow minimal SL sensitivity. Recently, studies have indicated that a small number of point mutations to HTL7 residues can confer SL sensitivity toAtKAI2. Here, we analyze both wild-typeAtKAI2 and SL-sensitive mutant Var64 through all-atom, long-timescale molecular dynamics simulations to determine the effects of these mutations on receptor function at a molecular level. We demonstrate that the mutations stabilize SL binding by about 2 kcal/mol. They also result in a doubling of the average pocket volume, and eliminate the dependence of binding on certain pocket conformational arrangements. While the probability of certain non-binding SL-receptor interactions increases in the mutant compared with the wild-type, the rate of binding also increases by a factor of ten. All these changes account for the increased SL sensitivity in mutant KAI2, and suggest mechanisms for increasing functionality of host crop SL receptors.
Effects of Dopamine Receptor Antagonists and Radiation on Mouse Neural Stem/Progenitor Cells
Authors: He Ling , Bhat Kruttika , Ioannidis Angeliki , Pajonk Frank
Published: January 2023

Background

Dopamine receptor antagonists are psychotropic drugs that have been originally developed against psychiatric disorders. We recently identified dopamine receptor antagonists as potential anti-cancer agents and some have entered clinical trials against glioblastoma. Radiotherapy is known to cause cognitive impairment in patients receiving cranial irradiation through the elimination of neural stem/progenitor cells and subsequent loss of neurogenesis.

Methods

Using transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of enhanced green fluorescent protein, the effects of dopamine receptor antagonists alone or in combination with radiation on murine neural stem/progenitor cells were assessed in sphere-formation assays, flow cytometry and immunofluorescencein vitroandin vivo.

Results

We report that several dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells bothin vitroandin vivo. Hydroxyzine, trifluoperazine, amisulpride, nemonapride or quetiapine alone or in combination with radiation significantly increased the number of neural stem/progenitor cells in female neurospheres but not in male mice. Dopamine receptor antagonists either protected neural stem/progenitor cells from radiation or expanded the stem cell pool, thus indicating that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis.

Conclusions

We conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exist, making it a novel combination therapy against glioblastoma. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be taken into consideration when designing clinical trials.

Key Points

- Neural stem/progenitor cells show sex-dependent sensitivity to dopamine receptor antagonists

- Dopamine receptor antagonists active against GBM increase Neural stem/progenitor cells counts

Importance of the Study

Combination therapy of dopamine receptor antagonists with radiation have entered clinical trials against glioblastoma but the normal tissue toxicity of this combination has not been fully explored yet. Here we present evidence that some dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells either by protecting neural stem/progenitor cells from radiation or inducing an expansion of the stem cell pool, suggesting that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be further explored in clinical trials.
Phantom controllers: Misspecified models create the false appearance of adaptive control during value-based choice
Authors: Ritz H. , Frömer R. , Shenhav A.
Published: January 2023

Decision scientists have grown increasingly interested in how people adaptively control their decision making. Researchers have demonstrated that parameters governing the accumulation of evidence towards a choice, such as the decision threshold, are shaped by information available prior to or in parallel with one’s evaluation of an option set (e.g., recent outcomes or choice conflict). A recent account has taken a bold leap forward in this approach, suggesting that adjustments in decision parameters can be motivated by the value of the options under consideration. This motivated control account predicts that when faced with difficult choices (similarly valued options) under time pressure, people will adaptively lower their decision threshold to ensure that they make a choice in time. This account was supported by drift diffusion modeling of a deadlined choice task, demonstrating that decision thresholds decrease for difficult relative to easy choices. Here, we reanalyze the data from this experiment, and show that evidence for this novel account does not hold up to further scrutiny. Using a more systematic and comprehensive modeling approach, we show that this previously observed threshold adjustment disappears (or even reverses) under a more complete model of the data. Importantly, we further show how this and other apparent evidence for motivated control arises as an artifact of model (mis)specification, where one model’s putatively controlled decision process (e.g., value-driven threshold adjustments) can mimic another model’s stimulus-driven decision processes (e.g., accumulator competition or collapsing bounds). Collectively, this work reveals crucial insights and constraints in the pursuit of understanding how control guides decision-making, and when it doesn’t.