bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of striatal action selection and reinforcement learning
Authors: Lindsey Jack , Markowitz Jeffrey E. , Gillis Winthrop F. , Datta Sandeep Robert , Litwin-Kumar Ashok
Published: February 2024

Spiny projection neurons (SPNs) in dorsal striatum are often proposed as a locus of reinforcement learning in the basal ganglia. Here, we identify and resolve a fundamental inconsistency between striatal reinforcement learning models and known SPN synaptic plasticity rules. Direct-pathway (dSPN) and indirect-pathway (iSPN) neurons, which promote and suppress actions, respectively, exhibit synaptic plasticity that reinforces activity associated with elevated or suppressed dopamine release. We show that iSPN plasticity prevents successful learning, as it reinforces activity patterns associated with negative outcomes. However, this pathological behavior is reversed if functionally opponent dSPNs and iSPNs, which promote and suppress the current behavior, are simultaneously activated by efferent input following action selection. This prediction is supported by striatal recordings and contrasts with prior models of SPN representations. In our model, learning and action selection signals can be multiplexed without interference, enabling learning algorithms beyond those of standard temporal difference models.
A Gold Standard Dataset for Lineage Abundance Estimation from Wastewater
Authors: Ferdous Moon Jannatul , Kunkleman Samuel , Taylor William , Harris April , Gibas Cynthia , Schlueter Jessica
Published: February 2024

During the SARS-CoV-2 pandemic, genome-based wastewater surveillance sequencing has been a powerful tool for public health to monitor circulating and emerging viral variants. As a medium, wastewater is very complex because of its mixed matrix nature, which makes the deconvolution of wastewater samples more difficult. Here we introduce a gold standard dataset constructed from synthetic viral control mixtures of known composition, spiked into a wastewater RNA matrix and sequenced on the Oxford Nanopore Technologies platform. We compare the performance of eight of the most commonly used deconvolution tools in identifying SARS-CoV-2 variants present in these mixtures. The software evaluated was primarily chosen for its relevance to the CDC wastewater surveillance reporting protocol, which until recently employed a pipeline that incorporates results from four deconvolution methods: Freyja, kallisto, Kraken2/Bracken, and LCS. We also tested Lollipop, a deconvolution method used by the Swiss SARS-CoV2 Sequencing Consortium, and three recently-published methods: lineagespot, Alcov, and VaQuERo. We found that the commonly used software Freyja outperformed the other CDC pipeline tools in correct identification of lineages present in the control mixtures, and that the newer method VaQuERo was similarly accurate, with minor differences in the ability of the two methods to avoid false negatives and suppress false positives. These results provide insight into the effect of the tiling primer scheme and wastewater RNA extract matrix on viral sequencing and data deconvolution outcomes.

Highlights

Generation of a gold standard dataset

Comparative evaluation of relative abundance estimation software

Evaluation of deconvolution methods used in CFSAN’s CWAP pipeline
SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF A CLC-1 INHIBITOR - A FIRST-IN-CLASS COMPOUND THAT ENHANCES MUSCLE EXCITABILITY: A PHASE I, SINGLE- AND MULTIPLE-ASCENDING DOSE STUDY
Authors: Ruijs Titia Q , de Cuba Catherine M.K.E. , Heuberger Jules A.A.C. , Hutchison John , Bold Jane , Groennebaek Thomas , Jensen Klaus G. , Chin Eva , Quiroz Jorge , Petersen Thomas K. , Flagstad Peter , de Kam Marieke L. , van Esdonk Michiel J. , Klaassen Erica , Doll Robert J. , Koopmans Ingrid W. , de Goede Annika A. , Pedersen Thomas H , Groeneveld Geert Jan
Published: February 2024

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human administration of ClC-1 inhibitor NMD670. In this randomized, double-blind, placebo-controlled study we evaluated safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects. Single-ascending doses were administered in a (partial) cross-over design; multiple-ascending doses were administered in a parallel design. Differences in pharmacokinetics between males/females and fed/fasted state were evaluated. Pharmacodynamic effects were evaluated using muscle velocity recovery cycles (MVRC), and analyzed using mixed effects modelling, with baseline as covariate. NMD670 was considered safe and well-tolerated. Symptoms of myotonia were observed at the highest dose levels. Moreover, NMD670 significantly increased the following MVRC parameters after a single dose of 1200mg compared to placebo: early supernormality (estimated difference (ED) 2.04; 95% confidence interval (CI) (0.379, 3.70); p=0.0242); early supernormality after 5 conditioning stimuli (ED 2.51; 95%CI (0.599, 4.41); p=0.0177; supernormality at 20 ms (ED 2.78; 95%CI (1.377, 4.181); p=0.0021. Importantly, the results of this study indicate pharmacological target engagement of NMD670 as ClC-1 inhibitor, at dose levels that were considered safe in healthy subjects. Firstly, because myotonia was an expected exaggerated on-target pharmacological effect. Secondly, because the effects on MVRC indicate increased muscle cell excitability. This study in healthy subjects indicates proof-of-mechanism and provides a solid base for translation to patients with neuromuscular diseases.
SARS-CoV-2 infection and Pregnancy outcome: A cross-sectional study from Eastern U.P. Population, India
Authors: Rai Sangeeta , Ashish Ashish , Mishra Shivani , Kumar Bhupendra , Kusum Kusum , Singh Royana
Published: February 2024

Pregnant women with coronavirus infection are at a higher risk for severe diseases. In the present study, we evaluated and compared clinical characteristics and outcomes in pregnancy of normal females and females with SARS-CoV-2 infection. Our study was a cross-sectional study. The pregnant females were examined, their blood samples were taken for Covid Panel (D-Dimer, Ferritin, IL-6, CRP, PCT (Procalcitonin)); and oral-nasal swabs were taken for SARS-CoV-2 infection. Both SARS-CoV-2 positive and negative (control) females were followed up every trimester for any complication related to pregnancy. We found that females suffering from SARS-CoV-2 infection had reduced gestation periods, and had higher percentage of caesarean and pre-term delivery than SARS-CoV-2 negative females. Based on our findings, it appears that there exist close associations between SARS-CoV-2 infection in pregnant females and increased risk of reduced gestation periods, and spontaneous caesarean and pre-term delivery. However, more studies are still needed to validate present findings.
Trajectory Analysis of Hepatic Stellate Cell Differentiation Reveals Metabolic Regulation of Cell Commitment and Fibrosis
Authors: Martínez García de la Torre Raquel A. , Vallverdú Julia , Xu Qing , Ariño Silvia , Aguilar-Bravo Beatriz , Ruiz-Blázquez Paloma , Fernandez-Fernandez Maria , Navarro-Gascon Artur , Blasco-Roset Albert , Sànchez-Fernàndez-de-Landa Paula , Pera Garcia Juan , Romero-Moya Damià , Ayuso Garcia Paula , Martínez Sánchez Celia , Zanatto Laura , Sererols Laura , Cantallops Vilà Paula , Antoine Bénédicte , Azkargorta Mikel , Lozano Juan José , Martínez-Chantar Maria L , Giorgetti Alessandra , Elortza Félix , Planavila Anna , Varela Marta , Woodhoo Ashwin , Zorzano Antonio , Graupera Isabel , Moles Anna , Coll Mar , Affo Silvia , Sancho-Bru Pau
Published: February 2024

Defining the trajectory of cells during differentiation and disease offers the possibility to understand the mechanisms driving cell fate and identity. However, trajectories of human cells are largely unexplored. By investigating the proteome trajectory of iPSCs differentiation to hepatic stellate cells (dHSCs), we identified RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for HSCs’ commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we showed that RORA is required for mesoderm differentiation and prevents dHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice had enhanced fibrosis, RORA agonists rescued multi- organ fibrosis inin vivomodels. RORA expression was consistently found to be negatively correlated with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, crucial for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease mechanisms.

This study describes the trajectory of induced pluripotent stem cells (iPSCs) differentiation to hepatic stellate cells (dHSCs). We identify RAR-related orphan receptor alpha (RORA) as a transcription factor essential for mesoderm commitment and dHSCs identity and fibrogenic activation by regulating metabolic plasticity.
Differences in RAD51 transcriptional response and cell cycle dynamics reveal varying sensitivity to DNA damage among Arabidopsis thaliana root cell types
Authors: Kutashev Konstantin , Meschichi Anis , Reeck Svenja , Fonseca Alejandro , Sartori Kevin , White Charles I , Sicard Adrien , Rosa Stefanie
Published: February 2024

Throughout their lifecycle, plants are subjected to DNA damage from various sources, both environmental and endogenous. Investigating the mechanisms of the DNA damage response (DDR) is essential to unravel how plants adjust to the changing environment that can elicit varying amounts of DNA damage. Using a combination of state-of-the-art cell biology methods including whole-mount single- molecule RNA fluorescence in situ hybridization (WM-smFISH), allowing detection of individual mRNA molecules in intact plant tissue and plant cell cycle reporter lines we investigated how the transcriptional activation of a key homologous recombination (HR) gene, RAD51, occurs in response to increasing amounts of DNA damage in Arabidopsis thaliana roots. The results uncover consistent variations in RAD51 transcriptional response and cell cycle arrest among distinct cell types and developmental zones. Furthermore, we demonstrate that DNA damage induced by genotoxic stress results in RAD51 transcription throughout the whole cell cycle, dissociating its traditional link with S/G2 phases. This work advances the current comprehension of DNA damage response in plants showing quantitative differences in DDR activation. In addition, it reveals new associations with the cell cycle and cell types, providing crucial insights for further studies of the broader response mechanisms in plants.
Tissue-resident regulatory T cells exert dualistic anti-tumour and pro-repair function in the exocrine pancreas
Authors: Stockis Julie , Yip Thomas , Raghunathan Shwetha , Garcia Celine , Lee Sheng , Simpson Charlotte , Silvain Silvain , Schuijs Martijn J. , Araos Joaquin , Png Shaun , Raddi Gianmarco , Bricard Orian , So Tsz Y. , Mack Stephanie , Papadopoulos Panagiotis , Sawle Ashley , Jodrell Duncan I. , McKenzie Andrew N.J. , Thaventhiran James , Clatworthy Menna , Biffi Giulia , Saeb-Parsy Kourosh , Liston Adrian , Halim Timotheus Y.F.
Published: February 2024

Regulatory T cells are fundamentally important for maintaining immune homeostasis, and their potent immune-suppressive roles make them attractive immunotherapeutic targets in cancer. Recent work suggests potential functions of tissue-resident Tregs (trTregs) in tissue-repair and epithelial cell homeostasis. Here, we describe a rare population of trTreg in the exocrine pancreas. We show that these cells share common features of trTregs, including expression of the IL-33 receptor ST2 and production of the epithelial growth factor Amphiregulin, and display an oligoclonal T cell receptor repertoire. Using a mouse model of acute pancreatitis, we show that pancreatic Tregs rapidly expand upon release of IL-33 by fibroblasts. Moreover, depletion of Tregs after initiation of pancreatic injury impairs the regeneration of the exocrine parenchyma. This effect is due, in part, through a direct effect of Tregs on acinar cell proliferation. Finally, we show that transient Treg depletion in established orthotopic pancreatic tumours leads to tumour rejection yet provokes long-lasting damages to surrounding exocrine parenchyma. In all, our results demonstrate the tissue-repair capacity of pancreatic Tregs, and highlight a dualistic role of these cells in the pancreatic tumour ecosystem, with their harmful immune-suppressive function in the tumour coupled to a beneficial tissue-repair function in the surrounding tissue.
Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.
Authors: Hetzer Shelby , Bellary Rohan , Torrens Jordyn N , Grimaldi Robert F , Evanson Nathan K
Published: February 2024

Traumatic brain injury (TBI) can induce traumatic axonal injury in the optic nerve, which is referred to as traumatic optic neuropathy (TON). TON occurs in up to 5% of TBI cases and leads to irreversible visual deficits. TON-induced phosphorylation of eIF2α, a downstream ER stress activator in the PERK pathway presents a potential point for therapeutic intervention. For eIF2α phosphorylation can lead to apoptosis or adaptation to stress. We hypothesized that dephosphorylation, rather than phosphorylation, of eIF2α would lead to reduced apoptosis and improved visual performance and retinal cell survival. Adult male mice were injected with Salubrinal (increases p-eIF2α) or ISRIB (decreases p-eIF2α) 60 minutes post-injury. Contrary to literature, both drugs hindered control animal visual function with minimal improvements in injured mice. Additionally, differences in eIF2α phosphorylation, antioxidant responses, and protein folding chaperones were different when examining protein expression between the retina and its axons in the optic nerve. These results reveal important compartmentalized ER stress responses to axon injury and suggest that interventions in the PERK pathway may alter necessary homeostatic regulation of the UPR in the retina.
The Backpack Quotient Filter: a dynamic and space-efficient data structure for queryingk-mers with abundance.
Authors: Levallois Victor , Andreace Francesco , Le Gal Bertrand , Dufresne Yoann , Peterlongo Pierre
Published: February 2024

Genomic data sequencing has become indispensable for elucidating the complexities of biological systems. As databases storing genomic information, such as the European Nucleotide Archive, continue to grow exponentially, efficient solutions for data manipulation are imperative. One fundamental operation that remains challenging is querying these databases to determine the presence or absence of specific sequences and their abundance within datasets. This paper introduces a novel data structure indexingk-mers (substrings of lengthk), the Backpack Quotient Filter (BQF), which serves as an alternative to the Counting Quotient Filter (CQF). The BQF offers enhanced space efficiency compared to the CQF while retaining key properties, including abundance information and dynamicity, with a negligible false positive rate, below 10-5%. The approach involves a redefinition of how abundance information is handled within the structure, alongside with an independent strategy for space efficiency. We show that the BQF uses 4x less space than the CQF on some of the most complex data to index: sea-water metagenomics sequences. Furthermore, we show that space efficiency increases as the amount of data to be indexed increases, which is in line with the original objective of scaling to ever-larger datasets.
Tracing the evolutionary history of Tunisian HPV 16 and 18 across the genetic diversity in L1 gene
Authors: Ardhaoui Monia , Dekhil Naira , Bouslama Zied , Bel Hadj Rhouma Rahima , Fehri Emna , Ennaifer Emna , Guizani Ikram
Published: February 2024

HPV16 and HPV18 are the most prevalent high risk HPV types, recognized to be HPV vaccine target. Currently, available vaccines against HPV infections are based on virus-like particles (VLPs) derived from the L1 protein. Understanding the emergence of HPV isolates and exploring the genetic diversity of their L1 gene is crucial to assess the effectiveness of vaccine introduction in different populations. This is the first study aiming to investigate the evolutionary dynamics of HPV16 and HPV18 variants circulating in Tunisia. We constructed evolutionary history of HPV16 and HPV18 based on partial L1 sequence dataset of 733 Tunisian and worldwide representative isolates. Phylogeographic analysis confirmed the European origin of Tunisian strains that have emerged in 90's. Strikingly, four nonsense mutations in HPV16 and one in HPV18 within the HI surface loop, a critical immunogenic region were identified. Moreover, the latter showed an excess of non-synonymous over synonymous substitutions, a hallmark of local adaptation. By elucidating the genetic variability in the L1 gene, our study unveils several new features that pose challenges to the ongoing fight against HPV. These insights underscore the importance of continuous surveillance and adaptation of vaccination strategies to address evolving viral dynamics effectively.
Young guard cells function dynamically despite low mechanical anisotropy but gain efficiency during stomatal maturation in Arabidopsis thaliana
Authors: Jaafar Leila , Chen Yintong , Keynia Sedighe , Turner Joseph A , Anderson Charles T
Published: February 2024

Stomata are pores at the leaf surface that enable gas exchange and transpiration. The signaling pathways that regulate the differentiation of stomatal guard cells and the mechanisms of stomatal pore formation have been characterized in Arabidopsis thaliana. However, the process by which stomatal complexes develop after pore formation into fully mature complexes is poorly understood. We tracked the morphogenesis of young stomatal complexes over time to establish characteristic geometric milestones along the path of stomatal maturation. Using 3D-nanoindentation coupled with finite element modeling of young and mature stomata, we found that despite having thicker cell walls than young guard cells, mature guard cells are more energy efficient with respect to stomatal opening, potentially attributable to the increased mechanical anisotropy of their cell walls and smaller changes in turgor pressure between the closed and open states. Comparing geometric changes in young and mature guard cells of wild-type and cellulose-deficient plants revealed that although cellulose is required for normal stomatal maturation, mechanical anisotropy appears to be achieved by the collective influence of cellulose and additional wall components. Together, these data elucidate the dynamic geometric and biomechanical mechanisms underlying the development process of stomatal maturation.
Altered gut microbial functional pathways in people with Irritable Bowel Syndrome enable precision health insights
Authors: Patridge Eric , Gorakshakar Anmol , Molusky Matthew M. , Ogundijo Oyetunji , Julian Cristina , Hu Lan , Antoine Grant , Vuyisich Momchilo , Wohlman Robert , Banavar Guruduth
Published: February 2024

Functional gastrointestinal disorders present diagnostic and therapeutic challenges, and there is a strong need for molecular markers that enable early detection and intervention. Herein, we present an approach to assess an abnormal gut microbiome associated with irritable bowel syndrome using stool-based gut metatranscriptome data from a large adult human population (n= 80,570). We develop a suite of eight gut microbial functional pathway scores, each of which represents the activity of a set of interacting microbial functional features (based on KEGG orthology) relevant to known gut biochemical activities. We use a normative approach within a subpopulation (n= 9,350) to define “Good” and “Not Optimal” activities for these functional pathway scores. We hypothesize that Not Optimal scores are associated with irritable bowel syndrome (IBS) and its subtypes (i.e., IBS-Constipation, IBS-Diarrhea, IBS-Mixed Type). We show that Not Optimal functional pathway scores are associated with higher odds of IBS or its subtypes within an independent cohort (n= 71,220) using both the Rome IV Diagnostic Questionnaire as well as self-reported phenotypes. Rather than waiting to diagnose IBS after symptoms appear, these functional scores can help to provide early health insights into molecular pathways that may lead to IBS. These molecular endpoints could also assist with measuring the efficacy of practical interventions, developing related algorithms, providing personalized nutritional recommendations, diagnostics, and treatments for gastrointestinal disorders like IBS.

Graphical Abstract
Expression of a mammalian RNA demethylase increases flower number and floral stem branching in Arabidopsis thaliana
Authors: Markel Kasey , Waldburger Lucas M , Shih Patrick
Published: February 2024

RNA methylation plays a central regulatory role in plant biology and is a relatively new target for plant improvement efforts. In nearly all cases, perturbation of the RNA methylation machinery results in deleterious phenotypes. However, a recent landmark paper reported that transcriptome-wide use of the human RNA demethylase FTO substantially increased the yield of rice and potatoes. Here, we have performed the first independent replication of those results and broader transferability of the trait, demonstrating increased flower and fruit count in the model species Arabidopsis thaliana. We also performed RNA-seq of our FTO-transgenic plants, which we analyzed in conjunction with previously-published datasets to detect several previously-recognized patterns in the functional and structural classification of the upregulated and downregulated genes. From these, we present mechanistic hypotheses to explain these surprising results with the goal of spurring more widespread interest in this promising new approach to plant engineering.
50,000 years of Evolutionary History of India: Insights from ~2,700 Whole Genome Sequences
Authors: Kerdoncuff Elise , Skov Laurits , Patterson Nick , Zhao Wei , Lueng Yuk Yee , Schellenberg Gerard D , Smith Jennifer A , Dey Sharmistha , Ganna Andrea , Dey AB , Kardia Sharon L.R , Lee Jinkook , Moorjani Priya
Published: February 2024

India has been underrepresented in whole genome sequencing studies. We generated 2,762 high coverage genomes from India - including individuals from most geographic regions, speakers of all major languages, and tribal and caste groups - providing a comprehensive survey of genetic variation in India. With these data, we reconstruct the evolutionary history of India through space and time at fine scales. We show that most Indians derive ancestry from three ancestral groups related to ancient Iranian farmers, Eurasian Steppe pastoralists and South Asian hunter-gatherers. We uncover a common source of Iranian-related ancestry from early Neolithic cultures of Central Asia into the ancestors of Ancestral South Indians (ASI), Ancestral North Indians (ANI), Austro-asiatic-related and East Asian-related groups in India. Following these admixtures, India experienced a major demographic shift towards endogamy, resulting in extensive homozygosity and identity-by-descent sharing among individuals. At deep time scales, Indians derive around 1-2% of their ancestry from gene flow from archaic hominins, Neanderthals and Denisovans. By assembling the surviving fragments of archaic ancestry in modern Indians, we recover ~1.5 Gb (or 50%) of the introgressing Neanderthal and ~0.6 Gb (or 20%) of the introgressing Denisovan genomes, more than any other previous archaic ancestry study. Moreover, Indians have the largest variation in Neanderthal ancestry, as well as the highest amount of population-specific Neanderthal segments among worldwide groups. Finally, we demonstrate that most of the genetic variation in Indians stems from a single major migration out of Africa that occurred around 50,000 years ago, with minimal contribution from earlier migration waves. Together, these analyses provide a detailed view of the population history of India and underscore the value of expanding genomic surveys to diverse groups outside Europe.
Inverted encoding of neural responses to audiovisual stimuli reveals super-additive multisensory enhancement
Authors: Buhmann Zak , Robinson Amanda K. , Mattingley Jason B. , Rideaux Reuben
Published: February 2024

A central challenge for the brain is how to combine separate sources of information from different sensory modalities to optimally represent objects and events in the external world, such as combining someone’s speech and lip movements to better understand them in a noisy environment. At the level of individual neurons, audiovisual stimuli often elicit super-additive interactions, where the neural response is greater than the sum of auditory and visual responses. However, investigations using electroencephalography (EEG) to record brain activity have revealed inconsistent interactions, with studies reporting a mix of super- and sub-additive effects. A possible explanation for this inconsistency is that standard univariate analyses obscure multisensory interactions present in EEG responses by overlooking multivariate changes in activity across the scalp. To address this shortcoming, we investigated EEG responses to audiovisual stimuli using inverted encoding, a population tuning approach that uses multivariate information to characterise feature-specific neural activity. Participants (n = 41) completed a spatial localisation task for both unisensory stimuli (auditory clicks, visual flashes) and combined audiovisual stimuli (spatiotemporally congruent clicks and flashes). To assess multivariate changes in EEG activity, we used inverted encoding to recover stimulus location information from event-related potentials (ERPs). Participants localised audiovisual stimuli more accurately than unisensory stimuli alone. For univariate ERP analyses we found an additive multisensory interaction. By contrast, multivariate analyses revealed a super-additive interaction ∼180 ms following stimulus onset, such that the location of audiovisual stimuli was decoded more accurately than that predicted by maximum likelihood estimation. Our results suggest that super-additive integration of audiovisual information is reflected within multivariate patterns of activity rather than univariate evoked responses.
Molecular chaperone BiP controls activity of the ER stress sensor Ire1 through interactions with its oligomers
Authors: Dawes Sam , Hurst Nicholas , Grey Gabriel , Wieteska Lukasz , Wright Nathan V. , Manfield Iain W. , Hussain Mohammed H. , Kalverda Arnout P. , Lewandowski Jozef R. , Chen Beining , Zhuravleva Anastasia
Published: February 2024

The complex multistep activation cascade of Ire1 involves changes in the Ire1 conformation and oligomeric state. Ire1 activation enhances ER folding capacity, in part by overexpressing the ER Hsp70 molecular chaperone BiP; in turn, BiP provides tight negative control of Ire1 activation. This study demonstrates that BiP regulates Ire1 activation through a direct interaction with Ire1 oligomers. Particularly, we demonstrated that the binding of Ire1 luminal domain (LD) to unfolded protein substrates not only trigger conformational changes in Ire1-LD that favour the formation of Ire1-LD oligomers but also exposes BiP binding motifs, enabling the molecular chaperone BiP to directly bind to Ire1-LD in an ATP-dependent manner. These transient interactions between BiP and two short motifs in the disordered region of Ire1-LD are reminiscent of interactions between clathrin and another Hsp70, cytoplasmic Hsc70. BiP binding to substrate-bound Ire1-LD oligomers enables unfolded protein substrates and BiP to synergistically and dynamically control Ire1-LD oligomerisation, helping to return Ire1 to its deactivated state when an ER stress response is no longer required.
Microbial community assembly during aging of food waste-derived hydrochar: key bacterial guilds mediate nutrient dynamics
Authors: Ruan Yang , Wang Ziyan , Tan Shiyong , Xu Hao , Wang Liyue , Ren Lixuan , Liu Zhipeng , Guo Shiwei , Shen Qirong , Xu Guohua , Ling Ning
Published: February 2024

Hydrochar aging may mitigate the adverse effects of direct application on plant growth. However, little is known about the strategies for accelerating this process and the microbiological mechanisms involved. This study explored the effects of three strategies, including the additions of straw and efficient-degrading microorganisms, on the aging processes of food waste-derived hydrochar, and the key microbial drivers. The bacterial and fungal community compositions in hydrochar were estimated at different aging periods (i.e., day 1, 7, 14 and 35) using 16S and ITS rRNA gene sequencing. The results showed that straw and microbial inoculum addition improved the temperature and shortened the aging time by ~30%. Three bacterial guilds, mainly including Bacillus-like species, were identified that had significant correlations with the nitrogen (N) and phosphorus (P) dynamics during aging. This study demonstrates the feasibility of manipulating key microbial guilds artificially to achieve efficient harmless-treatment of hydrochar.
Transinfection of Wolbachia wAlbB into Culex quinquefasciatus mosquitoes does not alter vector competence for Hawaiian avian malaria (Plasmodium relictum GRW4)
Authors: Kilpatrick A. Marm , Seidl Christa M. , Ipsaro Isaiah J. , Garrison Chris E. , Fabbri Giulia , Howell Paul I , McGowan Austin G. , White Bradley J. , Mitchell Sara N.
Published: February 2024

Avian malaria is expanding upslope with warmer temperatures and driving multiple species of Hawaiian birds towards extinction. Methods to reduce malaria transmission are urgently needed to prevent further declines. Releasing Wolbachia-infected incompatible male mosquitoes suppress mosquito populations and releasing Wolbachia-infected female mosquitoes could reduce pathogen transmission if the Wolbachia strain reduced vector competence. We cleared Culex quinquefasciatus of their natural Wolbachia pipientis wPip infection and transinfected them with Wolbachia wAlbB isolated from Aedes albopictus. We show that wAlbB infection was transmitted transovarially, and demonstrate cytoplasmic incompatibility with wild-type mosquitoes infected with wPip from Oahu and Maui, Hawaii. We measured vector competence for avian malaria, Plasmodium relictum, lineage GRW4, of seven mosquito lines (two with wAlbB; three with natural wPip infection, and two cleared of Wolbachia infection) by allowing them to feed on canaries infected with recently collected field isolates of Hawaiian P. relictum. We tested 73 groups (Ntotal = 1176) of mosquitoes for P. relictum infection in abdomens and disseminated (thorax) infections 6-14 days after feeding across a range of parasitemias from 0.028% to 2.49%, and a smaller subset of salivary glands. We found no measurable effect of Wolbachia on any endpoint, but strong effects of parasitemia, days post feeding, and mosquito strain on both abdomen infection prevalence and disseminated infection prevalence. These results suggest that releasing male wAlbB-infected C. quinquefasciatus mosquitoes could suppress wPip-infected mosquito populations, but would have little positive or negative impact on mosquito vector competence for P. relictum if wAlbB became established in local mosquito populations. More broadly, the lack of Wolbachia effects on vector competence we observed highlights the variable impacts of both native and transfected Wolbachia infections in mosquitoes.
Delineating the Effective Use of Self-Supervised Learning in Single-Cell Genomics
Authors: Richter Till , Bahrami Mojtaba , Xia Yufan , Fischer David S. , Theis Fabian J.
Published: February 2024

Self-supervised learning (SSL) has emerged as a powerful method for extracting meaningful representations from vast, unlabeled datasets, already transforming computer vision and natural language processing. Similarly, in single-cell genomics (SCG), representation learning is well-recognized for offering insights into complex biological data, even more so by the advent of early foundation model approaches. However, despite these advancements, identifying scenarios in SCG where SSL outperforms traditional supervised or unsupervised learning methods remains a nuanced challenge. Furthermore, selecting the most effective pretext tasks within the SSL framework for SCG is a critical yet unresolved question. Here, we address this gap by adapting and benchmarking SSL techniques in SCG, including masked autoencoders with multiple masking strategies and contrastive learning approaches. Trained on over 20 million cells, this study rigorously examines multiple downstream tasks, including cell type prediction, gene expression reconstruction, cross-modality prediction, and data integration. Our empirical analyses underscore the nuanced role of SSL, namely in transfer learning scenarios leveraging auxiliary data or analyzing novel datasets. Masked autoencoders excel over contrastive methods in SCG, diverging from computer vision trends. Moreover, our findings reveal notable capabilities of SSL in zero-shot cell type prediction and offer insights into its potential benefits in cross-modality prediction and data integration. In summary, we study the application of SSL in SCG, minimizing model bias through simple, fully connected networks, and benchmark SSL's utility across key representation learning scenarios.
Functional brain imaging predicts population-level visits to urban spaces
Authors: Kaur Ardaman , Rodrigues Andre Leite , Hoogstraten Sarah , Blanco-Mora Diego Andres , Miranda Bruno , Morgado Paulo , Meshi Dar
Published: February 2024

Urbanization is increasing around the world, and urban development strategies focusing on sustainability and the welfare of urban residents are needed. In response to this need, the field of neurourbanism has emerged, which leverages research on the human brain to understand and predict the influence of urban environments. For example, studying brain regions involved in reward processing and value-based decision making, such as the ventromedial prefrontal cortex (vmPFC), may help us understand how people interact with and navigate through urban environments. In this study, we aimed to ascertain whether neural activity within the vmPFC can predict population-level visits around the urban spaces of a city – in our case, Lisbon, Portugal. We used the density of photographs taken around Lisbon as a proxy measure of these visits. To do this, we created a stimulus set featuring 160 images of Lisbon sourced from the social media platform, Flickr. Then, study participants in the U.S. who had never visited Lisbon, viewed these images while we recorded their brain activity. We found that in our sample, activity in the vmPFC predicted the density of photographs taken around Lisbon, and hence, the population-level visits. Our research highlights the crucial role of the brain, especially reward-related brain regions, in shaping human behavior within urban environments. By shedding light on the neural mechanisms underlying urban behavior in humans, our research opens exciting possibilities for the future of urban planning. With this knowledge, policymakers and urban planners can potentially design cities that can promote well-being, social interaction, and sustainable living.
Cortical beta oscillations map to shared brain networks modulated by dopamine
Authors: Chikermane Meera , Weerdmeester Liz , Rajamani Nanditha , Köhler Richard M. , Merk Timon , Vanhoecke Jonathan , Horn Andreas , Neumann Wolf-Julian
Published: February 2024

Brain rhythms can facilitate neural communication for the maintenance of brain function. Beta rhythms (13–35 Hz) have been proposed to serve multiple domains of human ability, including motor control, cognition, memory and ewmotion, but the overarching organisational principles remain unknown. To uncover the circuit architecture of beta oscillations, we leverage normative brain data, analysing over 30 hours of invasive brain signals from 1772 channels from cortical areas in epilepsy patients, to demonstrate that beta is the most distributed cortical brain rhythm. Next, we identify a shared brain network from beta dominant areas with deeper brain structures, like the basal ganglia, by mapping parametrised oscillatory peaks to whole-brain functional and structural MRI connectomes. Finally, we show that these networks share significant overlap with dopamine uptake as indicated by positron emission tomography. Our study suggests that beta oscillations emerge in cortico-subcortical brain networks that are modulated by dopamine. It provides the foundation for a unifying circuit-based conceptualisation of the functional role of beta activity beyond the motor domain and may inspire an extended investigation of beta activity as a feedback signal for closed-loop neurotherapies for dopaminergic disorders.
Phylochemical mapping of natural products onto the plant tree of life using text mining and large language models.
Authors: Busta Lucas , Hall Drew , Johnson Braidon , Schaut Madelyn , Hanson Caroline M. , Gupta Anika , Gondrum Megan , Wang Yuer , Maeda Hiroshi
Published: February 2024

Plants produce a staggering array of chemicals that are the basis for organismal function and diversity and also provide essential human nutrients and medicine. However, it is poorly defined how these compounds have evolved and are distributed across the diverse lineages of the plant kingdom, hindering a systematic view and understanding of plant chemical diversity. Recent advances in plant genome/transcriptome sequencing have provided a well-defined molecular phylogeny of plants, on which the presence of diverse natural products can be mapped to systematically determine their phylogenetic distribution. Here, we built a proof-of-concept workflow via which previously reported diverse tyrosine-derived plant natural products were mapped on to the plant tree of life. Plant chemical-species associations were mined from literature, filtered, evaluated through manual inspection of over 2,500 scientific articles, and mapped onto the plant phylogeny. The resulting 'phylochemical' map confirmed several highly lineage-specific compound class distributions, such as betalain pigments and Amaryllidaceae alkaloids. The map also highlighted several lineages enriched in dopamine-derived compounds, including the orders Caryophyllales, Liliales, and Fabales. Additionally, the application of large language models using our manually curated data as a ground truth set showed that post-mining manual processing steps can largely be automated with a low false positive rate. Our study demonstrates that a workflow combining text mining with language model-based processing can generate broader phylochemical maps, which will serve as a critical community resource to uncover key evolutionary events that underlie plant chemical diversity and enable system-level views of nature's millions of years of chemical experimentation.
miR858a-encoded peptide, miPEP858a, interacts with miR858a promoter and requires C-terminus for the associated functions
Authors: Gautam Himanshi , Sharma Ashish , Anyatama Anwesha , Trivedi Prabodh Kumar
Published: February 2024

MicroRNAs (miRNAs) play a crucial role in regulating gene expression as processed products of primary miRNAs (pri-miRNAs). Recent studies suggest that certain pri-miRNAs encode miRNA-encoded Peptides (miPEPs), influencing miRNA function. Despite this emerging insight, molecular mechanisms and the specific domain or essential amino acid residues required for the functionality of these miPEPs have yet to be explored. Here, we report that the pri-miR858a-encoded peptide, miPEP858a, interacts with the promoter region of the MIR858 gene and its C-terminal region consisting of 14 amino acid residues is indispensable for its functionality. DNA-protein interaction through Yeast-one-hybrid and ChIP-qPCR analysis revealed that miPEP858 interacts with specific region in the MIR858 promoter. An exogenous application of a truncated peptide, the C-terminal region, resulted in enhanced expression and related phenotypic effects, similar to complete miPEP858. Furthermore, the C-terminal region of miPEP858a complemented mutant plants lacking miPEP858, highlighting their regulatory role in miR858a expression and associated target genes, impacting flavonoid biosynthesis and plant development. These findings suggest that full-length miPEP858a may not be essential for its functionality. Identifying functional domains of other peptides offers promise, potentially reducing synthesis costs for application in crop plants and avoiding laborious biotechnological approaches to enhance agronomic traits.
Nuclear pore complexes undergo Nup221 exchange during blood stage asexual replication of Plasmodium parasites.
Authors: Blauwkamp James A , Ambekar Sushma V , Hussain Tahir , Mair Gunnar R , Beck Josh R , Absalon Sabrina
Published: February 2024

Plasmodium parasites, which are the causative agents of malaria, undergo closed mitosis without breakdown of the nuclear envelope. Unlike the closed mitosis in yeast, P. berghei parasites undergo multiple rounds of asynchronous nuclear divisions in a shared cytoplasm result in a multinucleated (8-24) organism prior to formation of daughter cells within an infected red blood cell. During this replication process, intact nuclear pore complexes (NPCs) and their component nucleoporins are likely to play critical roles in parasite growth, facilitating selective bi-directional nucleocytoplasmic transport and genome organization. Here we utilize ultrastructure expansion microscopy (U-ExM) to investigate P. berghei Nup138, Nup221, and Nup313 at the single nucleus level throughout the 24 hour blood-stage replication cycle. Our findings reveal that these Nups are evenly distributed around the nuclei and organized in a rosette structure previously undescribed around the centriolar plaque, which is responsible for intranuclear microtubule nucleation during mitosis. We also detect an increased number of NPCs compared with previously reported, highlighting the power of U-ExM. By adapting the recombination-induced tag exchange (RITE) system to P. berghei, we provide evidence of NPC maintenance, demonstrating Nup221 turnover during parasite asexual replication. Our data shed light on the distribution of NPCs and their homeostasis during the blood-stage replication of P. berghei parasites. Further studies into the nuclear surface of these parasites will allow for a better understanding of parasites nuclear mechanics and organization.
The ABA Receptor Antagonist Antabactin Restores Germination of Thermoinhibited Lettuce
Authors: Eckhardt James , Cutler Sean
Published: February 2024

Germination is critical to agricultural productivity because low germination rates and/or asynchronous germination negatively affect stand establishment and subsequent yields. Exposure to high temperatures during seed imbibition can decrease both germination synchrony and rates through an ABA-mediated process called thermoinhibition. Methods to reduce thermoinhibition would be agriculturally valuable, particularly with increasing global mean temperatures. Lettuce seed germination is particularly sensitive to high temperatures and is a classic system for studying thermoinhibition. Extensive evidence using mutants and carotenoid biosynthetic inhibitors (e.g. fluridone) has demonstrated that endogenous abscisic acid (ABA) biosynthesis is required for thermoinhibition in lettuce and Arabidopsis. In principle, ABA biosynthetic inhibitors could be used to block thermoinhibition, but carotenoid biosynthetic inhibitors are not well-suited for this application due to their herbicidal effects and current hydroxamate ABA biosynthetic inhibitors lack potency. Here we explore the potential of ABA receptor antagonism to disrupt thermoinhibition using Antabactin (ANT), a broad spectrum high-affinity receptor antagonist. We show low uM ANT treatments (10uM) during seed imbibition reduce thermoinhibition at temperatures of up to 40C, demonstrating that ABA signaling is required for thermoinhibition. We further explored interactions between ANT and seed priming, which is used commercially to improve seed germination and reduce thermoinhibition and is achieved by partial hydration and subsequent desiccation of seeds. We show that primed lettuce seeds have improved germination rates at high temperatures, consistent with previous observations; moreover, seeds primed in the presence of ANT show further increases in germination at elevated temperatures, showing that the two treatments can be combined to improve lettuce seed germination. Our data demonstrate that ABA antagonists are candidate agrochemicals for mitigating the effects of high temperature on seed germination and stand establishment that may be of increasing importance due to climate change.
Transcriptomic Dissection of the AMF-Solanum melongenaInteraction: Unveiling Molecular Secrets
Authors: Jha Subhesh Saurabh , Songachan L.S.
Published: February 2024

Fungus-based biofertilizers, in particular, have been shown to improve plant growth and health by providing essential nutrients and improving soil health. Arbuscular mycorrhizal fungi (AMF) form mutualistic symbiotic relationships with plants, including those in the Solanaceae family. They colonize the root systems of plants and aid in enhancing nutrient absorption efficiency, particularly in phosphorus-deficient soils. The present study was carried out to study the interaction betweenSolanum melongenaL. withGlomus macrocarpumandFunneliformis mosseae(formely known asGlomus mosseae) at transcript level. In this study a total of 365 transcripts were upregulated (>1.5x) folds inS. melongenain response to both the fungi, while 44 transcripts were upregulated only in response toG. macrocarpumand 28 transcripts were upregulated only in response toF. mosseae. Similarly, 49 transcripts were downregulated less than −1.5 folds in response to both the fungi while 78 were downregulated only in response to theG. macrocarpumand 36 were downregulated only in response toF. mosseae.

KEGG pathway analysis ofS. melongenatreated withG. macrocarpumrevealed carbon metabolism, cofactor biosynthesis and Endocytosis as the dominant metabolic pathway, while analysis of theF. mosseaetreatment revealed Glycerophospholipid and Endocytosis metabolism as dominant metabolic pathways.