bluuebunny/crossref_metadata_2025 huggingface dataset:
A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimer’s Disease
Authors: Jin Mengmeng , Ma Ziyuan , Dang Rui , Zhang Haiwei , Kim Rachael , Xue Haipeng , Pascual Jesse , Finkbeiner Steven , Head Elizabeth , Liu Ying , Jiang Peng
Published: March 2024

While challenging, identifying individuals displaying resilience to Alzheimer’s disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline. Furthermore, DS individuals are at an increased risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Recent studies indicate that somatic mutations in hematopoietic cells may lead to resilience to neurodegeneration. Microglia, derived from hematopoietic lineages, play a central role in AD etiology. We therefore hypothesize that microglia carrying the somatic mutations associated with DS myeloid leukemia may impart resilience to AD. Using CRISPR-Cas9 gene editing, we introduce a trisomy 21-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-basedin vitromicroglia culture andin vivohuman microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses microglial type-1 interferon signaling, independent of trisomy 21 genetic background. This mutation reduces neuroinflammation and enhances phagocytic and autophagic functions, thereby ameliorating senescent and dystrophic phenotypes in human microglia. Moreover, the CSF2RB A455D mutation promotes the development of a unique microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity in chimeric mouse brains where human microglia largely repopulate the hippocampus. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize and replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest that hPSC-derived CSF2RB A455D microglia could be employed to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need to deplete endogenous diseased microglia prior to cell transplantation.
Investigating the Role and Regulation of GPNMB in Progranulin-deficient Macrophages
Authors: Gillett Drew A. , Neighbarger Noelle K. , Cole Cassandra , Wallings Rebecca L. , Tansey Malú Gámez
Published: March 2024

Progranulin is a holoprotein that is critical for successful aging, and insufficient levels of progranulin are associated with increased risk for developing age-related neurodegenerative diseases like AD, PD, and FTD. Symptoms can vary widely, but a uniting feature among these different neurodegenerative diseases is prodromal peripheral immune cell phenotypes. However, there remains considerable gaps in the understanding of the function(s) of progranulin in immune cells, and recent work has identified a novel target candidate called GPNMB. We addressed this gap by investigating the peritoneal macrophages of 5-6-month-oldGrnKO mice, and we discovered that GPNMB is actively increased as a result of insufficient progranulin and that MITF, a transcription factor, is also dysregulated in progranulin-deficient macrophages. These findings highlight the importance of early-stage disease mechanism(s) in peripheral cell populations that may lead to viable treatment strategies to delay disease progression at an early, prodromal timepoint and extend therapeutic windows.
Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominantCRXretinopathy models
Authors: Zheng Yiqiao , Stormo Gary D , Chen Shiming
Published: March 2024

Paired-class homeodomain transcription factors (HD TFs) play essential roles in vertebrate development, and their mutations are linked to human diseases. One unique feature of paired-class HD is cooperative dimerization on specific palindrome DNA sequences. Yet, the functional significance of HD cooperative dimerization in animal development and its dysregulation in diseases remain elusive. Using the retinal TF Cone-rod Homeobox (CRX) as a model, we have studied how blindness-causing mutations in the paired HD, p.E80A and p.K88N, alter CRX's cooperative dimerization, lead to gene misexpression and photoreceptor developmental deficits in dominant manners. CRXE80Amaintains binding at monomeric WT CRX motifs but is deficient in cooperative binding at dimeric motifs. CRXE80A's cooperativity defect impacts the exponential increase of photoreceptor gene expression in terminal differentiation and produces immature, non-functional photoreceptors in theCrxE80Aretinas. CRXK88Nis highly cooperative and localizes to ectopic genomic sites with strong enrichment of dimeric HD motifs. CRXK88N's altered biochemical properties disrupt CRX's ability to direct dynamic chromatin remodeling during development to activate photoreceptor differentiation programs and silence progenitor programs. Our study here providesin vitroandin vivomolecular evidence that paired-class HD cooperative dimerization regulates neuronal development and dysregulation of cooperative binding contributes to severe dominant blinding retinopathies.
Changes in the senescence profile and immune checkpoints in HIV-infected individuals after COVID-19
Authors: Crespo-Bermejo Celia , Brochado-Kith Óscar , Grande-García Sergio , Lara-Aguilar Violeta , Llamas-Adán Manuel , Arca-Lafuente Sonia , Martín-Carbonero Luz , de los Santos Ignacio , Jiménez Sousa M Ángeles , Resino Salvador , Berenguer Juan , Madrid Ricardo , Fernández-Rodríguez Amanda , Briz Verónica
Published: March 2024

Background

Both SARS-CoV-2 and HIV infection exhibit alterations in the senescence profile and immune checkpoint (IC) molecules. However, the midterm impact of SARS-CoV-2 on these profiles in people with HIV (PWH) remains unclear. This study aimed to evaluate differences in plasma biomarker levels related to ICs, the senescence-associated secretory phenotype (SASP), and pro- and anti-inflammatory cytokines in PWH following recovery from SARS-CoV-2 infection.

Methods

We conducted a cross-sectional study of 95 PWH receiving antiretroviral therapy, stratified by SARS-CoV-2 infection status: a) 48 previously infected (HIV/SARS) and b) 47 controls without previous infection (HIV). Plasma biomarkers (n=44) were assessed using Procartaplex Multiplex Immunoassays. Differences were analyzed using a generalized linear model adjusted for sex and ethnicity and corrected for the false discovery rate. Significant values were defined as an adjusted arithmetic mean ratio ≥1.2 or ≤0.8 and a qvalue<0.1. Spearman correlation evaluated relationships between plasma biomarkers (significant correlations, rho≥0.3 and q value<0.1).

Results

The median age of the PWH was 45 years, and 80% were men. All SARS-CoV-2-infected PWH experienced symptomatic infection; 83.3% had mild symptomatic infection, and sample collection occurred at a median of 12 weeks postdiagnosis. The HIV/SARS group showed higher levels of ICs (CD80, PDCD1LG2, CD276, PDCD1, CD47, HAVCR2, TIMD4, TNFRSF9, TNFRSF18, and TNFRSF14), SASP (LTA, CXCL8, and IL13), and inflammatory plasma biomarkers (IL4, IL12B, IL17A, CCL3, CCL4, and INF1A) than did the HIV group.

Conclusions

SARS-CoV-2 infection in PWH causes significant midterm disruptions in plasma ICs and inflammatory cytokine levels, highlighting SASP-related factors, which could be risk factors for the emergence of complications in PWH.
Distinct changes to hippocampal and medial entorhinal circuits emerge across the progression of cognitive deficits in epilepsy
Authors: Feng Yu , Diego Keziah S. , Dong Zhe , Wick Zoé Christenson , Page-Harley Lucia , Page-Harley Veronica , Schnipper Julia , Lamsifer Sophia I. , Pennington Zachary T. , Vetere Lauren M. , Philipsberg Paul A. , Soler Ivan , Jurkowski Albert , Rosado Christin J. , Khan Nadia N. , Cai Denise J. , Shuman Tristan
Published: March 2024

Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneousin vivoelectrophysiology in hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within MEC and between HPC-MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.
Development and application of GlycanDIA workflow for glycomic analysis
Authors: Xie Yixuan , Liu Xingyu , Zhao Chenfeng , Chen Siyu , Wang Shunyang , Lin Zongtao , Robison Faith M. , George Benson M. , Flynn Ryan A. , Lebrilla Carlito B. , Garcia Benjamin A.
Published: March 2024

Glycans modify protein, lipid, and even RNA molecules to form the regulatory outer coat on cells called the glycocalyx. The changes in glycosylation have been linked to the initiation and progression of many diseases. Thus, while the significance of glycosylation is well established, a lack of accessible methods to characterize glycans has hindered the ability to understand their biological functions. Mass spectrometry (MS)-based methods have generally been at the core of most glycan profiling efforts; however, modern data-independent acquisition (DIA), which could increase sensitivity and simplify workflows, has not been benchmarked for analyzing glycans. Herein, we developed a DIA-based glycomic workflow, termed GlycanDIA, to identify and quantify glycans with high sensitivity and accuracy. The GlycanDIA workflow combined higher energy collisional dissociation (HCD)-MS/MS and staggered windows for glycomic analysis, which facilitates the sensitivity in identification and the accuracy in quantification compared to conventional data-dependent acquisition (DDA)-based glycomics. To facilitate its use, we also developed a generic search engine, GlycanDIA Finder, incorporating an iterative decoy searching for confident glycan identification and quantification from DIA data. The results showed that GlycanDIA can distinguish glycan composition and isomers fromN-glycans,O-glycans, and human milk oligosaccharides (HMOs), while it also reveals information on low-abundant modified glycans. With the improved sensitivity, we performed experiments to profileN-glycans from RNA samples, which have been underrepresented due to their low abundance. Using this integrative workflow to unravel theN-glycan profile in cellular and tissue glycoRNA samples, we found that RNA-glycans have specific forms as compared to protein-glycans and are also tissue-specific differences, suggesting distinct functions in biological processes. Overall, GlycanDIA can provide comprehensive information for glycan identification and quantification, enabling researchers to obtain in-depth and refined details on the biological roles of glycosylation.

Graphical Abstract
Detection of oat crown rust disease in Taiwan (2019-2021)
Authors: Ho Chung-Ying , Henningsen Eva C , Chen Ssu-Tung , Ariyawansa Hiran A. , Nazareno Eric S. , Sperschneider Jana , Dodds Peter N. , Riddle Jakob , Kianian Shahryar F. , Figueroa Melania , Huang Yung-Fen
Published: March 2024

Oat is a minor forage crop grown in Taiwan. Only a few historical records of oat rust disease have been reported in the country, therefore the pathogen population remains poorly characterized. A rust-like disease outbreak was detected at the Experimental Farm of National Taiwan University in 2019, which caused significant damage to the field experiments. To determine the identity of the pathogen responsible for this disease outbreak, we collected infected foliar material. Disease signs suggested infection by the oat crown rust fungus. Hence, common procedures in rust pathology were applied to confirm the identity of the pathogen with phenotypic and molecular diagnostic techniques. A total of 50 field samples from infected oat cultivars were collected in 2019 and five rust isolates were purified in 2020 and 2021. Phylogenetic analysis based on ITS sequences indicated that the pathogen was likelyPuccinia coronataf. sp.avenae(Pca), which was further supported by the placement of Taiwanese isolate NTU-01 with otherPcarepresentatives in a phylogenetic tree of Basidiomycete fungi. Phenotyping assays across 36 oat differential lines demonstrated that Taiwanese isolates are phenotypically similar with relatively limited virulence. This study presents the first molecular confirmation ofPcain Taiwan and reports the virulence profiles of TaiwanesePcapopulation.
Automated high-throughput profiling of single-cell total transcriptome with scComplete-seq
Authors: Dinçaslan Fatma Betül , Ngang Shaun Wei Yang , Tan Rui Zhen , Cheow Lih Feng
Published: March 2024

Detecting the complete portrait of the transcriptome is essential to understanding the roles of both polyadenylated and non-polyadenylated RNA species. However, current efforts to investigate the heterogeneity of the total cellular transcriptome in single cells are limited by the lack of an automated, high-throughput assay that can be carried out on existing platforms. To address this issue, we developed scComplete-seq, a method that can easily augment existing high-throughput droplet-based single-cell mRNA sequencing to provide additional information on the non-polyadenylated transcriptome. Using scComplete-seq, we have successfully detected long and short non-polyadenylated RNAs at single-cell resolution, including cell-cycle-specific histone RNAs, cell-type-specific short non-coding RNA, as well as enhancer RNAs in cancer cells and PBMCs. By applying scComplete-seq, we have identified changes in both coding and non-coding transcriptome in PBMCs during different stimulations. Measuring the enhancer RNA expression also revealed the activation of specific biological processes and the transcription factors regulating such changes.
Interoceptive disruption in functional neurological disorder: a multimodal brain imaging study
Authors: Sojka Petr , Serranová Tereza , Khalsa Sahib S. , Perez David L. , Diez Ibai
Published: March 2024

This multimodal brain imaging study investigated functional MRI (fMRI) neural processing of cardiac interoceptive signals in 38 patients with functional neurological disorder (FND) compared to 38 healthy controls (HCs). Additionally, we characterized how brain fMRI responses during heartbeat counting (interoception) vs. tone counting (exteroception) or rest related to grey matter volume, interoceptive awareness, and psychopathology scores. For both interoception vs. rest and interoception vs. exteroception contrasts, principal component analyses showed that principal component 1 (PC1) as derived from all study participants was comprised primarily of salience, ventral attention and sensorimotor network co-activations, along with default mode and visual processing network co-deactivations. Compared to HCs, patients with FND showed reduced contribution to these PC1 co-activation/co-deactivations patterns in both interoception vs. exteroception and interoception vs. rest contrasts; only the interoception vs. exteroception between-group fMRI findings held adjusting for depression/anxiety scores, antidepressant use and FND subtype. For the interoception vs. rest contrast, increasingly negative PC1 contribution scores positively correlated with decreased cingulate gyrus volumes and increased psychopathology scores. This multimodal brain imaging study underscores a role for salience and default-mode networks in the pathophysiology of FND, and sets the stage for comprehensive research efforts further contextualizing the mechanistic importance of altered interoception in patients with FND.
Flies tune the sensitivity of their multifunctional gyroscope
Authors: Verbe Anna , Lea Kristianna M. , Fox Jessica L. , Dickerson Bradley H.
Published: March 2024

Locomotion requires navigating unpredictable and complex environments, demanding both stability and maneuverability within short timeframes. This is particularly important for flying insects, and the true flies (Diptera) stand out among this group for their impressive flight capabilities. Flies’ aerial abilities are partially attributed to halteres, tiny club-shaped structures that evolved from the hindwings and play a crucial role in flight control. Halteres oscillate during flight, in antiphase with the wings, providing rhythmic input to the wing steering systemviaarrays of embedded mechanosensors called campaniform sensilla. These sensor arrays convey timing information to the wing steering muscles, but linking haltere sensor location to sensor activity and the functional organization of the wing steering system remains a central challenge. Here, we usein vivocalcium imaging during tethered flight to obtain population-level recordings of the haltere sensory afferents in specific fields of sensilla. We find that haltere feedback is continuously modulated by visual stimuli to stabilize flight. Additionally, this feedback is present during saccades and help flies actively maneuver. We also find that the haltere’s multifaceted role arises from the steering muscles of the haltere itself, regulating haltere stroke amplitude to modulate campaniform activity. Taken together, our results underscore the crucial role of biomechanics in regulating the dynamic range of sensors and provide insight into how the sensory and motor systems of flies coevolved.

Abstract Figure
The dynamic genomes of Hydra and the anciently active repeat complement of animal chromosomes
Authors: Kon-Nanjo Koto , Kon Tetsuo , Koubkova Yu Tracy Chih-Ting , Rodriguez-Terrones Diego , Falcon Francisco , Martinez Daniel E. , Steele Robert E. , Tanaka Elly Margaret , Holstein Thomas W , Simakov Oleg
Published: March 2024

Many animal genomes are characterized by highly conserved chromosomal homologies that pre-date the ancient origin of this clade. Despite such conservation, the evolutionary forces behind the retention, expansion, and contraction of chromosomal elements, and the resulting macro-evolutionary implications, are unknown. Here we present a comprehensive stem-cell resolved genomic and transcriptomic study of the fresh-water cnidarian Hydra, an animal characterized by its high regenerative capacity, the ability to propagate clonally, and an apparent lack of aging. Using single-haplotype telomere-to-telomere genome assemblies of two recently diverged hydra strains, we show how the macro-evolutionary history of chromosomal elements is shaped by both old and recent transposable element (TE) expansions. Unique features of hydra biology allowed us to compare the individual genomes of hydra's three stem cell lineages. We show that distinct TE families are active at both transcriptional and genomic levels via non-random insertions in the genomes of each of these lineages. In transcriptomes, over 14,000 transcripts were composed of nearly complete TE sequences, and further classification into families, subfamilies, and individual loci reveals cell type-specific TE expression. The active TEs include elements that differentially contribute to changes in the genome size as well as persistent structural variants around loci associated with cell proliferation. Our study reveals 14 active TE families that primarily act in this role and are predominantly composed of DNA elements. Evolutionary analysis revealed that these families constitute a highly conserved TE core in eukaryotic and metazoan genomes. Our results suggest an ancient role for these core TEs as self-renewing genomic components that persist beyond ancient chromosomal homologies.
Electrophysiological signatures of a developmental delay in a stem cell model ofKCNQ2developmental and epileptic encephalopathy
Authors: Rosa Filip , Theiss Stephan , Krepp Susanne , Loeffler Heidi , Mendes Dulini , Klingenstein Stefanie , Liebau Stefan , Weckhuysen Sarah , Alber Michael , Petrou Steven , Lerche Holger , Maljevic Snezana , Wuttke Thomas V
Published: March 2024

Background

KCNQ2, encoding KV7.2 ion channels, has emerged as one of the prominent genes causing early onset seizures with developmental delay (KCNQ2developmental and epileptic encephalopathy;KCNQ2-DEE).KCNQ2 de novoloss-of-function (LOF) and associated neuronal hyperexcitability have been accepted as mechanisms contributing to seizures. To investigate the developmental impact ofKCNQ2LOF, we generated patient iPSC-derived models for two previously reportedde novovariants, p.(Arg325Gly) and p.(Gly315Arg), linked to severe congenital DEE.

Methods

Functional investigation of the two variants was initially performed inXenopus laevisoocyte system. Patient-derived iPSC lines were differentiated using NGN2- and embryoid body-based protocols yielding neurons roughly corresponding to mid- and mid-late gestational stages, respectively. KV7- mediated M-current, passive neuronal properties, action potential generation and spontaneous oscillatory network activities were analysed with whole-cell patch clamping.

Findings

Studied KCNQ2 variants showed LOF with a dominant-negative effect in the heterologous system. Reduced M-currents in patient iPSC-derived neurons corroborated a LOF as the main pathomechanism. Interestingly, this led to the reduced neuronal firing of the early neurons and to a disruption of complex oscillatory activity, with significantly reduced duration and amplitude of these events in patient iPSC-derived neurons.

Interpretation

We provide experimental evidence for changing roles of the M-current throughout development and place disease variant-mediated M-current reduction in the context of the neuronal maturation in the prenatal brain. Based on the reduced neuronal firing and disrupted oscillatory activity seen in patient iPSC-derived neurons, we propose that a delayed/impaired maturation of neuronal and network properties underliesKCNQ-DEE caused by LOF variants.
A vector system for single and tandem expression of cloned genes and multi-colour fluorescent tagging inHaloferax volcanii
Authors: Ithurbide Solenne , de Silva Roshali T. , Brown Hannah J. , Shinde Vinaya , Duggin Iain G.
Published: March 2024

Archaeal cell biology is an emerging field expected to identify fundamental cellular processes, help resolve the deep evolutionary history of cellular life, and contribute new components and functions in biotechnology and synthetic biology. To facilitate these, we have developed plasmid vectors that allow convenient cloning and production of proteins and fusion proteins with flexible, rigid, or semi-rigid linkers in the model archaeonHaloferax volcanii. For protein subcellular localization studies using fluorescent protein (FP) tags, we created vectors incorporating a range of codon-optimized fluorescent proteins for N- or C-terminal tagging, including GFP, mNeonGreen, mCherry, YPet, mTurquoise2 and mScarlet-I. Obtaining functional fusion proteins can be challenging with proteins involved in multiple interactions, mainly due to steric interference. We demonstrated the use of the new vector system to screen for improved function in cytoskeletal protein FP fusions, and identified FtsZ1-FPs that are functional in cell division and CetZ1-FPs that are functional in motility and rod cell development. Both the type of linker and the type of FP influenced the functionality of the resulting fusions. The vector design also facilitates convenient cloning and tandem expression of two genes or fusion genes, controlled by a modified tryptophan-inducible promoter, and we demonstrated its use for dual-colour imaging of tagged proteins inH. volcaniicells. These tools should promote further development and applications of archaeal molecular and cellular biology and biotechnology.
Scalable design of repeat protein structural dynamics via probabilistic coarse-grained models
Authors: Sarvaharman Seeralan , Neary Timon E. , Gorochowski Thomas E. , Parmeggiani Fabio
Published: March 2024

Computational protein design has emerged as a powerful tool for creating proteins with novel functionalities. However, most existing methods ignore structural dynamics even though they are known to play a central role in many protein functions. Furthermore, methods like molecular dynamics that are able to simulate protein movements are computationally demanding and do not scale for the design of even moderately sized proteins. Here, we develop a probabilistic coarse-grained model to overcome these limitations and support the design of the structural dynamics of modular repeat proteins. Our model allows us to rapidly calculate the probability distribution of structural conformations of large modular proteins, enabling efficient screening of design candidates based on features of their dynamics. We demonstrate this capability by exploring the design landscape of 4–6 module repeat proteins. We assess the flexibility, curvature and multi-state potential of over 65,000 protein variants and identify the roles that particular modules play in controlling these features. Although our focus here is on protein design, the methods developed are easily generalised to any modular structure (e.g., DNA origami), offering a means to incorporate dynamics into diverse biological design workflows.
Convergent gene expression in endometrial epithelial cells illuminates the evolution of uterine receptivity
Authors: Brulport Axelle , Gazda Małgorzata Anna , Liorzou Eulalie , Daunesse Maëlle , Raquillet Bruno , Lepelletier Anthony , Sopena-Rios Maria , Raliou Mariam , Regnard Pierrick , Fellmann Lyne , Faccin Lucie , Garbit Slaveia , Cermolacce Alexia , Kondova Ivanela , Marcellin Louis , Abo Carole , Doridot Ludivine , Berthelot Camille
Published: March 2024

The epithelium of the uterine endometrium is the first maternal interface encountered by the embryo, and plays crucial roles in the maternal-embryonic crosstalk necessary to embryo implantation. Mechanisms of embryo implantation are highly variable between mammals: humans and mice have convergently evolved similar embryo implantation phenotypes, where the embryo embeds in the maternal mucosa, which differs from the ancestral mammalian and primate phenotypes. This phenomenon is thought to be partly controlled by maternal epithelial receptivity signals during the window of implantation. Here, we combined endometrial epithelial organoid models and single-cell transcriptomics to investigate how gene expression has evolved in endometrial epithelial cells between human, non-human primates and mouse at key time points in the hormonal cycle. We discovered that many maternal genes involved in uterine receptivity and embryo implantation exhibit more similar expression patterns between human and mouse compared to macaque and marmoset. In particular, we show that the endometrial expression ofLIF, a crucial actor of endometrial receptivity in both human and mouse, is likely an evolutionary convergence rather than a conserved feature as previously hypothesised.
Tribus: Semi-automated discovery of cell identities and phenotypes from multiplexed imaging and proteomic data
Authors: Kang Ziqi , Szabo Angela , Farago Teodora , Perez-Villatoro Fernando , Junquera Ada , Shah Saundarya , Launonen Inga-Maria , Anttila Ella , Casado Julia , Elias Kevin , Virtanen Anni , Haltia Ulla-Maija , Färkkilä Anniina
Published: March 2024

Motivation

Multiplexed imaging and single-cell analysis are increasingly applied to investigate the tissue spatial ecosystems in cancer and other complex diseases. Accurate single-cell phenotyping based on marker combinations is a critical but challenging task due to (i) low reproducibility across experiments with manual thresholding, and, (ii) labor-intensive ground-truth expert annotation required for learning-based methods.

Results

We developed Tribus, an interactive knowledge-based classifier for multiplexed images and proteomic datasets that avoids hard-set thresholds and manual labeling. We demonstrated that Tribus recovers fine-grained cell types, matching the gold standard annotations by human experts. Additionally, Tribus can target ambiguous populations and discover phenotypically distinct cell subtypes. Through benchmarking against three similar methods in four public datasets with ground truth labels, we show that Tribus outperforms other methods in accuracy and computational efficiency, reducing runtime by an order of magnitude. Finally, we demonstrate the performance of Tribus in rapid and precise cell phenotyping with two large in-house whole-slide imaging datasets.

Availability

Tribus is available athttps://github.com/farkkilab/tribusas an open-source Python package.
Algebraic structures emerge from the self-supervised learning of natural sounds
Authors: Orhan Pierre , Boubenec Yves , King Jean-Remi
Published: March 2024

Humans can spontaneously detect complex algebraic structures. Historically, two opposing views explain this ability, at the root of language and music acquisition. Some argue for the existence of an innate and specific mechanism, like “merge” (Chomsky) or “neural recursion” (Dehaene). Others argue that this ability emerges from experience (e.g. Bates): i.e. when generic learning principles continuously process sensory inputs. These two views, however, remain difficult to test experimentally. Here, we use deep learning models to evaluate the factors that lead to the spontaneous detection of algebraic structures in the auditory modality. Specifically, we train multiple deep learning models with a variable amount of natural sounds and a self-supervised learning objective. We then expose these models to the experimental paradigms classically used to evaluate the processing of algebraic structures. Like humans, these models spontaneously detect repeated sequences, probabilistic chunks and complex algebraic structures. Also like humans, this ability diminishes with structure complexity. Importantly, this ability can emerge from experience alone: the more the models are exposed to natural sounds, the more they spontaneously detect increasingly complex structures. Finally, this ability does not emerge in models pretrained only on speech, and emerges more rapidly in models pretrained with music than environmental sounds. Overall, our study provides an operational framework to clarify sufficient built-in and acquired principles that model human’s advanced capacity to detect algebraic structures in sounds.

Significance Statement

Experimentalists have repeatedly observed a human advantage in the detection of algebraic structures, notably through auditory paradigms. This ability to detect structure is thought to be key to the emergence of complex cognitive operations. Yet, it remains debated if this ability is discovered or innate in the form of a specific mechanism. In this article, the authors show how a model progressively and spontaneously learns to detect auditory structure. The model replicate several experimental findings but only under certain developmental conditions. Notably, exposition to music or environmental sounds, but not speech, is sufficient for the emergence of algebraic structure detection. As a result, this work proposes self-supervised learning as a developmental model of abstract cognitive abilities.
tstrait: a quantitative trait simulator for ancestral recombination graphs
Authors: Tagami Daiki , Bisschop Gertjan , Kelleher Jerome
Published: March 2024

Ancestral recombination graphs (ARGs) encode the ensemble of correlated genealogical trees arising from recombination in a compact and efficient structure, and are of fundamental importance in population and statistical genetics. Recent breakthroughs have made it possible to simulate and infer ARGs at biobank scale, and there is now intense interest in using ARG-based methods across a broad range of applications, particularly in genome-wide association studies (GWAS). Sophisticated methods exist to simulate ARGs using population genetics models, but there is currently no software to simulate quantitative traits directly from these ARGs. To apply existing quantitative trait simulators users must export genotype data, losing important information about ancestral processes and producing prohibitively large files when applied to the biobank-scale datasets currently of interest in GWAS. We presenttstrait, an open-source Python library to simulate quantitative traits on ARGs, and show how this user-friendly software can quickly simulate phenotypes for biobank-scale datasets on a laptop computer.

Availability and Implementation

tstraitis available for download on the Python Package Index. Full documentation with examples and workflow templates is available onhttps://tskit.dev/tstrait/docs/, and the development version is maintained on GitHub (https://github.com/tskit-dev/tstrait).

Contact

daiki.tagami@hertford.ox.ac.uk
Oligonucleotide insecticides (contact unmodified antisense DNA biotechnology) and RNA biocontrols (double-stranded RNA technology): newly born fraternal twins in plant protection
Authors: Oberemok V.V. , Gal’chinsky N.V.
Published: March 2024

The rapid development of molecular genetics, methods of synthesis of nucleic acids, and bioinformatics have created fundamentally new opportunities in plant protection. DNA and RNA have become active ingredients of insecticides, going beyond their usual role as carriers of hereditary information. Now nucleic acids are increasingly acting as active tools for insect pest control using the mechanisms of DNA containment (oligonucleotide insecticides, contact unmodified antisense DNA (CUAD) biotechnology) and RNA interference (RNA biocontrols, double-stranded RNA biotechnology). Partial understanding of how antisense DNA oligonucleotides might work began in the late 1970s of XX century and for a long time (until the beginning of the XXI century) these biomolecules had not been implemented in plant protection in the form of any biotechnology based on unmodified or modified DNA fragments. RNA interference was discovered in the late 90s of XX century and also went through quite a long path of development in plant protection before the first encouraging results of its application as insecticides appeared. Both, CUAD biotechnology and double-stranded RNA technology aim to inactivate the expression of genes of insect pests using antisense DNA and double-stranded RNA that help trigger degradation of the target RNA. As two new classes of the next-generation insecticides, these products are supposed to have long operational life, low carbon footprint, high selectivity in action and rapid biodegradation in ecosystems. To date, antisense CUAD biotechnology shows the best results on sap-sucking insects while double-stranded RNA technology shows the best insecticidal potential on beetles from Tenebrionidae and Chrysomelidae families. With a high probability, oligonucleotide insecticides and RNA biocontrols, will be effective against certain groups of insects and can complement each other in complex formulations for control of wide range of pests.
Chronic IL-6 overproduction induces a tolerogenic response in aged mice after peripheral nerve injury
Authors: Manich Gemma , Barbanti Ruggero , Peris Marta , Villacampa Nàdia , Almolda Beatriz , González Berta , Castellano Bernardo
Published: March 2024

Highlights/Main points

Astrocyte-targeted IL-6 overproduction during aging increases basal microglial acivation in the facial nucleus.

During aging, chronic IL-6 overproduction does not modify microglial response after peripheral nerve injury but increases T-lymphocyte infiltration.

Chronic IL-6 overproduction in aged mice does not modify facial motor neuron survival after facial nerve axotomy.

Interleukin-6 (IL-6) is the main cytokine controlling neuroinflammation and microglial activation during aging, and the increase of IL-6 levels correlate well with chronic neuroinflammation and age-related neurodegenerative diseases. Despite the relevance of IL-6 in these conditions, the effect of this cytokine in microglia activation and neuroinflammation upon CNS injuries during aging has been scarcely explored. Previous results from our group showed that adult and aged transgenic mice with astrocyte-targeted overproduction of IL-6 (GFAP-IL6Tg) presented features of a primed microglial phenotype in basal conditions compared to wild-type (WT) mice, and that after CNS lesions, microglia showed and exacerbated response associated with increased neuronal death in adult mice. In this work, we aimed to study whether chronic IL-6 overproduction influenced microglia response to CNS injury during aging. With this aim, we performed facial nerve axotomy (FNA) in aged 21-23-month-old WT and GFAP-IL6Tg animals, and analysed facial motor neuron (FMN) survival, glial reactivity, antigen presentation, and lymphocyte infiltration both at basal conditions (non-lesioned) and after FNA. Our results showed that non-lesioned aged transgenic mice presented higher Iba1, CD11b, and CD68 levels than aged WT mice, indicative of a priming effect in the aged facial nucleus. After FNA, we detected similar levels of microglial and astroglia activation, but a remarkable increase in T-lymphocyte infiltration in GFAP-IL6Tg axotomized group. Despite slight differences in the neuroinflammatory response, aged GFAP-IL6Tg animals showed a similar rate of FMN death compared to aged WT mice. Overall, our work shows that transgenic IL-6 overproduction induces a primed microglial phenotype under basal conditions in aged animals, with a reduced fold-increase in the microglial response after FNA compared to aged WT mice and similar lesion outcomes, suggestive of a tolerant microglial phenotype. This study suggests a tolerant effect of chronic IL-6 overproduction in microglia during aging in basal conditions and after CNS lesions.
Differences in Protein Capture by SP3 and SP4 Demonstrate Mechanistic Insights of Proteomics Clean-up Techniques
Authors: Conforti Jessica M. , Ziegler Amanda M. , Worth Charli S. , Nambiar Adhwaitha M. , Bailey Jacob T. , Taube Joseph H. , Gallagher Elyssia S.
Published: March 2024

The goal of proteomics experiments is to identify proteins to observe changes in cellular processes and diseases. One challenge in proteomics is the removal of contaminants following protein extraction, which can limit protein identification. Single-pot, solid-phase-enhanced sample preparation (SP3) is a clean-up technique in which proteins are captured on carboxylate-modified particles through a proposed hydrophilic-interaction-liquid-chromatography (HILIC)-like mechanism. However, recent results have suggested that proteins are captured in SP3 due to a protein-aggregation mechanism. Thus, solvent precipitation, single-pot, solid-phase-enhanced sample preparation (SP4) is a newer clean-up technique that employs protein-aggregation to capture proteins without modified particles. SP4 has previously enriched low-solubility proteins, though differences in protein capture could affect which proteins are detected and identified. We hypothesize that the mechanisms of capture for SP3 and SP4 are distinct. Herein, we assess the proteins identified and enriched using SP3 versus SP4 for MCF7 subcellular fractions and correlate protein capture in each method to protein hydrophobicity. Our results indicate that SP3 captures more hydrophilic proteins through a combination of HILIC-like and protein-aggregation mechanisms, while SP4 captures more hydrophobic proteins through a protein-aggregation mechanism. From these results, we recommend clean-up techniques based on protein-sample hydrophobicity to yield high proteome coverage in biological samples.
Enabling Greenhouse Gas Emission Reduction while Improving Rice Yield with a Methane-Derived Microbial Biostimulant
Authors: Kumar Sarma Rajeev , David Einstein Mariya , Pavithra Gangigere Jagadish , Sajith Gopalakrishnan Kumar , Lesharadevi Kuppan , Akshaya Selvaraj , Bassavaraddi Chavaddi , Navyashree Gopal , Arpitha Panakanahalli Shivaramu , Sreedevi Padmanabhan , Zainuddin Khan , Saiyyeda Firdous , Babu Bondalakunta Ravindra , Prashanth Muralidhar Udagatti , Ravikumar Ganesan , Basavaraj Palabhanvi , Kumar Chavana Sandeep , Kumar Vinod Munisanjeeviah Lakshmi Devi , Parthasarathi Theivasigamani , Subbian Ezhilkani
Published: March 2024

Rice is a vital crop for food security and human nutrition, yet its cultivation produces ∼11% of total global anthropogenic methane (CH4) emissions - the second most important greenhouse gas (GHG). Modifications to rice management practice are necessary, both to increase yield and mitigate GHG emissions. We investigated the effect of a methane-derived microbial biostimulant on grain yield and GHG emissions from rice fields. Applications of microbial biostimulant resulted in significant enhancement of grain yield, even under different nitrogen management, with consistent reduction in GHG emissions. The study further outlines a potential mechanism for broad and diverse positive effects of microbial biostimulant on the paddy crop including in photosynthesis, tillering and panicle development. Observations from the study will help stakeholders and policy makers, leverage biological solutions like methane-derived microbial biostimulant to improve crop yield and address food security, while reducing anthropogenic CH4 emissions to meet targets agreed at COP26.
Testing realistic SO(10) SUSY GUTs with proton decay and gravitational waves
Authors: Fu Bowen , King Stephen F. , Marsili Luca , Pascoli Silvia , Turner Jessica , Zhou Ye-Ling
Published: March 2024

We present a comprehensive analysis of a supersymmetric SO(10) grand unified theory, which is broken to the Standard Model via the breaking of two intermediate symmetries. The spontaneous breaking of the first intermediate symmetry, B−L, leads to the generation of cosmic strings and right-handed neutrino masses and further to an observable cosmological background of gravitational waves and generation of light neutrino masses via type-I seesaw mechanism. Supersymmetry breaking manifests as sparticle masses below the B−L breaking but far above the electroweak scale due to proton decay limits. This naturally pushes the B−L breaking scale close to the grand unified theory scale, leading to the formation of metastable cosmic strings, which can provide a gravitational wave spectrum consistent with the recent pulsar timing arrays observation. We perform a detailed analysis of this model using two-loop renormalization group equations, including threshold corrections, to determine the symmetry-breaking scale consistent with the recent pulsar timing arrays signals such as NANOGrav 15-year data and testable by the next-generation limits on proton decay from Hyper-K and JUNO. Simultaneously, we find the regions of the model parameter space that can predict the measured quark and lepton masses and mixing, baryon asymmetry of our Universe, a viable dark matter candidate and can be tested by a combination of neutrinoless double beta decay searches and limits on the sum of neutrinos masses.

Published by the American Physical Society
2024
Deep learning insights into cosmological structure formation
Authors: Lucie-Smith Luisa , Peiris Hiranya V. , Pontzen Andrew , Nord Brian , Thiyagalingam Jeyan
Published: March 2024

The evolution of linear initial conditions present in the early Universe into extended halos of dark matter at late times can be computed using cosmological simulations. However, a theoretical understanding of this complex process remains elusive; in particular, the role of anisotropic information in the initial conditions in establishing the final mass of dark matter halos remains a long-standing puzzle. Here, we build a deep learning framework to investigate this question. We train a three-dimensional convolutional neural network to predict the mass of dark matter halos from the initial conditions, and quantify in full generality the amounts of information in the isotropic and anisotropic aspects of the initial density field about final halo masses. We find that anisotropies add a small, albeit statistically significant amount of information over that contained within spherical averages of the density field about final halo mass. However, the overall scatter in the final mass predictions does not change qualitatively with this additional information, only decreasing from 0.9 dex to 0.7 dex. Given such a small improvement, our results demonstrate that isotropic aspects of the initial density field essentially saturate the relevant information about final halo mass. Therefore, instead of searching for information directly encoded in initial conditions anisotropies, a more promising route to accurate, fast halo mass predictions is to add approximate dynamical information based e.g. on perturbation theory. More broadly, our results indicate that deep learning frameworks can provide a powerful tool for extracting physical insight into cosmological structure formation.

Published by the American Physical Society
2024
Quantum Monte Carlo algorithm for arbitrary spin-1/2 Hamiltonians
Authors: Barash Lev , Babakhani Arman , Hen Itay
Published: March 2024

We present a universal parameter-free quantum Monte Carlo (QMC) algorithm designed to simulate arbitrary spin-1/2 Hamiltonians. To ensure the convergence of the Markov chain to equilibrium for every conceivable case, we devise a clear and simple automated protocol that produces QMC updates that are provably ergodic and satisfy detailed balance. We demonstrate the applicability and versatility of our method by considering several illustrative examples, including the simulation of the XY model on a triangular lattice, the toric code, and random k-local Hamiltonians.

Published by the American Physical Society
2024
Dicke Superradiance in Ordered Arrays of Multilevel Atoms
Authors: Masson Stuart J. , Covey Jacob P. , Will Sebastian , Asenjo-Garcia Ana
Published: March 2024

In inverted atomic ensembles, photon-mediated interactions give rise to Dicke superradiance, a form of many-body decay that results in a rapid release of energy as a photon burst. While originally studied in pointlike ensembles, this phenomenon persists in extended ordered systems if the interparticle distance is below a certain bound. Here, we investigate Dicke superradiance in a realistic experimental setting using ordered arrays of alkaline-earth(-like) atoms, such as strontium and ytterbium. Such atoms offer exciting new opportunities for light-matter interactions, as their internal structure allows for trapping at short interatomic distances compared to their long-wavelength transitions, providing the potential for collectively enhanced dissipative interactions. Despite their intricate electronic structure, we show that two-dimensional arrays of these atomic species should exhibit many-body superradiance for achievable lattice constants. Moreover, superradiance effectively “closes” transitions, such that multilevel atoms become more two-level like. This occurs because the avalanchelike decay funnels the emission of most photons into the dominant transition, overcoming the single-atom decay ratios dictated by their fine structure and Zeeman branching. Our work represents an important step in harnessing alkaline-earth atoms as quantum optical sources and as platforms to explore many-body dissipative dynamics.

Published by the American Physical Society
2024