bluuebunny/crossref_metadata_2025 huggingface dataset:
Social drivers of health in communicative outcomes of racially and ethnically minoritized autistic adolescents and adults
Authors: Girolamo Teresa , Escobedo Alicia , Butler Lindsay , Larson Caroline A. , Campos Iván , Greene-Pendelton Kyle
Published: June 2024

Despite their importance, little is known about how social drivers of health shape communicative outcomes in autism. Even less is known when considering the intersection of race and language impairment. An understanding of factors in communicative outcomes is key for characterizing developmental trajectories and informing supports. This cross-sectional observational study examined the role of social drivers of health in communicative outcomes of racially and ethnically minoritized autistic adolescents and adults. Participants ages 13 to 30 (N= 73) completed a behavioral assessment protocol, including language and nonverbal cognitive skills, as well as social drivers of health (sense of community, unmet services, barriers to services). Correlational analyses revealed associations between social drivers of health on social communication impairment and real-world communication. Generalized linear mixed-effects modeling revealed that language predicted real-world communication, but sense of community predicted social communication impairment. Findings point to the importance of assessing both individual differences and social drivers of health in outcomes in autism research. Future work should focus on social drivers of health in larger-scale analyses of outcomes in minoritized autistic individuals during the transition to adulthood, considering supports that align with service eligibility and person-centered outcomes.

Lay Abstract

Where people live, work, and spend their time is important. Environments can have more or less services or differ in how much they help people feel like they belong to their community. These parts of the environment are called social drivers of health. Social drivers of health are important for outcomes in autism, but we do not know much about them in racially and ethnically minoritized autistic teens or adults. We recruited 73 minoritized autistic teens and adults ages 13 to 30 years and 52 caregivers (parents, grandparents, sibling) to our study. Teens and adults did language and NVIQ tests on Zoom. Teens, adults, and caregivers also answered questionnaires. Sense of community was important for social communication impairment, and language was important for real-world communication. These findings tell us two things. First, thinking about how to create supportive communication environments for autistic teens and adults is important. Second, understanding how social drivers of health shape outcomes is important. In the future, we should focus on how improving environments can help minoritized autistic teens and adults meet their communication goals.
Steering From the Rear: Coordination of Central Pattern Generators Underlying Navigation by Ascending Interneurons
Authors: Jonaitis Julius , Hibbard Karen L. , Layte Kaity McCafferty , Hiramoto Atsuki , Cardona Albert , Truman James W. , Nose Akinao , Zwart Maarten F. , Pulver Stefan R.
Published: June 2024

Understanding how animals coordinate movements to achieve goals is a fundamental pursuit in neuroscience. Here we explore how neurons that reside in posterior lower-order regions of a locomotor system project to anterior higher-order regions to influence steering and navigation. We characterized the anatomy and functional role of a population of ascending interneurons in the ventral nerve cord ofDrosophilalarvae. Through electron microscopy reconstructions and light microscopy, we determined that the cholinergic 19f cells receive input primarily from premotor interneurons and synapse upon a diverse array of postsynaptic targets within the anterior segments including other 19f cells. Calcium imaging of 19f activity in isolated central nervous system (CNS) preparations in relation to motor neurons revealed that 19f neurons are recruited into most larval motor programmes. 19f activity lags behind motor neuron activity and as a population, the cells encode spatio-temporal patterns of locomotor activity in the larval CNS. Optogenetic manipulations of 19f cell activity in isolated CNS preparations revealed that they coordinate the activity of central pattern generators underlying exploratory headsweeps and forward locomotion in a context and location specific manner. In behaving animals, activating 19f cells suppressed exploratory headsweeps and slowed forward locomotion, while inhibition of 19f activity potentiated headsweeps, slowing forward movement. Inhibiting activity in 19f cells ultimately affected the ability of larvae to remain in the vicinity of an odor source during an olfactory navigation task. Overall, our findings provide insights into how ascending interneurons monitor motor activity and shape interactions amongst rhythm generators underlying complex navigational tasks.
Context-dependent coordination of movement inTribolium castaneumlarvae
Authors: Xu Ying Bella , Zwart Maarten F. , Pulver Stefan R.
Published: June 2024

Insect pests, like the red flour beetleTribolium castaneum, destroy up to 20% of stored grain products worldwide, making them a significant threat to food security. Their success hinges upon adapting their movements to unpredictable, heterogeneous environments like flour.Triboliumis well developed as a genetic model system; however, little is known about their natural locomotion and how their nervous systems coordinate adaptive movement. Here, we employed videographic whole-animal and leg tracking to assess howTriboliumlarvae locomote over different substrates and analyze their gait kinematics across speeds. Unlike many hexapods, larvae employed a bilaterally symmetric, posterior-to-anterior wave gait during fast locomotion. At slower speeds, coordination within thoracic segments was disrupted, although intersegmental coordination remained intact. Moreover, larvae used terminal abdominal structures (pygopods) to support challenging movements, such as climbing overhangs. Pygopod placement coincided with leg swing initiation, suggesting a stabilizing role as adaptive anchoring devices. Surgically lesioning the connective between thoracic and abdominal ganglia impaired pygopod engagement and led to escalating impairments in flat-terrain locomotion, climbing and tunnelling. These results suggest that effective movement inTriboliumlarvae requires thoracic-abdominal coordination, and that larval gait and limb recruitment is context-dependent. Our work provides the first kinematic analysis ofTriboliumlarval locomotion and gives insights into its neural control, creating a foundation for future motor control research in a genetically tractable beetle that jeopardizes global food security.

Summary statement

Red flour beetle larvae walk with a legged wave gait and use their tails as anchors to climb inclines and tunnel into flour.
TheBrachypodium distachyonpangenome highlights Transposable Element dynamics in the species
Authors: Saidi Somia , Blaison Mathieu , del Pilar Rodríguez-Ordóñez María , Confais Johann , Quesneville Hadi
Published: June 2024

The role of transposable elements (TEs) in host adaptation can be explored with a pangenomic approach. Individuals of the same species undergo independent TE insertions, causing genetic variability upon which natural selection acts. This can lead to improved adaptation of individuals to their environment. The advent of third-generation sequencing has enabled use of multiple whole-genomede novoassemblies for a given species, avoiding bias introduced by a single reference genome. We developed a new pipeline, panREPET, for such data. It compares TE copies between each pair of individuals then identifies copies shared by a group of individuals. This gives the exact sequence and genomic context of each TE copy. We describe here TE insertions shared among 54Brachypodium distachyon genomes. We were able to date two major TE bursts corresponding to major climate events: 22 kya during the Last Glacial Maximum and 10 kya during the Holocene.
The cell cycle oscillator and spindle length set the speed of chromosome separation inDrosophilaembryos
Authors: Xu Yitong , Chao Anna , Rinaldin Melissa , Kickuth Alison , Brugués Jan , Di Talia Stefano
Published: June 2024

Anaphase is tightly controlled in space and time to ensure proper separation of chromosomes. The mitotic spindle, the self-organized microtubule structure driving chromosome segregation, scales in size with the available cytoplasm. Yet, the relationship between spindle size and chromosome movement remains poorly understood. Here, we address how the movement of chromosomes changes during the cleavage divisions of theDrosophilablastoderm. We show that the speed of chromosome separation gradually decreases during the 4 nuclear divisions of the blastoderm. This reduction in speed is accompanied by a similar reduction in the length of the spindle, thus ensuring that these two quantities are tightly linked. Using a combination of genetic and quantitative imaging approaches, we find that two processes contribute to controlling the speed at which chromosomes move at mitotic exit: the activity of molecular motors important for microtubule depolymerization and sliding, and the cell cycle oscillator. Specifically, we found that the levels of Klp10A, Klp67A, and Klp59C, three kinesin-like proteins important for microtubule depolymerization, and the level of microtubule sliding motor Klp61F (kinesin-5) contribute to setting the speed of chromosome separation. This observation is supported by quantification of microtubule dynamics indicating that poleward flux rate scales with the length of the spindle. Perturbations of the cell cycle oscillator using heterozygous mutants of mitotic kinases and phosphatases revealed that the duration of anaphase increases during the blastoderm cycles and is the major regulator of chromosome velocity. Thus, our work suggests a potential link between the biochemical rate of mitotic exit and the forces exerted by the spindle. Collectively, we propose that the cell cycle oscillator and spindle length set the speed of chromosome separation in anaphase.
A transcription factor quintet orchestrating bundle sheath expression in rice
Authors: Hua Lei , Wang Na , Stanley Susan , Donald Ruth M. , Kumar Eeda Satish , Billakurthi Kumari , Borba Ana Rita , Hibberd Julian M.
Published: June 2024

C4photosynthesis has evolved in over sixty plant lineages and improves photosynthetic efficiency by ∼50%. One unifying character of C4plants is photosynthetic activation of a compartment such as the bundle sheath, but gene regulatory networks controlling this cell type are poorly understood. In Arabidopsis a bipartite MYC-MYB transcription factor module restricts gene expression to these cells but in grasses the regulatory logic allowing bundle sheath gene expression has not been defined. Using the global staple and C3crop rice we identified theSULFITE REDUCTASEpromoter as sufficient for strong bundle sheath expression. This promoter encodes an intricatecis-regulatory logic with multiple activators and repressors acting combinatorially. Within this landscape we identified a distal enhancer activated by a quintet of transcription factors from the WRKY, G2-like, MYB-related, IDD and bZIP families. This module is necessary and sufficient to pattern gene expression to the rice bundle sheath. Oligomerisation of the enhancer and fusion to core promoters containing Y-patches allowed activity to be increased 220-fold. This enhancer generates bundle sheath-specific expression inArabidopsisindicating deep conservation in function between monocotyledons and dicotyledons. In summary, we identify an ancient, short, and tuneable enhancer patterning expression to the bundle sheath that we anticipate will be useful for engineering this cell type in various crop species.
Synchronicity transitions determine connection fluctuations in a model of coupled oscillators with plasticity
Authors: Kuroki Satoshi , Mizuseki Kenji
Published: June 2024

Sleep and rest are crucial for knowledge reorganization and creativity. During these periods, synapses between neurons are plastically altered and neuronal activities are collectively synchronized, accompanied by large differences in excitation-inhibition (EI) balance. These processes are assumed to be dissimilar from the learning process during task engagement. The detailed mechanism of how synchronized neuronal activities modify neural circuits via plasticity has yet to be fully understood. The Kuramoto model is utilized to study the collective synchronization of oscillators, including neurons. We previously proposed the EI-Kuramoto model, in which the EI balance was implemented in the Kuramoto model. The model alters its synchronicity based on the EI balance of the interaction strength. In this study, we developed this EI-Kuramoto model by implementing plasticity, leading to the plastic EI-Kuramoto (pEI-Kuramoto) model. Models with high inhibition displayed desynchronized dynamics and consistent connection strengths. Models with low inhibition exhibited bistable dynamics between synchronized and desynchronized states and fluctuation of interaction strengths in middle strength connections, while the strongest connections remained stable. These results, stabilizing a few strong connections and fluctuating the other connections in low inhibition conditions, could facilitate knowledge abstraction and reorganization. Our findings shed light on how varying inhibitory effects influence network stability and coupling, offering deeper insights into synaptic networks and knowledge reshaping.
Balancing complexity, performance and plausibility to meta learn plasticity rules in recurrent spiking networks
Authors: Confavreux Basile , Agnes Everton J. , Zenke Friedemann , Sprekeler Henning , Vogels Tim P.
Published: June 2024

Synaptic plasticity is a key player in the brain’s life-long learning abilities. However, due to experimental limitations, the mechanistic link between synaptic plasticity rules and the network-level computations they enable remain opaque. Here we use evolutionary strategies (ES) to meta-learn local co-active plasticity rules in large recurrent spiking net-works, using parameterizations of increasing complexity. We discover rules that robustly stabilize network dynamics for all four synapse types acting in isolation (E-to-E, E-to-I, I-to-E and I-to-I). More complex functions such as familiarity detection can also be included in the search constraints. However, our meta-learning strategy begins to fail for co-active rules of increasing complexity, as it is challenging to devise loss functions that effectively constrain net-work dynamics to plausible solutionsa priori. Moreover, in line with previous work, we can ﬁnd multiple degenerate solutions with identical network behaviour. As a local optimization strategy, ES provides one solution at a time and makes exploration of this degeneracy cumbersome. Regardless, we can glean the interdependecies of various plasticity parameters by considering the covariance matrix learned alongside the optimal rule with ES. Our work provides a proof of principle for the success of machine-learning-guided discovery of plasticity rules in large spiking networks, and points at the necessity of more elaborate search strategies going forward.
Eugenol loaded lipid nanoparticles derived hydrogels ameliorate psoriasis-like skin lesions by lowering oxidative stress and modulating inflammation
Authors: Keshari Roshan , Tharmatt Abhay , Pillai Mamatha M. , Chitkara Deepak , Tayalia Prakriti , Banerjee Rinti , Sen Shamik , Srivastava Rohit
Published: June 2024

Psoriasis is a chronic T-cell-mediated autoimmune skin disorder characterized by excessive epidermal thickening, keratinocyte over-proliferation, disruption of epidermal cell differentiation, and increased blood vessel growth in the dermal layer. Despite the common use of corticosteroids in psoriasis treatment, their limited efficacy and numerous side effects pose significant challenges. This research introduces a promising alternative approach by presenting hydrogels loaded with Eugenol (EU) in combination with Carbopol 974P (EUNPGel) for potential psoriasis management. EUN-loaded lipid nanoparticles (EUNPs) exhibit superior drug loading, enhanced release kinetics, long-term stability, and the ability to scavenge reactive oxygen species (ROS). Furthermore, EUNPs have been shown to inhibit keratinocyte proliferation, induce apoptosis, and augment the uptake of IL-6-mediated inflammation in human keratinocyte cells. Application of EUNPs-loaded gels (EUNPGel) to imiquimod-induced psoriatic lesions has demonstrated effective dermal penetration, suppressing keratinocyte hyperplasia and restoring epidermal growth. This led to a remarkable reduction in the Psoriasis Area and Severity Index (PASI) score from 3. 75 to 0. 5 within five days. These findings highlight the potential of EUNPGel as an innovative nanomedicine for treating inflammation. This novel approach enhances ROS scavenging capacity, improves cellular uptake, facilitates skin penetration and retention, reduces the activity of hyperactive immune cells, and suggests potential applications for treating other immune-related disorders such as acne and atopic dermatitis.

Highlights

Hydrogel loaded with eugenol is an innovative alternative for psoriasis management.

Superior drug loading, release kinetics, stability, and ROS scavenging capacity.

Curb (human keratinocyte) HaCaT cells proliferation, induce apoptosis, lower IL-6 mediated inflammation.

Effective dermal penetration and retention both in vivo and ex vivo.
Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function inDrosophila
Authors: Muñoz-Carvajal Francisco , Sanhueza Nicole , Sanhueza Mario , Court Felipe A.
Published: June 2024

Abstract

Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPRMT), a pathway that activates mitochondrial chaperones and antioxidant enzymes. Critical to the efficacy of the UPRMTis the cellular chromatin state, influenced by the methylation of lysine 9 on histone 3 (H3K9). While it has been observed that the UPRMTresponse can diminish with an increase in H3K9 methylation, its direct impact on age-related neurodegenerative processes, especially in the context of olfactory function, has not been clearly established. UsingDrosophila,we demonstrate that an age-dependent increase in H3K9 trimethylation by the methyltransferase dSetdb1 reduces the activation capacity of the UPRMTin olfactory projection neurons leading to neurodegeneration and loss of olfactory function. Age-related neuronal degeneration was associated with morphological alterations in mitochondria and an increase in reactive oxygen species levels. Importantly, forced demethylation of H3K9 through knockdown of dSetdb1 in olfactory projection neurons restored the UPRMTactivation capacity in aged flies, and suppressed age-related mitochondrial morphological abnormalities. This in turn prevented age-associated neuronal degeneration and rescued age-dependent loss of olfactory function. Our findings highlight the effect of age-related epigenetic changes on the response capacity of the UPRMT, impacting neuronal integrity and function. Moreover, they suggest a potential therapeutic role for UPRMTregulators in age-related neurodegeneration and loss of olfactory function.
Assessment of microphytobenthos communities in the Kinzig catchment using photosynthesis-related traits, digital light microscopy and 18S-V9 amplicon sequencing
Authors: Mayombo Ntambwe Albert Serge , Dani Mimoza , Kloster Michael , Vidakovic Danijela , Buchner Dominik , Burfeid-Castellanos Andrea M. , Beszteri Bánk
Published: June 2024

Microalgae form an essential group of benthic organisms that respond swiftly to environmental changes. They are widely used as bioindicators of anthropogenic stressors in freshwater ecosystems. We aimed to assess the responses of microalgae communities to multiple environmental stressors in the Kinzig River catchment, home to a long-term ecological monitoring site, in Germany. We used a photosynthetic biomass proxy alongside community composition of diatoms assessed by digital light microscopy, and of microalgae by 18S-V9 amplicon sequencing, to characterise microalgae at 19 sampling sites scattered across the catchment. Our results revealed significant effects of physical and chemical factors on microalgae biomass and community compositions. We found that conductivity, water temperature and pH were the most important factors affecting microalgae community composition, as observed in both microscopy and amplicon analysis. In addition to these three variables, the effect of total phosphate on all microalgae, together with water discharge on the diatom (Bacillariophyta) communities, as assessed by amplicon analysis, may reveal taxon-specific variations in the ecological responses of different microalgal groups. Our results highlighted the complex relationship between various environmental variables and microalgae biomass and community composition. Further investigations, involving the collection of time series data, are required to fully understand the underlying biotic and abiotic parameters that influence these microalgae communities.
Rosettes in a matrix: Predicting spatial variation in density of a large felid in a forest-production mosaic
Authors: Paul Anish , Kumar Nitish , Mukherjee Tonmoy , Chhetri Amir Kumar , Kshettry Aritra
Published: June 2024

Large carnivores are keystone for ecosystems and flagships for conservation efforts but face severe threats globally. Protected Areas are vital for the conservation of these charismatic species along with a host of ecological processes. However, the extent and scope of protected areas for conservation of all threatened species is limited, especially in the global south. Considering larger landscapes that can be compatible with large carnivore conservation goals is an alternative approach to ensure their persistence. This study explores the potential of multi-use landscapes for the persistence of a globally threatened large felid, the leopard. This study investigated the spatial variability of leopard densities across a land-use gradient using spatially explicit capture-recapture framework in a tea-plantation dominated forest-production landscape mosaic. While the density of leopards in this landscape was estimated to be 7.96 ± 1.56 (SE) per 100 km2, significant (p=0.048, t=2.02, df=61) differences in estimates were observed between tea-plantations (11.53 ± 2.72 (SE) leopards per 100 km2) and the forested habitats (4.67 ± 2.07 (SE) per 100 km2). Densities between tea plantations and Protected Areas (a subset of the forested habitat) were found to be comparable (9.19 ± 4.55 (SE) per 100 km2). The study posits that conservation-compatible land use in landscapes shared with people can host a higher density of large felids than forested areas and that conservation planning needs to move beyond the dominant PA-centric paradigm. The study also reinforces the importance of multi-use landscapes for wildlife conservation, especially for an adaptable large felid.
Various plasmid strategies limit the effect of bacterial Restriction-Modification systems against conjugation
Authors: Dimitriu Tatiana , Szczelkun Mark D. , Westra Edze R.
Published: June 2024

In bacteria, genes conferring antibiotic resistance are mostly carried on conjugative plasmids, mobile genetic elements which spread horizontally between bacterial hosts. Bacteria carry defence systems which defend them against genetic parasites, but how effective these are against plasmid conjugation is poorly understood. Here, we study to what extent Restriction-Modification (RM) systems – by far the most prevalent bacterial defence systems - act as a barrier against plasmids. Using 10 different RM systems and 13 natural plasmids conferring antibiotic resistance inEscherichia coli, we uncovered variation in defence efficiency ranging from none to 105-fold protection. Further analysis revealed genetic features of plasmids that explain the observed variation in defence levels. First, the number of RM recognition sites present on the plasmids generally correlates with defence levels, with higher numbers of sites being associated with stronger defence. Secondly, some plasmids encode methylases that protect against restriction activity. Finally, we show that a high number of plasmids in our collection encode anti-restriction genes that provide protection against several types of RM systems. Overall, our results show that it is common for plasmids to encode anti-RM strategies, and that, as a consequence, RM systems form only a weak barrier for plasmid transfer by conjugation.
Cell fate plasticity of xylem-pole-pericycle inArabidopsisroots
Authors: Wang Xin , Ye Lingling , Zhang Jing , Melnyk Charles W. , Mähönen Ari Pekka
Published: June 2024

InArabidopsisroots, xylem-pole-pericycle (XPP) cells exhibit remarkable cell fate plasticity by contributing to both lateral root (LR) and cambium formation. Despite significant progress in understanding these individual processes, the mechanism orchestrating these two fates and their effects on root architecture and secondary growth remain unclear. Here we combined lineage tracing with molecular genetics to study the fate dynamics of XPP cells. We showed that developmentally arrested lateral root primordia (LRP) that fail to emerge as lateral roots, gradually obtain cambium identity thus contributing to secondary growth. Conversely, preestablished procambium identity within XPP cells can be reverted to LR identity when simulated by auxin, an important player in LR development. This competence for auxin-induced LR formation from XPP cells, termed LR potency, however, decreases as the root matures. We found key cambium regulators play essential roles in shaping LR potency by promoting cambium activation and inhibiting LR development. Consistently, corresponding mutants with impaired cambium activity display broader LR potency. Moreover, cytokinins, essential players in cambium development, facilitate the identity transition of LRPs to cambium and reduce LR potency through key cambium regulators. Overall, our findings highlight the inherent cellular plasticity of XPP cells and elucidate how plant hormones influence root architecture and secondary growth through balancing the two cell fates of XPP cells.
Histidine limitation causes alteration in the TOR network and plant development
Authors: Guérin Amandine , Levasseur Caroline , Herger Aline , Renggli Dominik , Sotiropoulos Alexandros Georgios , Kadler Gabor , Hou Xiaoyu , Schaufelberger Myriam , Meyer Christian , Wicker Thomas , Bigler Laurent , Ringli Christoph
Published: June 2024

Plant growth depends on growth regulators, nutrient availability, and amino acids levels. The TOR (Target of Rapamycin) network senses these parameters and influences cell wall formation and expansion accordingly. Cell wall integrity and structures are surveyed and modified by a complex array of cell wall integrity sensors, including LRR-extensins (LRXs), that function as hormone receptors and help to compact cell walls. Expressing the Arabidopsis root-hair specific LRX1 without the extensin domain, which anchors the protein to the cell wall, has a negative effect on root hair development. The mechanism of this negative effect was investigated by a suppressor screen, which led to the identification of asune(suppressor of dominant-negative LRX1) mutant collection. Thesune82mutant was identified as an allele ofHISN2which encodes an enzyme essential for histidine biosynthesis. Thesune82mutation leads to reduced accumulation of histidine, and this influences the TOR network. Thesune82mutant reflects the impact of the TOR network on cell wall formation processes involving LRX proteins. It also represents an excellent tool to study the effects of reduced histidine levels on plant development, as it is a rare example of a viable partial loss-of-function allele in an essential biosynthetic pathway.

Highlight

Partial loss of function ofHISN2insune82results in a significant reduction in histidine content, which subsequently alters the TOR network.
Posterior parietal cortex maps progress along routes sharing the same meta-structure
Authors: Johnson Alexander B. , Nitz Douglas A.
Published: June 2024

Neurons of posterior parietal cortex were recorded as rats performed a working memory task within a network of intersecting paths. The specific routes utilized in task performance provided opportunity to contrast responses of posterior parietal cortex sub-populations to linear and angular velocity with more complex responses that map route progress. We found evidence for the presence of posterior parietal cortex neurons that generalize in their firing patterns across routes having the same shape but opposite action series. The results indicate that posterior parietal cortex has the capacity to generalize the mapping of route progress independent of the specific actions taken to move through those routes. We suggest that such encoding can form the basis for learning the meta-structural organization of a non-random path network structure, such as that commonly found in cities.
The UPRERgoverns the cell-specific response of human dopaminergic neurons to mitochondrial stress
Authors: Heneine Jana , Colace-Sauty Claire , Zhu Christiane , Galet Benjamin , Guégan Justine , Lejeune François-Xavier , Gareau Thomas , Asfogo Noemi , Pardanaud-Glavieux Corinne , Corti Olga , Ravassard Philippe , Cheval Hélène
Published: June 2024

Mitochondrial dysfunction is thought to be central to the pathophysiology of Parkinson’s disease. The preferential vulnerability of dopaminergic (DA) neurons of thesubstantia nigra pars compactato mitochondrial stress may underlie their massive degeneration and the occurrence of motor symptoms. Using LUHMES-derived DA neurons, we demonstrated that inhibition of the mitochondrial electron transport chain resulted in a severe alteration of mitochondrial turnover, pushing the balance towards mitochondrial loss, a reduction of the maturation status of the DA population and an increased proportion of apoptotic cells. PERK-mediated Unfolded Protein Response of the Endoplasmic Reticulum (UPRER) emerged as the key coordinator of the stress response, governing the inactivation of the mitochondrial UPR (UPRmt), the initiation of mitophagy and the cell-specific expression of long non-coding RNAs (lncRNAs). Importantly, we discovered novel lncRNAs specifically expressed in human DA neurons upon stress. Among them, we showed that lnc-SLC6A15-5 contributes to the resumption of translation after mitochondrial stress.

The Unfolded Protein Response of the Endoplasmic Reticulum is induced upon stress in human dopaminergic neurons and modulates mitochondrial homeostasis and transcriptional programs including expression of long non-coding RNAs (lncRNAs). We discovered a lncRNA involved in translation resumption after stress.
Multi omics aided small RNA profiling of wheat rhizosphere and their potential targets in contrasting soils forRhizoctonia solani-AG8 suppression
Authors: Regmi Roshan , Panchal Shivangi , Hicks Marcus , Kroker Stasia , Anderson Jonathan , Vadakattu Gupta
Published: June 2024

Next-generation sequencing helps describe microbial communities in rhizosphere environments, but understanding rhizosphere-plant interactions’ synergistic effects on plant traits and health outcomes remains challenging. This study analyses rhizosphere sRNAs’ ability to manipulate host gene targets in plants grown in suppressive (SP) and non-suppressive (NSP) soils with an integrated multi omics dataset. The results showed that rhizosphere sRNAs exhibited specific compositional features that may be important for rhizosphere-plant interaction. Small RNAs, less than 30 nt in size, were predominant in both samples, with a 5-prime bias towards cytosine enrichment, suggesting potential association with wheat specific argonauts. Mapping of sRNA reads to microbial metagenomes assembled draft genomes from SP and NSP soils showed sRNA loci were differentially expressed (DE) between the soils with contrasting disease suppressive capacities. In total, 96 and 132 non redundant rhizosphere sRNAs were abundant in SP and NSP rhizosphere communities, respectively. While 55 known bacterial sRNA loci were predicted from both SP and NSP metagenomes, 127 sRNAs originated from these loci were differentially expressed. Global wheat target prediction and functional analysis from DE rhizosphere sRNAs showed both soil type specific and common pathways. Upregulated NSP sRNAs target metabolic pathways, secondary metabolite biosynthesis, MAPK signalling, while SP sRNAs target glycerophospholipid metabolism, pathways such as polycomb repressive complex, starch/sucrose metabolism, and plant-pathogen interactions were targeted by both sets of sRNAs. This is the first study showing evidence for rhizosphere sRNAs and their corresponding plant transcripts in the context of biological disease suppression in agricultural soils.

Importance

Small RNAs (sRNAs) have gained attention in host-microbe interactions due to their diverse roles in controlling biological processes. Studies have identified numerous sRNAs with novel functions across various organisms. Echoing growing evidence of sRNAs in different plant-microbe interaction, we show an evidence of rhizosphere sRNAs regulating wheat genes in soil disease suppression context. This understanding could significantly enhance our comprehension of gene regulation in biological functions, potentially paving the way for the development of microbiome-based methods to influence host traits. Understanding the microbiome community’s mechanisms in different environments offers opportunities to modify them for agriculture, including modifying farming practices, host genetics/immunity, and synthetic communities for disease suppression.
The differential effect of SARS-COV-2 NSP1 on mRNA translation and stability reveals new insights linking ribosome recruitment, codon usage and virus evolution
Authors: Berlanga Juan José , Matamoros Tania , Pulido Miguel Rodríguez , Sáiz Margarita , Bayón Mercedes Núñez , Toribio René , Ventoso Iván
Published: June 2024

The non-structural protein 1 (NSP1) of SARS-CoV-2 blocks the mRNA entry channel of the 40S ribosomal subunit, causing inhibition of translation initiation and subsequent degradation of host mRNAs. However, target mRNA specificity and the way in which viral mRNAs escape NSP1-mediated degradation have not been clarified to date. Here we found that NSP1 acts as a translational switch capable of blocking or enhancing translation depending on how preinitiation complex 43S-PIC is recruited to the mRNA, whereas NSP1-mediated mRNA degradation mostly depends on codon usage bias. Thus, fast-translating mRNAs with optimal codon usage for human cells that preferentially recruit 43S-PIC by threading, showed a dramatic sensitivity to NSP1. On the contrary, slow-translating mRNAs with suboptimal codon usage and 5’ UTR that enabled slotting on 43S-PIC were resistant to or even enhanced by NSP1. Translation of SARS-CoV-2 mRNAs escapes NSP1-mediated inhibition by a proper combination of suboptimal codon usage and slotting-prone 5’ UTR that also confers efficient translation. Thus, the prevalence of non-optimal codons found in SARS-CoV-2 and other coronavirus genomes is favored by the distinctive effect that NSP1 plays on translation and mRNA stability.
Analysis of 30 chromosome-levelDrosophilagenome assemblies reveals dynamic evolution of centromeric satellite repeats
Authors: Gebert Daniel , Hay Amir D. , Hoang Jennifer P. , Gibbon Adam E. , Henderson Ian R. , Teixeira Felipe Karam
Published: June 2024

TheDrosophilagenus is ideal for studying genome evolution due to its simple chromosome structure and small genome size, with rearrangements mainly restricted to within chromosome arms. However, work on the rapidly evolving repetitive genomic regions, composed of transposons and tandem repeats, have been hampered by the lack of genus-wide chromosome-level assemblies. Integrating long read genomic sequencing and chromosome capture technology, we produced and annotated 30 chromosome-level genome assemblies within theDrosophilagenus. Based on this dataset, we were able to reveal the evolutionary dynamics of genome rearrangements across theDrosophilaphylogeny, including the identification of genomic regions that show comparatively high structural stability throughout evolution. Moreover, within theananassaesubgroup, we uncovered the emergence of new chromosome conformations and the rapid expansion of novel satellite DNA sequence families which form large and continuous peri/centromeric domains with higher-order repeat structures that are reminiscent to those observed in the human andArabidopsisgenomes. These chromosome-level genome assemblies present a highly valuable resource for future research, the power of which was demonstrated by our analysis of genome rearrangements and chromosome evolution. In addition, based on our findings, we propose theananassaesubgroup as an ideal model system for studying the evolution of centromere structure.
Reelin marks cocaine-activated striatal ensembles, promotes neuronal excitability, and regulates cocaine reward
Authors: Brida Kasey L. , Jorgensen Emily T. , Phillips Robert A. , Newman Catherine E. , Tuscher Jennifer J. , Morring Emily K. , Zipperly Morgan E. , Ianov Lara , Montgomery Kelsey D. , Tippani Madhavi , Hyde Thomas M. , Maynard Kristen R. , Martinowich Keri , Day Jeremy J.
Published: June 2024

Drugs of abuse activate defined neuronal ensembles in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, the mechanisms that sculpt NAc ensemble participation are largely unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling to identify expression of the secreted glycoprotein Reelin (encoded by theRelngene) as a marker of cocaine-activated neuronal ensembles within the rat NAc. Multiplexed in situ detection confirmed selective expression of the immediate early geneFosinReln+neurons after cocaine experience, and also revealed enrichment ofRelnmRNA inDrd1+ medium spiny neurons (MSNs) in both the rat and human brain. Using a novel CRISPR interference strategy enabling selectiveRelnknockdown in the adult NAc, we observed altered expression of genes linked to calcium signaling, emergence of a transcriptional trajectory consistent with loss of cocaine sensitivity, and a striking decrease in MSN intrinsic excitability. At the behavioral level, loss ofRelnprevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. Together, these results identify Reelin as a critical mechanistic link between ensemble participation and cocaine-induced behavioral adaptations.
Adolescent alcohol exposure promotes mechanical allodynia and alters synaptic function at inputs from the basolateral amygdala to the prelimbic cortex
Authors: Obray J. Daniel , Wilkes Erik T. , Scofield Michael D. , Chandler L. Judson
Published: June 2024

Binge drinking is common among adolescents despite mounting evidence linking it to various adverse health outcomes that include heightened pain perception. The prelimbic (PrL) cortex is vulnerable to insult from adolescent alcohol exposure and receives input from the basolateral amygdala (BLA) while sending projections to the ventrolateral periaqueductal gray (vlPAG) - two brain regions implicated in nociception. In this study, adolescent intermittent ethanol (AIE) exposure was carried out in male and female rats using a vapor inhalation procedure. Assessments of mechanical and thermal sensitivity revealed that AIE exposure induced protracted mechanical allodynia. To investigate synaptic function at BLA inputs onto defined populations of PrL neurons, retrobeads and viral labelling were combined with optogenetics and slice electrophysiology. Recordings from retrobead labelled cells in the PrL revealed AIE reduced BLA driven feedforward inhibition of neurons projecting from the PrL to the vlPAG, resulting in augmented excitation/inhibition (E/I) balance and increased intrinsic excitability. Consistent with this finding, recordings from virally tagged PrL parvalbumin interneurons (PVINs) demonstrated that AIE exposure reduced both E/I balance at BLA inputs onto PVINs and PVIN intrinsic excitability. These findings provide compelling evidence that AIE alters synaptic function and intrinsic excitability within a prefrontal nociceptive circuit.
Identification of ethanol analgesia quantitative trait loci and candidate genes in BXD recombinant inbred mouse lines
Authors: Rogers Walker D. , White Alyssa , Damaj M. Imad , Miles Michael F.
Published: June 2024

Alcohol consumption produces acute analgesic effects, and people experiencing pain conditions may drink alcohol to alleviate discomfort. However, tolerance to the analgesic properties of alcohol could prompt escalating consumption and dependence. Both nociception and alcohol-induced analgesia are under significant genetic control. Understanding the genetic architecture of these processes could inform better treatment options for people with pain conditions. This study aims to identify quantitative trait loci (QTL) driving variation in ethanol-induced analgesia across BXD recombinant inbred mouse lines. Male and female mice from 62 BXD strains received ethanol or saline oral gavage for five days and were tested for hot plate (HP) latency at baseline, Day 1, and Day 5. QTL mapping of HP phenotypes identified a significant provisional QTL on chromosome 17 for Day 1 HP latency in mice receiving ethanol. An additional highly suggestive QTL was present on chromosome 9 for the difference in pre- and post-ethanol thermal nociception. Candidate genes within QTL support intervals were provisionally identified using HP phenotypic correlations to transcriptomic database, expression QTL analysis, and other bioinformatics inquiries. The combined behavioral and bioinformatic analyses yielded strong ethanol analgesia candidate genes, specificallyMyo6. Thus, the results of this genetic study of ethanol-induced analgesia in BXD mouse strains may contribute significantly to our understanding of the molecular basis for individual variation in the analgesic response to acute ethanol.
The meninges host a unique compartment of regulatory T cells that bulwarks adult hippocampal neurogenesis
Authors: Marin-Rodero Miguel , Reyes Elisa Cintado , Walker Alec J. , Jayewickreme Teshika , Pinho-Ribeiro Felipe A. , Richardson Quentin , Jackson Ruaidhrí , Chiu Isaac M. , Benoist Christophe , Stevens Beth , Trejo José Luís , Mathis Diane
Published: June 2024

Our knowledge about the meningeal immune system has recently burgeoned, particularly our understanding of how innate and adaptive effector cells are mobilized to meet brain challenges. However, information on how meningeal immunocytes guard brain homeostasis in healthy individuals remains sparse. This study highlights the heterogeneous and polyfunctional regulatory-T (Treg) cell compartment in the meninges. A Treg subtype specialized in controlling Th1-cell responses and another known to control responses in B-cell follicles were substantial components of this compartment, foretelling that punctual Treg-cell ablation rapidly unleashed interferon-gamma production by meningeal lymphocytes, unlocked their access to the brain parenchyma, and altered meningeal B-cell profiles. Distally, the hippocampus assumed a reactive state, with morphological and transcriptional changes in multiple glial-cell types; within the dentate gyrus, neural stem cells showed exacerbated death and desisted from further differentiation, associated with inhibition of spatial-reference memory. Thus, meningeal Treg cells are a multifaceted bulwark to brain homeostasis at steady-state.

One sentence summary

A distinct population of regulatory T cells in the murine meninges safeguards homeostasis by keeping local interferon-γ-producing lymphocytes in check, thereby preventing their invasion of the parenchyma, activation of hippocampal glial cells, death of neural stem cells, and memory decay.
Event structure sculpts neural population dynamics in the lateral entorhinal cortex
Authors: Kanter Benjamin R. , Lykken Christine M. , Moser May-Britt , Moser Edvard I.
Published: June 2024

Our experience of the world is a continuous stream of events which must be segmented and organized simultaneously at multiple timescales. The neural mechanisms underlying this process remain unknown. Here, we simultaneously recorded many hundreds of neurons in the lateral entorhinal cortex (LEC) of freely behaving rats as we manipulated event structure at multiple timescales. During foraging as well as during sleep, population activity drifted continuously and unidirectionally along a one-dimensional manifold. Boundaries between events were associated with discrete shifts in state space, suggesting that LEC dynamics directly reflect event segmentation. During tasks with a recurring temporal structure, activity traveled additionally in directions orthogonal to the flow of drift, enabling the LEC population to multiplex event information across different timescales. Taken together, these results identify a hierarchically organized neural coding scheme for segmenting and organizing events in time.
Liver-specific Mettl14 deletion induces nuclear heterotypia and dysregulates RNA export machinery
Authors: Berggren Keith A , Sinha Saloni , Lin Aaron E , Schwoerer Michael P , Maya Stephanie , Biswas Abhishek , Cafiero Thomas R , Liu Yongzhen , Gertje Hans P , Suzuki Saori , Berneshawi Andrew R. , Carver Sebastian , Heller Brigitte , Hassan Nora , Ali Qazi , Beard Daniel , Wang Danyang , Cullen John M , Kleiner Ralph E , Crossland Nicholas A , Schwartz Robert E , Ploss Alexander
Published: June 2024

Modification of RNA with N6-methyladenosine (m6A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m6A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examinedin vivo.For example, neither perturbation of the key m6A writersMettl3andMettl14, nor the m6A readersYthdf1andYthdf2have been thoroughly mechanistically characterizedin vivoas they have beenin vitro. To understand the functions of these machineries, we developed mouse models and found that deletingMettl14led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.