bluuebunny/crossref_metadata_2025 huggingface dataset:
Alcohol availability during withdrawal gates the impact of alcohol vapor exposure on responses to alcohol cues
Authors: Carpio M.J. , Gao Runbo , Wooner Erica , Cayton Christelle A. , Richard Jocelyn M.
Published: December 2021

Background

Chronic intermittent ethanol (CIE) vapor inhalation is a widely used model of alcohol dependence, but the impact of CIE on cue-elicited alcohol seeking is not well understood. Here, we assessed the effects of CIE on alcohol-seeking elicited by previously learned cues, and on acquisition of new cue-alcohol associations.

Methods

In Experiment 1, male and female Long Evans rats were first trained in a discriminative stimulus (DS) task, in which one auditory cue (the DS) predicts the availability of 15% ethanol and a control cue (the NS) predicts nothing. Rats then underwent CIE or served as controls. Subsets of each group received access to oral ethanol twice a week during acute withdrawal. After CIE, rats were presented with the DS and NS cues under extinction and retraining conditions to determine whether they would alter their responses to these cues. In Experiment 2, rats underwent CIE prior to training in the DS task. We also assessed alcohol consumption, aversion-resistant drinking, somatic withdrawal symptoms, and behavior in an open field.

Results

We found that CIE enhanced behavioral responses to previously learned alcohol cues, but only in rats that received access to alcohol during acute withdrawal. CIE disrupted cue responses in rats that did not. When CIE occurred before cue learning, male rats were slower to develop cue responses and less likely to enter the alcohol port, even though they had received alcohol during acute withdrawal. We also found that CIE increased alcohol consumption and aversion-resistant drinking in male but not female rats.

Conclusions

These results suggest that CIE alone does not potentiate the motivational value of alcohol cues, but that an increase in cue responses requires the potentiation of the value of alcohol during acute withdrawal. Further, under some conditions CIE may disrupt responses to previously learned and subsequently acquired alcohol cues.
SerpinB3 drives cancer stem cell survival in glioblastoma
Authors: Lauko Adam , Volovetz Josephine , Turaga Soumya M. , Bayik Defne , Silver Daniel J. , Mitchell Kelly , Mulkearns-Hubert Erin E. , Watson Dionysios C. , Desai Kiran , Midha Manav , Hao Jing , McCortney Kathleen , Steffens Alicia , Naik Ulhas , Ahluwalia Manmeet S. , Bao Shideng , Horbinski Craig , Yu Jennifer , Lathia Justin D.
Published: December 2021

Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC therapeutic resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. The knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. Mechanistically, SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown dramatically increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a novel GBM CSC-specific survival mechanism involving a previously uninvestigated cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of standard-of-care GBM therapies against therapeutically resistant CSCs.

Lauko et al. demonstrate a functional role for SerpinB3, which is elevated in glioblastoma cancer stem cells and protects against lysosomal-mediated cell death. SerpinB3 can be targeted to increase the efficacy of radiation in glioblastoma pre-clinical models.
The role of the angular gyrus in semantic cognition – A synthesis of five functional neuroimaging studies
Authors: Kuhnke Philipp , Chapman Curtiss A. , Cheung Vincent K.M. , Turker Sabrina , Graessner Astrid , Martin Sandra , Williams Kathleen A. , Hartwigsen Gesa
Published: December 2021

Semantic knowledge is central to human cognition. The angular gyrus (AG) is widely considered a key brain region for semantic cognition. However, the role of the AG in semantic processing is controversial. Key controversies concern response polarity (activation vs. deactivation) and its relation to task difficulty, lateralization (left vs. right AG), and functional-anatomical subdivision (PGa vs. PGp subregions). Here, we combined the fMRI data of five studies on semantic processing (n = 172) and analyzed the response profiles from the same anatomical regions-of-interest for left and right PGa and PGp. We found that the AG was consistently deactivated during non-semantic conditions, whereas response polarity during semantic conditions was inconsistent. However, the AG consistently showed relative response differences between semantic and non-semantic conditions, and between different semantic conditions. A combined analysis across all studies revealed that AG responses could be best explained by separable effects of task difficulty and semantic processing demand. Task difficulty effects were stronger in PGa than PGp, regardless of hemisphere. Semantic effects were stronger in left than right AG, regardless of subregion. These results suggest that the AG is engaged in both domain-general task-difficulty-related processes and domain-specific semantic processes. In semantic processing, we propose that left AG acts as a “multimodal convergence zone” that binds different semantic features associated with the same concept, enabling efficient access to task-relevant features.
Alignment of genetic differentiation across trophic levels in a fig community
Authors: Woodruff Gavin C. , Willis John H. , Phillips Patrick C.
Published: December 2021

Ecological interactions can generate close associations among species, which can in turn generate a high degree of overlap in their spatial distributions. Co-occurrence is likely to be particularly intense when species exhibit obligate comigration, in which they not only overlap in spatial distributions but also travel together from patch to patch. In theory, this pattern of ecological co-occurrence should leave a distinct signature in the pattern of genetic differentiation within and among species. Perhaps the most famous mutual co-isolation partners are fig trees and their co-evolved wasp pollinators. Here, we add another tropic level to this system by examining patterns of genomic diversity in the nematodeCaenorhabditis inopinata, a close relative of theC. elegansmodel system that thrives in figs and obligately disperses on fig wasps. We performed RADseq on individual worms isolated from the field across three Okinawan island populations. The male/femaleC. inopinatais about five times more diverse than the hermaphroditicC. elegans, and polymorphism is enriched on chromosome arms relative to chromosome centers.FSTis low among island population pairs, and clear population structure could not be easily detected among figs, trees, and islands, suggesting frequent migration of wasps between islands. Moreover, inbreeding coefficients are elevated inC. inopinata, consistent with field observations suggesting smallC. inopinatafounding populations in individual figs. These genetic patterns inC. inopinataoverlap with those previously reported in its specific fig wasp vector and are consistent withC. inopinatapopulation dynamics being driven by wasp dispersal. Thus, interspecific interactions can align patterns of genetic diversity across species separated by hundreds of millions of years of evolutionary divergence.

Highlights

The fig-dwelling female/male nematodeCaenorhabditis inopinatais five times more diverse than its closest relative, the self-fertilizing nematodeC. elegans.

C. inopinatamigrates frequently among three Okinawan islands despite high levels of inbreeding within individual figs.

C. inopinatahas patterns of genetic diversity that mirror its fig wasp vector.

Ecological specialization aligns patterns of genetic differentiation in closely interacting species.
Comprehensive Fitness Landscape of a Multi-Geometry Protein Capsid Informs Machine Learning Models of Assembly
Authors: Brauer Daniel D. , Santiago Celine B. , Merz Zoe N. , McCarthy Esther , Tullman-Ercek Danielle , Francis Matthew B.
Published: December 2021

Virus-like particles (VLPs) are non-infections viral-derived nanomaterials poised for biotechnological applications due to their well-defined, modular self-assembling architecture. Although progress has been made in understanding the complex effects that mutations may have on VLPs, nuanced understanding of the influence particle mutability has on quaternary structure has yet to be achieved. Here, we generate and compare the apparent fitness landscapes of two capsid geometries (T=3 and T=1 icosahedral) of the bacteriophage MS2 VLP. We find significant shifts in mutability at the symmetry interfaces of the T=1 capsid when compared to the wildtype T=3 assembly. Furthermore, we use the generated landscapes to benchmark the performance of in silico mutational scanning tools in capturing the effect of missense mutation on complex particle assembly. Finding that predicted stability effects correlated relatively poorly with assembly phenotype, we used a combination of de novo features in tandem with in silico results to train machine learning algorithms for the classification of variant effects on assembly. Our findings not only reveal ways that assembly geometry affects the mutable landscape of a self-assembled particle, but also establish a template for the generation of predictive mutational models of self-assembled capsids using minimal empirical training data.
Evolution of Gram+ Streptococcus pyogenes has maximized efficiency of the Sortase A cleavage site
Authors: Readnour Bradley M. , Ayinuola Yetunde A. , Russo Brady T. , Liang Zhong , Fischetti Vincent A. , Ploplis Victoria A. , Lee Shaun W. , Castellino Francis J.
Published: December 2021

Human plasminogen (hPg)-binding M-protein (PAM), a major virulence factor of Pattern D Streptococcus pyogenes (GAS), is the primary receptor responsible for binding and activating hPg. PAM is covalently bound to the cell wall (CW) through cell membrane (CM)-resident sortase A (SrtA)-catalyzed cleavage of the PAM-proximal C-terminal LPST↓-GEAA motif present immediately upstream of its transmembrane domain (TMD), and subsequent transpeptidation to the CW. These steps expose the N-terminus of PAM to the extracellular milieu (EM) to interact with PAM ligands, e.g., hPg. Previously, we found that inactivation of SrtA showed little reduction in functional binding of PAM to hPg, indicating that PAM retained in the cell membrane (CM) by the TMD nonetheless exposed its N-terminus to the EM. In the current study, we assessed the effects of mutating the Thr4 (P1) residue of the SrtA-cleavage site in PAM (Thr355 in PAM) to delay PAM in the CM in the presence of SrtA. Using rSrtA in vitro, LPSYGEAA and LPSWGEAA peptides were shown to have low activities, while LPSTGEAA had the highest activity. Isolated CM fractions of AP53/ΔSrtA cells showed that LPSYGEAA and LPSWGEAA peptides were cleaved at substantially faster rates than LPSTGEAA, even in CMs with an AP53/ΔSrtA/PAM[T355Y] double mutation, but the transpeptidation step did not occur. These results implicate another CM-resident enzyme that cleaves LPSYGEAA and LPSWGEAA motifs, most likely LPXTGase, but cannot catalyze the transpeptidation step. We conclude that the natural P1 (Thr) of the SrtA cleavage site has evolved to dampen PAM from nonfunctional cleavage by LPXTGase.

IMPORTANCE

We show in this study that functional cleavage of the sortase A (SrtA) cleavage signal for M-protein, LPST*GEAA, in the Gram+ cell membrane, which allows transpeptidation of M-protein to the cell wall, as opposed to non-functional cleavage by the highly active cell membrane nonribosomal enzyme, LPXTGase, at the downstream G-residue, is highly dependent on the presence of T at position 4. From our studies, we conclude that Streptococcus pyogenes has evolved in a manner that maximized T at this position so that SrtA preferentially cleaved the sorting signal in order that the virulence factor, M-protein, was stabilized on the cell surface through covalent attachment to the cell wall.
The first sheep graph-based pan-genome reveals the spectrum of structural variations and their effects on tail phenotypes
Authors: Li Ran , Gong Mian , Zhang Xinmiao , Wang Fei , Liu Zhenyu , Zhang Lei , Xu Mengsi , Zhang Yunfeng , Dai Xuelei , Zhang Zhuangbiao , Fang Wenwen , Yang Yuta , Zhang Huanhuan , Fu Weiwei , Cao Chunna , Yang Peng , Ghanatsaman Zeinab Amiri , Negari Niloufar Jafarpour , Nanaei Hojjat Asadollahpour , Yue Xiangpeng , Song Yuxuan , Lan Xianyong , Deng Weidong , Wang Xihong , Xiang Ruidong , Ibeagha-Awemu Eveline M. , Heslop-Harrison Pat (J.S.) , Lenstra Johannes A. , Gan Shangquan , Jiang Yu
Published: December 2021

Structural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely unexplored. Here, we assembled 26 haplotype-resolved genome assemblies from 13 genetically diverse sheep using PacBio HiFi sequencing. We constructed a graph-based ovine pan-genome and discovered 142,422 biallelic insertions and deletions, 7,028 divergent alleles and 13,419 multiallelic variations. We then used a graph-based approach to genotype the biallelic SVs in 684 individuals from 45 domestic breeds and two wild species. Integration with RNA-seq data allows to identify candidate expression-associated SVs. We demonstrate a direct link of SVs and phenotypes by localizing the putative causative insertion in HOXB13 gene responsible for the long-tail trait and identifying multiple large SVs associated with the fat-tail. Beyond generating a benchmark resource for ovine structural variants, our study highlights that animal genetic research will greatly benefit from using a pan-genome graph rather than a single reference genome.
Optineurin deficiency induces patchy hair loss but it is not sufficient to cause amyotrophic lateral sclerosis in mice
Authors: Moharir Shivranjani C , Swarup Ghanshyam
Published: December 2021

Genetic alterations and environmental factors contribute towards pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. Various types of mutations in the autophagy receptor protein optineurin (coded by OPTN gene) including deletions are causatively associated with ALS. To explore the role of OPTN in ALS pathogenesis, we used Optn knockout mice to study the features of ALS. The Optn-deficient mice did not show kyphosis, loss of body weight, weakening of front paw-grip strength or limb muscle strength. However, several Optn-deficient mice showed patchy loss of hair, which increased with age. Our results suggest that optineurin deficiency alone is not sufficient to induce ALS-like symptoms in mice. We suggest that optineurin deficiency may require cooperation with other genetic or environmental factors to cause ALS. Since endoplasmic reticulum (ER) stress plays an important role in ALS pathogenesis, and Optn modulates ER stress response signaling, Optn deficiency may contribute to ALS pathogenesis partly by potentiating ER stress response signaling.
Overcoming a “forbidden phenotype”: The parrot’s head supports, propels, and powers tripedal locomotion
Authors: Young Melody W. , Dickinson Edwin , Flaim Nicholas D. , Granatosky Michael C.
Published: December 2021

No vertebrate, living or extinct, is known to have possessed an odd number of limbs. Despite this “forbidden phenotype", gaits that utilize odd numbers of limbs (e.g., tripedalism or pentapedalism) have evolved in both avian and mammalian lineages. Tripedal locomotion is commonly employed by parrots during climbing, who utilize their beaks as an additional support. However, it is unclear whether the beak functions simply as a stabilizing hook, or as a propulsive limb. Here, we present data on kinetics of tripedal climbing in six rosy-faced lovebirds (Agapornis rosiecollis). Our findings demonstrate that parrots utilize cyclical tripedal gaits when climbing and the beak and hindlimbs generate comparable propulsive and tangential substrate reaction forces and power. Propulsive and tangential forces generated by the beak are of equal or greater magnitudes to those forces generated by the forelimbs of humans and non-human primates during vertical climbing. We conclude that the feeding apparatus and neck musculature of parrots has been co-opted to function biomechanically as a third limb during vertical climbing. We hypothesize that this exaptation required substantive alterations to the neuromuscular system including enhanced force-generating capabilities of the neck musculature and modifications to limb central pattern generators.
Activation of retinoic acid receptor reduces metastatic prostate cancer bone lesions through blocking endothelial-to-osteoblast transition
Authors: Yu Guoyu , Corn Paul G. , Shen Pengfei , Song Jian H. , Lee Yu-Chen , Lin Song-Chang , Pan Jing , Agarwal Sandeep K. , Panaretakis Theocharis , Pacifici Maurizio , Logothetis Christopher J. , Yu-Lee Li-Yuan , Lin Sue-Hwa
Published: December 2021

Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that contribute to progression and therapy resistance. Currently strategies targeting PCa-induced bone formation are lacking. We previously showed that PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces PCa-induced bone formation. We found that palovarotene, a RARγ agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralizationin vitro, and decreased tumor-induced bone formation and tumor growth in several osteogenic PCa models. RARα/β/γ isoform knockdown in 2H11 ECs blocked EC-to-OSB transition and osteoblast mineralization. Pan-RAR agonist ATRA inhibited MycCaP-BMP4-induced bone formation and tumor growth under castration. Furthermore, palovarotene or ATRA reduced plasma Tenascin C, a factor secreted by EC-OSB cells, which may be used to monitor treatment response. Mechanistically, BMP4-activated pSmad1 forms a complex with RAR in the nucleus of 2H11 cells. RAR activation by palovarotene or ATRA causes pSmad1 degradation by recruiting E3-ubiquitin ligase Smurf1 into the nuclear pSmad1/RARγ complex. Our findings suggest that palovarotene can be repurposed to target PCa-induced bone formation to improve clinical outcomes for bone metastasis.
Neuro-anatomical and neuro-molecular markers in salience network and their integration in machine learning-based prediction of cognitive dysfunction in mild cognitive impairment
Authors: Chand Ganesh B. , Thakuri Deepa S. , Soni Bhavin
Published: December 2021

Recent studies indicate disrupted functional mechanisms of salience network regions, especially right anterior insula (RAI), left AI (LAI), and anterior cingulate cortex (ACC), in mild cognitive impairment (MCI). However, the underlying neuro-anatomical and neuro-molecular mechanisms in these regions are not clearly understood yet. It is also unknown whether integration of multi-modal neuro-anatomical and neuro-molecular markers could predict cognitive impairment better in MCI. Herein we quantified neuro-anatomical volumetric markers via structural magnetic resonance imaging (sMRI) and neuro-molecular amyloid markers via positron emission tomography with Pittsburgh compound B (PET PiB) in SN regions of MCI (n = 33) and healthy controls (n = 27). We found that neuro-anatomical markers are significantly reduced while neuro-molecular markers are significantly elevated in SN nodes of MCI compared to healthy controls (p < 0.05). These altered markers in MCI patients were associated with their worse cognitive performance (p < 0.05). Our machine learning-based modeling further suggested that the integration of multi-modal markers predicts cognitive impairment in MCI superiorly compared to using single modality-specific markers. Overall, these findings shed light on the underlying neuro-anatomical volumetric and neuro-molecular amyloid alterations in SN regions and show the significance of multi-modal markers integration approach in better predicting cognitive impairment in MCI.
The what and where of synchronous sound perception
Authors: Van Bentum Guus C. , Van Opstal A. John , Van Wanrooij Marc M.
Published: December 2021

Abstract

Sound localization and identification are challenging in acoustically rich environments. The relation between these two processes is still poorly understood. As natural sound-sources rarely occur exactly simultaneously, we wondered whether the auditory system could identify (“what”) and localize (“where”) two spatially separated sounds with synchronous onsets. While listeners typically report hearing a single source at an average location, one study found that both sounds may be accurately localized if listeners are explicitly being told two sources exist. We here tested whether simultaneous source identification (one vs. two) and localization is possible, by letting listeners choose to make either one or two head-orienting saccades to the perceived location(s). Results show that listeners could identify two sounds only when presented on different sides of the head, and that identification accuracy increased with their spatial separation. Notably, listeners were unable to accurately localize either sound, irrespective of whether one or two sounds were identified. Instead, the first (or only) response always landed near the average location, while second responses were unrelated to the targets. We conclude that localization of synchronous sounds in the absence of prior information is impossible. We discuss that the putative cortical ‘what’ pathway may not transmit relevant information to the ‘where’ pathway. We examine how a broadband interaural correlation cue could help to correctly identify the presence of two sounds without being able to localize them. We propose that the persistent averaging behavior reveals that the ‘where’ system intrinsically assumes that synchronous sounds originate from a single source.

Significance Statement

It is poorly understood whether identification (‘what’) of sounds and their localization (‘where’) are inter-related, or independent neural processes. We measured sound-localization responses towards synchronous sounds to examine potential coupling of these processes. We varied the spatial configurations of two sounds and found that although identification improved considerably with larger spatial separation, their localization was unaffected: responses were always directed towards the average location. This shows absence of mutual coupling of information between the ‘what’ and ‘where’ streams in the auditory system. We also show how broadband interaural correlation could explain the improved identification results, without affecting localization performance, and explain how the persistent spatial averaging could be understood from strong internal priors regarding sound synchronicity.
Impact of carbon monoxide on early cardiac development in an avian model
Authors: Matias Filipa Rombo , Groves Ian , Herigstad Mari
Published: December 2021

Carbon monoxide (CO) is a toxic gas that can be lethal in large doses and may also cause physiological damage in lower doses. Epidemiological studies suggest that CO in lower doses over time may impact on embryo development, in particular cardiac development, however other studies have not observed this association. Here, we exposed chick embryosin ovoto CO at three different concentrations (1ppm, 8ppm, 25ppm) plus air control (4 protocols in total) for the first nine days of development, at which point we assessed egg and embryo weight, ankle length, developmental stage, heart weight and ventricular wall thickness. We found that heart weight was reduced for the low and moderate exposures compared to air, and that ventricular wall thickness was increased for the moderate and high exposures compared to air. Ventricular wall thickness was also significantly positively correlated with absolute CO exposures across all protocols. This intervention study thus suggests that CO even at very low levels may have a significant impact on cardiac development.
PeracetylN-cyclobutanoyl-D-mannosamine enhances expression of sialyl-Lewis X (sLeX / CD15s) and adhesion of leukocytes
Authors: Tasneem Anam , Parashar Shubham , Aittan Simran , Jain Tanya , Chauhan Charu , Rautela Jyoti , Bhat Zahoor Ahmad , Raza Kaisar , Madhumalar Arumugam , Sampathkumar Srinivasa-Gopalan
Published: December 2021

Sialyl-Lewis-X (sLeX/CD15s) epitopes regulate cell adhesionviainteractions with selectins. High levels of sLeX are associated with chronic inflammation. Intense efforts have been devoted for the development of sLeX mimetics for the prevention of atherosclerosis. By contrast, low levels of sLeX are associated with leukocyte adhesion deficiency (LAD) disorders. In this context, we employed metabolic glycan engineering to alter the fine structures of sialoglycans. Treatment of HL-60 (human acute myeloid leukemia) cells with peracetylN-cyclobutanoyl-D-mannosamine (Ac4ManNCb) resulted in a four-fold increase in both sLeX levels and adhesion to E-selectin-Fc chimera. Enhanced sLeX levels on CD162/PSGL-1, CD43, and CD44 were observed through immunoprecipitation. Molecular dynamics (MD) simulations on interactions with E-selectin revealed dramatic differentials in the conformational dynamics of sLeX-Cb compared to sLeX, highlighting the significance of remoteN-acyl side chains of sialic acids in facilitating bio-active conformations. These results provide opportunities for pharmacological interventions in both LAD and chronic inflammation.

Table of Contents

Remote substituents on the tetrasaccharide sialyl-Lewis X (sLeX / CD15s) influence ensembles of bio-active conformations and alter biological outcomes. Treatment with peracetylN-cyclobutanoyl-D-mannosamine (Ac4ManNCb) results in four-fold enhancement in the expression of sialyl-Lewis-X (sLeX / CD15s) and adhesion to E-selectin (CD62E). Molecular dynamics simulations show that the sLeX-Cb prefers a flatter bio-active conformation (gray) compared to wild-type sLeX (cyan).

Institute and/or researcher Twitter usernames: @NImmunology @Gops_GlycoIndia
Cannabinoid during adolescence phenocopies reelin haploinsufficiency in prefrontal cortex synapses
Authors: Thenzing Juda Silva-Hurtado T.J. , Giua Gabriele , Lassalle Olivier , Murphy Michelle N. , Wager-Miller Jim , Mackie Ken , Manzoni Olivier J. , Pascale Chavis P.
Published: December 2021

In humans and rodents, the protracted development of the prefrontal cortex (PFC) throughout adolescence represents a time for marked vulnerability towards environmental adversities, such as stress or drug exposure. We previously showed that the extracellular matrix protein reelin is an instrumental synaptic modulator that shapes medial PFC’s (mPFC) circuitry during maturation and is a critical mediator of the vulnerability to environmental stress. Emerging evidence highlight the role of the endocannabinoid system in the postnatal maturation of the PFC and reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence. Could the reelin-dependent maturation of prefrontal networks may be vulnerable to cannabinoid exposure during adolescence? To explore this hypothesis, we studied the effects of a single in-vivo exposure to a synthetic cannabinoid on reelin expression and mPFC functions in adolescent male mice. The results show that a single cannabinoid exposure mimics reelin haploinsufficiency by decreasing prefrontal reelin expression in a layer-specific pattern without changing its transcriptional levels. Furthermore, this treatment impeded synaptic plasticity: adolescent cannabinoid lowered long-term potentiation to the magnitude observed in age-matched reelin haploinsufficient males. Quantitative PCR analysis showed that changes in the mRNA levels of NMDARs does not account for the reduction of TBS-LTP. Together, the data show that exposure to cannabinoid during adolescence phenocopies reelin haploinsufficiency and further identifies reelin as a key component of the vulnerability of PFC to environmental insults.
Natural variation in the control of flowering and shoot architecture in diploid Fragaria species
Authors: Fan Guangxun , Andrés Javier , Olbricht Klaus , Koskela Elli , Hytönen Timo
Published: December 2021

In perennial fruit and berry crops of the Rosaceae family, flower initiation occurs in late summer or autumn after downregulation of a strong repressor TERMINAL FLOWER1 (TFL1) and flowering and fruiting takes place the following growing season. Rosaceous fruit trees typically form two types of axillary shoots, short flower-bearing shoots called spurs and long shoots that are respectively analogous to branch crowns and stolons in strawberry. However, regulation of flowering and shoot architecture differs between species and environmental and endogenous controlling mechanisms have just started to emerge. In woodland strawberry (Fragaria vesca L.), long days maintain vegetative meristems and promote stolon formation by activating TFL1 and GIBBERELLIN 20-OXIDASE4 (GA20ox4), respectively, while silencing of these factors by short days and cool temperatures induces flowering and branch crown formation. We characterized flowering responses of 14 accessions of seven diploid Fragaria species native to diverse habitats in the northern hemisphere, and selected two species with contrasting environmental responses, F. bucharica Losinsk. and F. nilgerrensis Schlecht. ex J. Gay for detailed studies together with F. vesca. Similar to F. vesca, F. bucharica was induced to flower in short days at 18°C and regardless of photoperiod at 11°C after silencing of TFL1. F. nilgerrensis maintained higher TFL1 expression level and likely required cooler temperatures or longer exposure to inductive treatments to flower. We also found that high expression of GA20ox4 was associated with stolon formation in all three species, and its downregulation by short days and cool temperature caused branch crown formation in F. vesca and F. nilgerrensis, although the latter did not flower. F. bucharica, in contrast, rarely formed branch crowns, regardless of flowering or GA20ox4 expression level. Our findings highlighted diploid Fragaria species as a rich source of genetic variation controlling flowering and plant architecture, with potential applications in breeding of Rosaceous crops.
Positive supercoiling buildup is a trigger of E. coli’s short-term response to cold shock
Authors: Dash Suchintak , Palma Cristina S.D. , Baptista Ines S.C. , Bahrudeen Mohamed N.M. , Almeida Bilena L.B. , Chauhan Vatsala , Jagadeesan Rahul , Ribeiro Andre S.
Published: December 2021

Adaptation to cold shock (CS) is a key survival skill of gut bacteria of warm-blooded animals. In E. coli, this skill emerges from a complex transcriptional program of multiple, timely-ordered shifts in gene expression. We identified short-term, cold shock repressed (CSR) genes by RNA-seq and provide evidence that their variability in evolutionary fitness is low and that their responsiveness to cold emanates from intrinsic features. Given that their single-cell variability in protein numbers increases after CS, we hypothesized that the responsiveness of a large portion of CSR genes is triggered by the high propensity for transcription locking due to positive supercoiling buildup (PSB). We then proposed a model of this phenomenon and, in support, show that nearly half of CSR genes are highly responsive to Gyrase inhibition. Also, their response strengths to CS and Gyrase inhibition correlate and most CSR genes increase their single-cell variability in protein numbers. Further, during CS, the cells’ nucleoid density increases (in agreement with increased numbers of positive supercoils), their energy levels become depleted (while the resolving of positive supercoils is ATP dependent), and the colocalization of Gyrases and the nucleoid increases (in agreement with increased time length for resolving supercoils). We conclude that high sensitivity to PSB is at the core of the short-term, cold shock responsive transcriptional program of E. coli and propose that this gene feature may be useful for providing temperature sensitivity to chromosome-integrated synthetic circuits.
Cultural diffusion dynamics depend on behavioural production rules
Authors: Chimento Michael , Barrett Brendan J. , Kandler Anne , Aplin Lucy M.
Published: December 2021

Culture is an outcome of both the acquisition of knowledge about behaviour through social transmission, and its subsequent production by individuals. Acquisition and production are often discussed interchangeably or modeled separately, yet to date, no study has accounted for both processes and explored their interaction. We present a generative model that integrates the two to explore how variation in production rules might shape cultural diffusion dynamics. Agents make behavioural choices that change as they learn from their productions. Their repertoires also change over time, and the social transmission of behaviours depends on their frequency. We diffuse a novel behaviour through social networks across a large parameter space to demonstrate how individual-level behavioural production rules influence population-level diffusion dynamics. We then investigate how linking transmission and production might affect the performance of two commonly used inferential models for social learning; Network-based Diffusion Analysis, and Experienced Weighted Attraction models. Clarifying the distinction between acquisition and production yields predictions for how production influences diffusion that are generalisable across species, and has consequences for how inferential methods are applied to empirical data. Our model illuminates the differences between social learning and social influence, demonstrates the overlooked role of reinforcement learning in cultural diffusions, and allows for clearer discussions about social learning strategies.
Life-stage and sex influencePhilornisectoparasitism in a Neotropical woodpecker (Melanerpes striatus) with essential male parental care
Authors: Lapergola Joshua B.
Published: December 2021

The nestlings of many Neotropical bird species suffer fromPhilornis(Diptera: Muscidae) ectoparasitism. While nestlings are typically considered the intended targets, recent work indicates thatPhilornisinfest adult birds more frequently than previously appreciated, yet few studies have concurrently surveyed nestlings and adults forPhilornisin the same population. Over six field seasons (2012–2017), I documented the presence of current or recent subcutaneousPhilornisinfestations on adult and nestling Hispaniolan WoodpeckersMelanerpes striatusfrom the same population in the central Dominican Republic. I tested the following three non-mutually exclusive hypotheses regarding occurrence ofPhilornison adult birds: (1) nestlings are more vulnerable toPhilornisparasitism than adults, (2) nesting is associated withPhilornisparasitism in adults, and (3)Philornisparasitism is associated with incubation and brooding investment. While nestling and adult woodpeckers exhibited similar prevalence of parasitism, parasitized nestlings hosted on average 3.5 times morePhilorniswounds (larvae plus empty wounds) than parasitized adults. Nestingper sewas not significantly associated with parasitism among adults, as breeding and non-breeding adults showed similar prevalence and intensity. However, nests withPhilornis-infested young were significantly more likely to have one or both parents also be infested in contrast to nests with infestation-free young. Furthermore, adult males, which perform overnight incubation and brooding, were significantly more likely to be parasitized than adult females. This last result supports the hypothesis that incubation and brooding investment increase the risk ofPhilornisparasitism for adults, but this conclusion is complicated by the lack of an association between parasitism and nesting status. Together, these results raise questions about the degree of host life-stage specialization and whether adult parasitism is incidental or part of an alternative parasitic strategy forPhilornis.
The Biomechanics of the Locust Ovipositor Valves: a Unique Digging Apparatus
Authors: Das Rakesh , Gershon Shmuel , Bar-On Benny , Tadayon Maryam , Ayali Amir , Pinchasik Bat-El
Published: December 2021

The female locust has a unique mechanism for digging in order to deposit its eggs deep in the ground. It utilizes two pairs of sclerotized valves to displace the granular matter, while extending its abdomen as it propagates underground. This ensures optimal conditions for the eggs to incubate, and provides them with protection from predators. Here, two major axes of operation of the digging valves are identified, one in parallel to the propagation direction of the ovipositor, and one perpendicular to it. The direction-dependent biomechanics of the locust major, dorsal digging valves are quantified and analyzed, under forces in the physiological range and beyond, considering hydration level, as well as the females’ age, or sexual maturation state. Our findings reveal that the responses of the valves to compression forces in the specific directions change upon sexual maturation to follow their function, and depend on environmental conditions. Namely, in the physiological force range, the valves are resistant to mechanical failure. In addition, mature females, which lay eggs, have stiffer valves, up to roughly nineteen times the stiffness of the pre-mature locusts. The valves are stiffer in the major working direction, corresponding to soil shuffling and compression, compared to the direction of propagation. Hydration of the valves reduces their stiffness but increases their resilience against failure. These findings provide mechanical and materials guidelines for the design of novel non-drilling excavating tools, including 3D-printed anisotropic materials based on composites.

Statement of significance

The female locust lay its eggs underground in order to protect them from predators and to provide them with optimal conditions for hatching. In order to dig into the ground, it uses two pairs of valves: The ventral pair is plugged as a wedge, while the dorsal pair performs the digging of the oviposition tunnel. We study the mechanical response of the digging valves, depending on age, hydration level and direction of operation. Our findings show that during the course of roughly two weeks in the life of the adult female, the digging valves become up to nineteen-fold stiffer against failure, in order to fulfill their function as diggers. While hydration reduces the stiffness, it also increases the resilience against failure and renders the valves unbreakable within the estimated physiological force range and beyond. The digging valves are consistently stiffer in the digging direction than in the perpendicular direction, implying on their form-follows-function design.

Graphical Abstract
Molecular liver fingerprint reflects the seasonal physiology of the grey mouse lemur (Microcebus murinus) during winter
Authors: Chazarin Blandine , Benhaim-Delarbre Margaux , Brun Charlotte , Anzeraey Aude , Bertile Fabrice , Terrien Jérémy
Published: December 2021

Grey mouse lemurs (Microcebus murinus) are a primate species exhibiting strong physiological seasonality in response to environmental energetic constraint. They notably store large amounts of lipids during early winter (EW), which are thereafter mobilized during late winter (LW), when food availability is low. In addition, they develop glucose intolerance in LW only. To decipher how the hepatic mechanisms may support such metabolic flexibility, we analyzed the liver proteome of adult captive male mouse lemurs, which seasonal regulations of metabolism and reproduction are comparable to their wild counterparts, during the phases of either constitution or use of fat reserves. We highlight profound changes that reflect fat accretion in EW at the whole-body level, however, without triggering an ectopic storage of fat in the liver. Moreover, molecular regulations would be in line with the lowering of liver glucose utilization in LW, and thus with reduced tolerance to glucose. However, no major regulation was seen in insulin signaling/resistance pathways, which suggests that glucose intolerance does not reach a pathological stage. Finally, fat mobilization in LW appeared possibly linked to reactivation of the reproductive system and enhanced liver detoxification may reflect an anticipation to return to summer levels of food intake. Altogether, these results show that the physiology of mouse lemurs during winter relies on solid molecular foundations in liver processes to adapt fuel partitioning while avoiding reaching a pathological state despite large lipid fluxes. This work emphasizes how the mouse lemur is of primary interest for identifying molecular mechanisms relevant to biomedical field.
A rhythmically pulsing leaf-spring nanoengine that drives a passive follower
Authors: Centola Mathias , Poppleton Erik , Centola Martin , Valero Julián , Šulc Petr , Famulok Michael
Published: December 2021

Molecular engineering seeks to create functional entities for the modular use in the bottom-up design of nanoassemblies that can perform complex tasks. Such systems require fuel-consuming nanomotors that can actively drive downstream passive followers. Most molecular motors are driven by Brownian motion, but the generated forces are scattered and insufficient for efficient transfer to passive second-tier components, which is why nanoscale driver-follower systems have not been realized. Here, we describe bottom-up construction of a DNA-nanomachine that engages in an active, autonomous and rhythmical pulsing motion of two rigid DNA-origami arms, driven by chemical energy. We show the straightforward coupling of the active nanomachine to a passive follower unit, to which it then transmits its own motion, thus constituting a genuine driver-follower pair. Our work introduces a versatile fuel-consuming nanomachine that can be coupled with passive modules in nanoassemblies, the function of which depends on downstream sequences of motion.
Comparative oncology reveals DNMT3B as a molecular vulnerability in soft-tissue sarcoma
Authors: Fuller Ashley M. , DeVine Ann , Murazzi Ileana , Mason Nicola J. , Weber Kristy , Eisinger-Mathason T. S. Karin
Published: December 2021

Undifferentiated pleomorphic sarcoma (UPS), an aggressive subtype of soft-tissue sarcoma (STS), is exceedingly rare in humans and lacks effective, well-tolerated therapies. In contrast, STS are relatively common in canine companion animals; thus, incorporation of veterinary patients into studies of UPS offers an exciting opportunity to develop novel therapeutic strategies for this rare human disease. Genome-wide studies have demonstrated that UPS is characterized by aberrant patterns of DNA methylation. However, the mechanisms and impact of this epigenetic modification on UPS biology and clinical behavior are poorly understood. Leveraging cell lines and tissue specimens derived from human and canine patients, we discovered that the DNA methyltransferase DNMT3B is overexpressed in UPS relative to normal mesenchymal tissues and associated with a poor prognosis. Consistent with these findings, genetic DNMT3B depletion strongly inhibited UPS cell proliferation and tumor progression. However, existing hypomethylating agents, including the clinically approved drug 5-aza-2’-deoxycytidine and the DNMT3B-inhibiting tool compound nanaomycin A, were ineffective in UPS due to cellular uptake and toxicity issues. Thus, further development of DNMT3B-targeting strategies for these patients is critical.
A synthetic membrane shaper for controlled liposome deformation
Authors: De Franceschi Nicola , Pezeshkian Weria , Fragasso Alessio , Bruininks Bart M.H. , Tsai Sean , Marrink Siewert J. , Dekker Cees
Published: December 2021

Shape defines the structure and function of cellular membranes. In cell division, the cell membrane deforms into a ‘dumbbell’ shape, while organelles such as the autophagosome exhibit ‘stomatocyte’ shapes. Bottom-up in vitro reconstitution of protein machineries that stabilize or resolve the membrane necks in such deformed liposome structures is of considerable interest to characterize their function. Here we develop a DNA-nanotechnology-based approach that we call Synthetic Membrane Shaper (SMS), where cholesterol-linked DNA structures attach to the liposome membrane to reproducibly generate high yields of stomatocytes and dumbbells. In silico simulations confirm the shape-stabilizing role of the SMS. We show that the SMS is fully compatible with protein reconstitution by assembling bacterial divisome proteins (DynaminA, FtsZ:ZipA) at the catenoidal neck of these membrane structures. The SMS approach provides a general tool for studying protein binding to complex membrane geometries that will greatly benefit synthetic cell research.