bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Developmental Lead and Phthalate Exposures on DNA Methylation in Adult Mouse Blood, Brain, and Liver Identifies Tissue- and Sex-Specific Changes with Implications for Genomic Imprinting
Authors: Morgan Rachel K. , Wang Kai , Svoboda Laurie K. , Rygiel Christine A. , Lalancette Claudia , Cavalcante Raymond , Bartolomei Marisa S. , Prasasya Rexxi , Neier Kari , Perera Bambarendage P.U. , Jones Tamara R , Colacino Justin A. , Sartor Maureen A. , Dolinoy Dana C.
Published: October 2023

Background

Maternal exposure to environmental chemicals can cause adverse health effects in offspring. Mounting evidence supports that these effects are influenced, at least in part, by epigenetic modifications.

Objective

We examined tissue- and sex-specific changes in DNA methylation (DNAm) associated with human-relevant lead (Pb) and di(2-ethylhexyl) phthalate (DEHP) exposure during perinatal development in cerebral cortex, blood, and liver.

Methods

Female mice were exposed to human relevant doses of either Pb (32ppm) via drinking water or DEHP (5 mg/kg-day) via chow for two weeks prior to mating through offspring weaning. Whole genome bisulfite sequencing (WGBS) was utilized to examine DNAm changes in offspring cortex, blood, and liver at 5 months of age. Metilene and methylSig were used to identify differentially methylated regions (DMRs). Annotatr and Chipenrich were used for genomic annotations and geneset enrichment tests of DMRs, respectively.

Results

The cortex contained the majority of DMRs associated with Pb (69%) and DEHP (58%) exposure. The cortex also contained the greatest degree of overlap in DMR signatures between sexes (n = 17 and 14 DMRs with Pb and DEHP exposure, respectively) and exposure types (n = 79 and 47 DMRs in males and females, respectively). In all tissues, detected DMRs were preferentially found at genomic regions associated with gene expression regulation (e.g., CpG islands and shores, 5’ UTRs, promoters, and exons). An analysis of GO terms associated with DMR-containing genes identified imprinted genes to be impacted by both Pb and DEHP exposure. Of these,GnasandGrb10contained DMRs across tissues, sexes, and exposures. DMRs were enriched in the imprinting control regions (ICRs) ofGnasandGrb10, with 15 and 17 ICR-located DMRs across cortex, blood, and liver in each gene, respectively. The ICRs were also the location of DMRs replicated across target and surrogate tissues, suggesting epigenetic changes these regions may be potentially viable biomarkers.

Conclusions

We observed Pb- and DEHP-specific DNAm changes in cortex, blood, and liver, and the greatest degree of overlap in DMR signatures was seen between exposures followed by sex and tissue type. DNAm at imprinted control regions was altered by both Pb and DEHP, highlighting the susceptibility of genomic imprinting to these exposures during the perinatal window of development.
DASH-CAM: Dynamic Approximate SearcH Content Addressable Memory for genome classification
Authors: Jahshan Zuher , Merlin Itay , Garzón Esteban , Yavits Leonid
Published: October 2023

We propose a novel dynamic storage-based approximate search content addressable memory (DASH-CAM) for computational genomics applications, particularly for identification and classification of viral pathogens of epidemic significance. DASH-CAM provides 5.5× better density compared to state-of-the-art SRAM-based approximate search CAM. This allows using DASH-CAM as a portable classifier that can be applied to pathogen surveillance in low-quality field settings during pandemics, as well as to pathogen diagnostics at points of care. DASH-CAM approximate search capabilities allow a high level of flexibility when dealing with a variety of industrial sequencers with different error profiles. DASH-CAM achieves up to 30% and 20% higherF1score when classifying DNA reads with 10% error rate, compared to state-of-the-art DNA classification tools MetaCache-GPU and Kraken2 respectively. Simulated at 1GHz, DASH-CAM provides 1, 178× and 1, 040× average speedup over MetaCache-GPU and Kraken2 respectively.

CCS CONCEPTS

•Hardware→Bio-embedded electronics.
Microbially Driven Reversible Actuation and Color Changing Materials
Authors: Kuang Hui Yan , Bonanno Shanna , Chang Wei-Ting , Bower Duncan Q. , Pratt Violet M. , Zerkowski Jillian , Scaperdas Nicholas , Young Lindsey A. , Wilson Daniel J. , Deravi Leila F. , Joshi Neel S.
Published: October 2023

A common feature of natural living systems that is underexplored in the field of engineered living materials (ELMs) is macroscale mechanical actuation, as driven by active cellular processes. Here we demonstrate an ELM whereinEscherichia colidrives the reversible swelling and de-swelling actuation of a pH-responsive hydrogel by producing or consuming acidic metabolites. We covalently incorporated a novel synthetic pH indicator dye into the hydrogel network that complements the hydrogel actuation with coordinated color change. Acid production or consumption is controlled by media composition and multiple hydrogel form factors are explored. This approach represents a new form of biologically driven actuation that could be compatible with a range of responsive hydrogel applications.
Vive la difference: why, how, and what trait combinations improve functional community ecology
Authors: Engler Alexandra , Fraser Dylan J. , Peres-Neto Pedro
Published: October 2023

Analyses of functional trait variation across ecological communities offer valuable insights into the factors that influence and predict trait composition, deepening our understanding of community structure. These analyses also shed light on patterns of trait dispersion, including underdispersion and overdispersion, which are often linked to the mechanisms underlying community assembly. However, striking a balance between characterizing complex phenotypes through the integration of comprehensive set of traits while ensuring the preservation of the distinct signals of overdispersion and underdispersion can pose significant challenges. This is because some trait combinations can result in high functional dispersion or overdispersion, while others may lead to underdispersion within the same community. In this study, we provide a rationale for the importance of trait selection in community ecology and develop a framework that optimizes patterns of functional trait variation among communities. We explored the responses of six trait sets along large-scale environmental gradients, using ∼700 lake-fish communities in Ontario (Canada). We started by adopting the conventional approaches of combining all traits as well as leveraging prior knowledge in fish biology to group traits that are functionally related (Diet, Morphology, Temperature Preference). We contrasted these approaches with a novel computational method to select combinations of traits that maximise overdispersion and minimise underdispersion. We found that separating traits according to their functions or by their patterns revealed signals in communities that appeared random when all the traits were pooled together. Combining our computational approach with environmental models revealed that functional patterns could be very well explained by multiple environmental predictors (model R2 up to 0.7). Our study also outlines future selection procedures to further uncover more complex patterns of species associations based on their traits.
Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations
Authors: Zhou Yufan , Li Tian , Choppavarapu Lavanya , Jin Victor X.
Published: October 2023

An integration of 3D chromatin structure and gene expression at single-cell resolution has yet been demonstrated. Here, we develop a computational method, a multiomic data integration (MUDI) algorithm, which integrates scHi-C and scRNA-seq data to precisely define the 3D-regulated and biological-context dependent cell subpopulations or topologically integrated subpopulations (TISPs). We demonstrate its algorithmic utility on the publicly available and newly generated scHi-C and scRNA-seq data. We then test and apply MUDI in a breast cancer cell model system to demonstrate its biological-context dependent utility. We found the newly defined topologically conserved associating domain (CAD) is the characteristic single-cell 3D chromatin structure and better characterizes chromatin domains in single-cell resolution. We further identify 20 TISPs uniquely characterizing 3D-regulated breast cancer cellular states. We reveal two of TISPs are remarkably resemble to high cycling breast cancer persister cells and chromatin modifying enzymes might be functional regulators to drive the alteration of the 3D chromatin structures. Our comprehensive integration of scHi-C and scRNA-seq data in cancer cells at single-cell resolution provides mechanistic insights into 3D-regulated heterogeneity of developing drug-tolerant cancer cells.
Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma
Authors: Li Zhuxuan , Zhuang Xueqian , Pan Chun-Hao , Yan Yan , Thummalapalli Rohit , Hallin Jill , Torborg Stefan , Singhal Anupriya , Chang Jason C. , Manchado Eusebio , Dow Lukas E. , Yaeger Rona , Christensen James G. , Lowe Scott W. , Rudin Charles M. , Joost Simon , Tammela Tuomas
Published: October 2023

Lung adenocarcinoma (LUAD), commonly driven byKRASmutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressingKrasinduced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.

Significance

Treatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy.
Identification of a convergent spinal neuron population that encodes itch
Authors: Sheahan Tayler D. , Warwick Charles A. , Cui Abby Y. , Baranger David A.A. , Perry Vijay J. , Smith Kelly M. , Manalo Allison P. , Nguyen Eileen K. , Koerber H. Richard , Ross Sarah E.
Published: October 2023

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca2+imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal neurons that is defined by the expression of GRPR. Moreover, we discover that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nucleus. Further, we show that nalfurafine, a clinically effective kappa opioid receptor agonist, relieves itch by inhibiting GRPR spinoparabrachial neurons. Finally, we demonstrate that a subset of GRPR spinal neurons show persistent, cell-intrinsic Ca2+oscillations. These experiments provide the first population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.

In brief

Through population imaging, Sheahan et al. identify a network of neurons in the dorsal horn that is activated by pruritogens and find that kappa opioid receptor signaling inhibits itch through the selective inhibition of GRPR spinoparabrachial neurons.

Highlights

Itch-inducing agents drive activity in a common population of GRPR-expressing spinal interneurons

GRPR spinal projection neurons transmit itch from the spinal cord to the brain

Kappa opioids reduce itch through the inhibition of GRPR spinoparabrachial neurons

GRPR activation elicits persistent, intrinsic Ca2+oscillations
Synchrony in Networks of Type 2 Interneurons is More Robust to Noise with Hyperpolarizing Inhibition Compared to Shunting Inhibition in Both the Stochastic Population Oscillator and the Coupled Oscillator Regimes
Authors: Baravalle Roman , Canavier Carmen C.
Published: October 2023

Synchronization in the gamma band (30-80 Hz) is mediated by PV+ inhibitory interneurons, and evidence is accumulating for the essential role of gamma oscillations in cognition. Oscillations can arise in inhibitory networks via synaptic interactions between individual oscillatory neurons (mean-driven) or via strong recurrent inhibition that destabilizes the stationary background firing rate in the fluctuation-driven balanced state, causing an oscillation in the population firing rate. Previous theoretical work focused on model neurons with Hodgkin’s type 1 excitability (integrators) connected by current-based synapses. Here we show that networks comprised of simple type 2 oscillators (resonators) exhibit a supercritical Hopf bifurcation between synchrony and asynchrony and a gradual transition via cycle skipping from coupled oscillators to stochastic population oscillator, as previously shown for type 1. We extended our analysis to homogeneous networks with conductance rather than current based synapses and found that networks with hyperpolarizing inhibitory synapses were more robust to noise than those with shunting synapses, both in the coupled oscillator and stochastic population oscillator regime. Assuming that reversal potentials are uniformly distributed between shunting and hyperpolarized values, as observed in one experimental study, converting synapses to purely hyperpolarizing favored synchrony in all cases, whereas conversion to purely shunting synapses made synchrony less robust except at very high conductance strengths. In mature neurons the synaptic reversal potential is controlled by chloride cotransporters that control the intracellular concentrations of chloride and bicarbonate ions, suggesting these transporters as a potential therapeutic target to enhance gamma synchrony and cognition.

Significance Statement

Brain rhythms in the gamma frequency band (30-80 Hz) depend on the activity of inhibitory interneurons and evidence for a causal role for gamma oscillations in cognitive functions is accumulating. Here we extend previous studies on synchronization mechanisms to interneurons that have an abrupt threshold frequency below which they cannot sustain firing. In addition to current based synapses, we examined inhibitory networks with conductance based synapses. We found that if the reversal potential for inhibition was below the average membrane potential (hyperpolarizing), synchrony was more robust to noise than if the reversal potential was very close to the average potential (shunting). These results have implications for therapies to ameliorate cognitive deficits.
Context dependent multisensory integration: Mechanosensation depends on luminance for robust performance
Authors: Sharma Varun P , Sponberg Simon
Published: October 2023

Multisensory, goal-directed behaviors are ubiquitous and essential in animals across taxa. Individual sensory modalities may be significantly tuned by environmental context, and yet they must continue to combine and produce multisensory behaviors. This necessitates either behavioral robustness or goal-relevant adaptation in sensorimotor systems. In the case of hover-feeding hawkmoths of the speciesManduca sexta, proboscis mechanosensation and vision are known to combine linearly in tracking of moving flowers. This tracking behavior is affected by light-levels, and visual compensation is necessary for robust flower-tracking. Whether the mechanosensory response also adjusts to light-level, in order to produce linear combination across luminance contexts, is not known. We applied control theoretic analyses to study integration of mechanosensory and visual information in flower tracking hawkmoths in the context of high luminance. This was performed using a two-part robotic flower system. Under the conditions of high luminance, we verified the linear combination of mechanosensory and visual systems, and the complementary modulation of these systems. We show that both systems tune their frequency response with changing environmental light level,while keeping their combined error low at relevant frequencies. Thus, the animal adapts to changing conditions, across modalities, even when only one of the modalities (vision) is directly affected. This cross-talk between sensorimotor systems is constrained, and possibly driven, by performance requirements.
DP/MM: A Hybrid Model for Zinc-Protein Interactions in Molecular Dynamics
Authors: Ding Ye , Huang Jing
Published: October 2023

Zinc-containing proteins are essential to a variety of biological processes, yet accurately modeling them using classical force fields is hindered by complicated polarization and charge transfer effects. This study introduces DP/MM, a hybrid force field model that combinesab initioaccuracy with MM-level efficiency for modeling zinc-protein interactions. The DP/MM scheme utilizes a deep potential model to correct the atomic forces of zinc ions and their coordinated atoms, elevating them from MM to QM levels of accuracy. The model is trained on the difference in atomic forces between MM and QM calculations across diverse zinc coordination groups. Simulations on a variety of zinccontaining proteins demonstrate that DP/MM faithfully reproduces their coordination geometry and structural characteristics, for example, the tetrahedral coordination structures for theCys4and theCys3His1groups. Furthermore, DP/MM is capable of handling exchangeable water molecules in the zinc coordination environment. With its unique blend of accuracy, efficiency, flexibility, and transferability, DP/MM not only serves as a valuable tool for studying zinc-containing proteins but also represents a pioneering approach that augments the growing landscape of machine learning potentials in molecular modeling.
Sensory adaptation modulates coding and perceptual quality of odor mixtures
Authors: Pírez Nicolás , Gascue Federico Andrés , Locatelli Fernando Federico
Published: October 2023

The sensitivity of the sensory systems must be dynamic in order to allow animals to adjust their behavior based on experience to optimize detection of relevant information while ignoring stimuli with no predictive value. In this context, one of the main phenomena that modulate the olfactory system is sensory adaptation. It is usually defined as a decrease in the sensitivity or response to a stimulus after a sustained exposure to it. Adaptation may occur in brief intervals of time and depends on the immediate prior experience. Here, we investigate aspects of the function and neurobiology of sensory adaptation in olfaction using the honeybeeApis mellifera. By means of electroantennograms we set stimulation protocols that induced sensory adaptation. We show that activation patterns that encode mixtures of odorants in the antennal lobe are drastically altered after sensory adaptation, favoring the representation of stimuli that are present at sub-threshold concentrations. We investigate the effects that sensory adaptation has on the perception of odorant mixtures and show that adapting animals to one of the components of a binary mixture, reduces the appetitive learning of the adapted stimulus and enhances the detection and learning of the non-adapted stimulus in cases in which it would stay normally occluded. These results suggest that olfactory sensory adaptation is critical to allow detection of minor components present in complex mixtures, emphasizing its role as a fundamental mechanism to improve sensitivity to discrete stimuli.
Remyelination protects neurons from DLK-mediated neurodegeneration
Authors: Duncan Greg J. , Ingram Sam D , Emberley Katie , Hill Jo , Cordano Christian , Abdelhak Ahmed , McCane Michael , Jenks Jennifer E. , Jabassini Nora , Ananth Kirtana , Ferrara Skylar J. , Stedelin Brittany , Sivyer Benjamin , Aicher Sue A. , Scanlan Thomas , Watkins Trent A. , Mishra Anusha , Nelson Jonathan W. , Green Ari J. , Emery Ben
Published: October 2023

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons.

Highlights

Characterization of a transgenic mouse model of demyelination without subsequent remyelination

Remyelination protects neurons from axon loss and neuronal apoptosis

MAPK and c-Jun phosphorylation are increased in mice featuring remyelination failure

DLK is necessary for the apoptosis of chronically demyelinated neurons
Incorporating extrinsic noise into mechanistic modelling of single-cell transcriptomics
Authors: Öcal Kaan
Published: October 2023

A mechanistic understanding of single-cell transcriptomics data requires differentiating between intrinsic, extrinsic and technical noise, but an abundance of the latter often obscures underlying biological patterns. Accurately modelling such data in the presence of large cell-to-cell heterogeneity due to factors such as cell size and cell cycle stage is a challenging task. We propose a tractable, fully Bayesian framework for mechanistic modelling of single-cell RNA sequencing data in the presence of cellular heterogeneity. Applied to murine transcriptomics data, we show that cell-specific effects can significantly alter previously inferred dynamics of individual genes. Our implementation is statistically exact and readily extensible, and we demonstrate how it can be combined with Bayesian model selection to compare various models of gene expression and measurement noise.
A Syndrome of Joint Hypermobility, Autonomic Dysfunction, Gastrointestinal Dysfunction and Autoimmune markers (JAG-A): Clinical Associations and Response to Intravenous Immunoglobulin Therapy
Authors: Pasricha Pankaj J. , McKnight Megan , Villatoro Luisa , Barahona Guillermo , Brinker Jeffrey , Hui Ken , Polydefkis Michael , Burns Robert , McMahan Zsuzsanna H. , Gould Neda , Goodman Brent , Hentz Joseph , Treisman Glenn
Published: October 2023

Background and aims

We examined autoimmunity markers (AIMs) in patients with unexplained gastrointestinal symptoms, their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD) and the response to intravenous immunoglobulin (IVIG).

Methods

The study comprised of three cohorts, consisting of adolescent or adult patients with gastrointestinal symptoms affecting more than one region of the gut who underwent laboratory tests, whole gut transit studies, and autonomic testing. AIM positive patients were defined based on a diagnosis of known rheumatic disease with one positive seromarker of autoimmunity or at least two positive seromarkers. The three cohorts were (a) Retrospective (n = 300); (b) Prospective validation cohort (n =133); and (c) Patients with AIM (n=32) prospectively treated with IVIG and followed with standardized questionnaires.

Results

AIMs were found in 39% of the retrospective cohort, of which the majority had a known rheumatic disorder. In the prospective cohort AIMs were noted in 35% overall but the rate was much higher in patients with JH/HSD (49% versus 21%, p=0.001). Significantly more patients with AIMs had elevations of C-reactive protein and erythrocyte sedimentation rate along with trends in tilt table test and HLADQ8 positivity. IVIG treatment was associated with a significantly greater overall treatment effect than controls and robust improvement over baseline in pain, gastrointestinal and autonomic symptoms.

Conclusions

Autoimmune markers and autonomic dysfunction are common in patients with unexplained gastrointestinal dysmotility, especially in those with joint hypermobility. IVIG treatment was associated with symptomatic improvement in both gastrointestinal and autonomic symptoms. These results need to be corroborated by randomized clinical trials of immunomodulators but suggest that an autoimmune etiology may be important to diagnose in such patients. Clinicaltrials.gov,NCT04859829
Non-obstetric risk factors for deformational plagiocephaly: A systematic review and meta-analysis
Authors: Hillyar Dr Christopher , Bishop Natalie , Bell-Davies Frances J , Ong Juling
Published: October 2023

Plagiocephaly is defined as asymmetrical distortion of the skull resulting in an oblique trapezoid or parallelogram head shape. In the absence of skull growth restriction due to craniosynostosis, deformational plagiocephaly (DP) is caused by deformational forces acting on one side of the back of the head which distorts the normal symmetry of the skull. The aims of this systematic review and meta-analysis were to critically assess the evidence for non-obstetric risk factors for DP and to make evidence-based recommendations for reducing the prevalence of DP. A search of PubMed and Web of Science was performed covering 21 August 2010 to 21 August 2022. The searches yielded 159 articles, of which 18 articles were eligible for inclusion in this study. 43 non-obstetric factors were identified. Of these, a total of 17 factors were associated with DP. With the notable exceptions of maternal age, mechanical ventilation and tummy time, these associations were either supported by non-conflicting evidence or a meta-analysis that resolved conflicting evidence into a significant association. Thirteen factors had significant odds ratios that ranged from 1.10 (mechanical ventilation) to 7.15 (insufficient vitamin D intake). Of the five factors assessed by meta-analysis (male gender, reaching fewer motor milestones by six months of age, maternal education level, head position preference, sleeping position), only one (male gender) was associated with significant inter-study heterogeneity. No evidence of publication bias was detected. In summary, this study provides the most comprehensive meta-analytic assessment of non-obstetric factors associated with DP published to date. It provides 13 evidence-based recommendations which can be adopted by healthcare systems globally, to reduce the prevalence of DP and its impact on child development.
PLASTICITY OF RESPONSE PROPERTIES OF MOUSE VISUAL CORTEX NEURONS INDUCED BY OPTOGENETIC TETANIZATIONIN VIVO
Authors: Osipova A.A. , Smirnov I.V. , Smirnova M.P. , Borodinova A.A. , Volgushev M.A. , Malyshev A.Y.
Published: October 2023

Heterosynaptic plasticity, along with Hebbian homosynaptic plasticity, is an important mechanism ensuring stable operation of learning neuronal networks. However, whether heterosynaptic plasticity occurs in the whole brain in vivo, and what role(s) in brain function in vivo it could play, remains unclear. Here, we used an optogenetics approach to apply a model of intracellular tetanization, which was established and employed to study heterosynaptic plasticity in brain slices, to study plasticity of response properties of neurons in mouse visual cortex in vivo. We show that optogenetically evoked high-frequency bursts of action potentials (optogenetic tetanization) in principal neurons of the visual cortex induce long-term changes of responses to visual stimuli. Optogenetic tetanization had distinct effects on responses to different stimuli: responses to optimal and orthogonal orientations decreased, response to null direction did not change, and responses to oblique orientations increased. As a result, direction selectivity of the neurons decreased, and orientation tuning became broader. Since optogenetic tetanization was a purely postsynaptic protocol, applied in the absence of sensory stimulation, and thus without association of presynaptic activity with bursts of action potentials, the observed changes were mediated by mechanisms of heterosynaptic plasticity. We conclude that heterosynaptic plasticity can be induced in vivo and propose that it may play important homeostatic roles in operation of neural networks by helping to prevent runaway dynamics of responses to visual stimuli and to keep the tuning of neuronal responses within the range optimized for encoding of multiple features in population activity.
Ancient genomes illuminate Eastern Arabian population history and adaptation against malaria
Authors: Martiniano Rui , Haber Marc , Almarri Mohamed A. , Mattiangeli Valeria , Kuijpers Mirte C. M. , Chamel Berenice , Breslin Emily M. , Littleton Judith , Almahari Salman , Aloraifi Fatima , Bradley Daniel G. , Lombard Pierre , Durbin Richard
Published: October 2023

The harsh climate of Arabia has posed challenges in generating ancient DNA from the region, hindering the direct examination of ancient genomes for understanding the demographic processes that shaped Arabian populations. In this study, we report whole genome sequence data obtained from four Tylos-period individuals from Bahrain. Their genetic ancestry can be modelled as a mixture of sources from ancient Anatolia, Levant and Iran/Caucasus, with variation between individuals suggesting population heterogeneity in Bahrain before the onset of Islam. We identify the G6PD Mediterranean mutation associated with malaria-resistance in three out of four ancient Bahraini samples and estimate that it rose in frequency in Eastern Arabia from 5-6 kya onwards, around the time agriculture appeared in the region. Our study provides the first characterisation of the genetic composition of ancient Arabians, shedding light on the population history of Bahrain and demonstrating the feasibility of aDNA studies in the region.
RNA virus-mediated gene editing for tomato trait breeding
Authors: Uranga Mireia , Aragonés Verónica , García Arcadio , Mirabel Sophie , Gianoglio Silvia , Presa Silvia , Granell Antonio , Pasin Fabio , Daròs José-Antonio
Published: October 2023

Virus-induced genome editing (VIGE) is a flexible and robust technology that relies on viral vectors for the transient delivery of CRISPR-Cas components into plants. Tomato (Solanum lycopersicumL.) is a mayor horticultural crop grown worldwide; despite its economic importance, little is known about VIGE applicability in this species.

This study presents the successful use of VIGE in tomato for fruit color breeding. We report (i) the generation of a transgenic Cas9-expressing line of tomato cv. Micro-Tom (MT-Cas9), (ii) the use of pLX-PVX, an enhanced RNA viral vector, for single-guide RNA (sgRNA) delivery into MT-Cas9 plants, (iii) heritable, proof-of-concept VIGE ofPHYTOENE DESATURASEand recovery of albino progeny, and (iv) the recovery of progeny with recoloredgreen-fleshfruits by VIGE ofSTAYGREEN 1, thus confirming the successful breeding of tomato fruit color.

Altogether, our results indicate that the presented VIGE approach can be readily applied for accelerated functional genomics of tomato variation, as well as for precision breeding of tomato traits with horticultural interest.

HIGHLIGHTS

Generation of a transgenic Cas9-expressing line of tomato cv. Micro-Tom

Use of PVX for sgRNA delivery into Micro-Tom Cas9 plants

Heritable proof-of-concept VIGE of tomatoPHYTOENE DESATURASE(PDS)

Recovery of green-flesh fruits by VIGE of tomato STAYGREEN 1 (SGR1)
Bronze Age Northern Eurasian Genetics in the Context of Development of Metallurgy and Siberian Ancestry
Authors: Childebayeva Ainash , Fricke Fabian , Rohrlach Adam Benjamin , Huang Lei , Schiffels Stephan , Vesakoski Outi , Semerau Lena , Aron Franziska , Moiseyev Vyacheslav , Khartanovich Valery , Kovtun Igor , Krause Johannes , Kuzminykh Sergey , Haak Wolfgang
Published: October 2023

The Eurasian Bronze Age (BA) has been described as a period of substantial human migrations, the emergence of pastoralism, horse domestication, and development of metallurgy. This study focuses on individuals associated with BA metallurgical production, specifically the Seima-Turbino (ST) phenomenon (∼2,200-1,900 BCE) associated with elaborate metal objects found across Northern Eurasia. The genetic profiles of nine ST-associated individuals vary widely ranging between ancestries maximized in individuals from the Eastern Siberian Late Neolithic/BA, and those of the Western Steppe Middle Late BA. The genetic heterogeneity observed is consistent with the current understanding of the ST metallurgical network as a transcultural phenomenon. The new data also shed light on the temporal and spatial range of an ancient Siberian genetic ancestry component, which is shared across many Uralic-speaking populations, and which we explore further via demographic modeling using additional genome-wide (2 individuals) and whole genome data (5 individuals, including a ∼30x genome) from northwestern Russia.
Modeling Stereospecific Drug Interactions with Beta-Adrenergic Receptors
Authors: Dawson John R.D. , DeMarco Kevin R. , Han Yanxiao , Bekker Slava , Clancy Colleen E. , Yarov-Yarovoy Vladimir , Vorobyov Igor
Published: October 2023

Beta adrenergic receptors (βARs) are G protein-coupled receptors that control processes as varied as heart rhythm and vascular tone by binding agonists such as norepinephrine to induce downstream signaling pathways. Beta blockers antagonize βARs to downregulate their activity, thus reducing heart rate and lowering vascular tone. We developed new Rosetta structural modeling protocol to develop state-specific models of β1AR, expressed in cardiac myocytes, as well as β2AR, expressed in the smooth muscle cells of vasculature and other tissues, and their atomistic-scale interactions with beta-blockers using RosettaLigand. We identified structural features of drug – receptor interactions, which may account for their receptor conformational state and drug stereospecific preferences. Furthermore, we estimated structural stabilities of our models using atomistic molecular dynamics (MD) simulations. In our recent study we validated our structural models of norepinephrine-bound β2AR and its complex with stimulatory G protein via multi-microsecond MD simulations. Thus, here we mostly focused on state-dependent and stereospecific β1AR interactions with beta-blocking drugs sotalol and propranolol. We observed expected inactive receptor state preferences and structural stabilities of our models in MD simulations, but neither those simulations nor RosettaLigand docking could clearly distinguish stereospecific preferences of those drugs. This warrants consideration of alternative hypotheses and enhanced sampling MD simulations, which we discussed as well. Nevertheless, our study provides basis for understanding conformational state selectivity and stereospecificity of beta-blockers for βARs, important pharmacological targets, and may be extended to other drug classes and receptor types.

Graphical abstract

Norepinephrine (NE) bound active-state beta-1 adrenergic receptor (β1AR) in complex with the stimulatory G protein (Gs) heterotrimer embedded in a lipid bilayer.

When expressed at the plasma membrane, the β1AR is oriented such that the ligand binding pocket (*) is accessible to ligands from the extracellular side (Ex.) of the membrane. The Gsα (red), Gβ (blue), and Gγ (yellow) subunits comprise the Gs heterotrimer. Nucleotides GDP or GTP bind Gα at the P-loop (**).Inset:Representative image of NE bound within the orthosteric ligand binding pocket.
Spores of the fungal pathogenCryptococcusexhibit cell type-specific carbon source utilization during germination
Authors: Ortiz Sébastien C. , McKeon Megan C. , Botts Michael R. , Gage Hunter , Frerichs Anna , Hull Christina M.
Published: October 2023

Spores are critical morphotypes required for long-term survival of most fungi. Under the right environmental conditions, spores can escape dormancy and differentiate into vegetatively growing cells through the process of germination. For fatal human fungal pathogens likeCryptococcus, germination is the key differentiation process required for spores to initiate vegetative growth and ultimately cause disease; however, relatively little is known about the molecular mechanisms that control germination. To this end, we performed an extensive characterization ofCryptococcusspore germination through the morphological assessment of germinating spores, the inhibition of key eukaryotic processes, and the detailed quantification of fungal spore germination kinetics under numerous nutrient conditions. We identified temporal associations between molecular and morphological events and determined that carbon metabolism pathways (both glycolysis and oxidative phosphorylation) were required from the beginning of germination. We further determined that carbon sources are primarily used as fuel rather than as simply triggers of germination ‘commitment,’ and identified spore-specific carbon source utilization that is absent in yeast. Finally, we discovered the first spore-specific enzyme, Nth2, a trehalase that is required for germination when trehalose is the primary available carbon source. Together this work provides an extensive characterization ofCryptococcusspore germination and suggests that germination is more than simply a ‘modified cell cycle’ but is rather a highly adapted differentiation process.
Controlling Genome Topology with Sequences that Trigger Post-replication Gap Formation During Replisome Passage: TheE. coliRRS Elements
Authors: Pham Phuong , Wood Elizabeth A. , Dunbar Emma L. , Cox Michael M. , Goodman Myron F.
Published: October 2023

We report that theEscherichia colichromosome includes novel GC-rich genomic structural elements that trigger formation of post-replication gaps upon replisome passage. The two nearly perfect 222 bp repeats, designated Replication Risk Sequences or RRS, are each 650 kb from the terminus sequencedifand flank the Ter macrodomain. RRS sequence and positioning is highly conserved in enterobacteria. At least one RRS appears to be essential unless a 200 kb region encompassing one of them is amplified. The RRS contain a G-quadruplex on the lagging strand which impedes DNA polymerase extension producing lagging strand ssDNA gaps, ≤2000 bp long, upon replisome passage. Deletion of both RRS elements has substantial effects on global genome structure and topology. We hypothesize that RRS elements serve as topological relief valves during chromosome replication and segregation. There have been no screens for genomic sequences that trigger transient gap formation. Functional analogs of RRS could be widespread, possibly including some enigmatic G-quadruplexes in eukaryotes.
Brassinosteroid recruits FERONIA to safeguard cell expansion in Arabidopsis
Authors: Chaudhary Ajeet , Hsiao Yu-Chun , Yeh Fang-Ling Jessica , Wu Hen-Ming , Cheung Alice Y. , Xu Shou-Ling , Wang Zhi-Yong
Published: October 2023

Plant cell expansion is driven by turgor pressure and regulated by hormones. How plant cells avoid cell wall rupture during hormone-induced cell expansion remains a mystery. Here we show that brassinosteroid (BR), while stimulating cell elongation, promotes the plasma membrane (PM) accumulation of the receptor kinase FERONIA (FER), which monitors cell wall damage and in turn attenuates BR-induced cell elongation to prevent cell rupture. The GSK3-like kinase BIN2 phosphorylates FER, resulting in reduced FER accumulation and translocation from endoplasmic reticulum to PM. By inactivating BIN2, BR signaling promotes dephosphorylation and increases PM accumulation of FER, thereby enhancing the surveillance of cell wall integrity. Our study reveals a vital signaling circuit that coordinates hormone signaling with mechanical sensing to prevent cell bursting during hormone-induced cell expansion.

One-Sentence Summary

Brassinosteroid recruits a cell wall integrity monitor to prevent growth-induced cell wall damage.
Aberrant functional brain network organization is associated with relapse during 1‐year follow‐up in alcohol‐dependent patients
Authors: Böhmer Justin , Reinhardt Pablo , Garbusow Maria , Marxen Michael , Smolka Michael N. , Zimmermann Ulrich S. , Heinz Andreas , Bzdok Danilo , Friedel Eva , Kruschwitz Johann D. , Walter Henrik
Published: October 2023

Alcohol dependence (AD) is a debilitating disease associated with high relapse rates even after long periods of abstinence. Thus, elucidating neurobiological substrates of relapse risk is fundamental for the development of novel targeted interventions that could promote long‐lasting abstinence. In the present study, we analysed resting‐state functional magnetic resonance imaging (rsfMRI) data from a sample of recently detoxified patients with AD (n = 93) who were followed up for 12 months after rsfMRI assessment. Specifically, we employed graph theoretic analyses to compare functional brain network topology and functional connectivity between future relapsers (REL, n = 59), future abstainers (ABS, n = 28) and age‐ and gender‐matched controls (CON, n = 83). Our results suggest increased whole‐brain network segregation, decreased global network integration and overall blunted connectivity strength in REL compared with CON. Conversely, we found evidence for a comparable network architecture in ABS relative to CON. At the nodal level, REL exhibited decreased integration and decoupling between multiple brain systems compared with CON, encompassing regions associated with higher‐order executive functions, sensory and reward processing. Among patients with AD, increased coupling between nodes implicated in reward valuation and salience attribution constitutes a particular risk factor for future relapse. Importantly, aberrant network organization in REL was consistently associated with shorter abstinence duration during follow‐up, portending to a putative neural signature of relapse risk in AD. Future research should further evaluate the potential diagnostic value of the identified changes in network topology and functional connectivity for relapse prediction at the individual subject level.
Milk as an indicator of dietary imbalance
Authors: Lean IJ , Golder HM
Published: October 2023

Background

Milk provides a readily available diagnostic fluid collected daily or more frequently on an individual animal or herd basis. Milk, as an aggregated sample in bulk tank milk (BTM) represents the status of a herd instead of a single animal. In this review, we examine the potential for milk to predict risks to efficient production, reproductive success, and health on the individual cow and herd level.

Findings

For many conditions related to disorders of metabolism including hyperlipdaemia and ketonaemia, improved individual cow milk testing may allow a temporally useful detection of metabolic disorder that can target intervention. However, the extension of these tests to the BTM is made more difficult by the tight temporal clustering of disorder to early lactation and the consequent mixing of cows at even moderately different stages of lactation. Integrating herd recording demographic information with Fourier‐transformed mid‐infrared spectra (FT‐MIR) can provide tests that are useful to identify cows with metabolic disorders. The interpretation of BTM urea and protein content provides useful indications of herd nutrition. These may provide indicators that encourage further investigations of nutritional influences on herd fertility but are unlikely to provide strong diagnostic value. The fat‐to‐protein ratio has a high specificity, but poor sensitivity for detection of fibre insufficiency and acidosis on an individual cow basis. Selenium, zinc, β‐carotene, and vitamin E status of the herd can be determined using BTM.

Conclusions

There appears to be increasing potential for the use of milk as a diagnostic fluid as more in‐parlour tests become available for individual cows. However, the BTM appears to have under‐utilised potential for herd monitoring.
Tax compliance and firm response to electronic sales monitoring
Authors: Boyer M. Martin , d'Astous Philippe
Published: October 2023

This paper analyzes how firms respond to an Internet of Things technology that reduces significantly the tax authorities' marginal cost of monitoring firm activity. More precisely, we analyze how mandating every restaurant of a single Canadian province to have sales recording modules (SRMs) affects restaurant sales, expenses and profits. We estimate that SRMs increase reported sales by 5.8% to 9.8% on average and that this increase is almost completely offset by an equal increase in expenses, including wages. As a result, the firms' taxable income remains mostly unchanged. Our results suggest that sales tax remittance enforcement at the firm level spills over to other firm stakeholders, such as employees and suppliers. Overall, the one‐time cost of the device needed to monitor sales more efficiently is small compared with the recurring benefits for tax authorities.
Vaping among young people—Our best defence is self‐defence
Authors: Stockings Emily A. , Gardner Lauren A. , Newton Nicola C.
Published: October 2023

Use of electronic cigarettes (e‐cigarettes or ‘vapes’) has risen rapidly among young Australians in recent years. To combat this, on 2 May 2023, the Albanese Government announced a suite of reforms to reduce the desirability and accessibility of e‐cigarettes to young people—including a ban on disposable e‐cigarettes, restricting flavours, colours and nicotine content and requiring pharmaceutical‐like packaging. While many have welcomed this announcement, the efficacy of such reforms in reducing the availability of e‐cigarettes to young people remain to be seen, particularly given the current prescription‐only model has done little to curb youth vaping. We argue that, in an uncertain landscape where e‐cigarettes will likely remain accessible and desirable to young people, it is critical that we also upskill, empower and arm our young people with the skills, resilience, resources and knowledge to make informed and positive health decisions so that: (i) fewer young people opt to take up vaping (primary prevention); and (ii) among those who already do vape, more seek help earlier on to reduce or cease their use before dependency develops (secondary prevention). Schools are an ideal setting for the delivery of these programs, where they can be delivered en masse, integrated into existing alcohol and other drug programs and aligned with school curricula. Skills‐based school prevention programs have demonstrated significant and sustained reductions in drug‐related harms up to 7 years post‐intervention. For as long as vapes remain widely available, desirable and purposefully marketed towards young people, we believe our best defence is self‐defence.