bluuebunny/crossref_metadata_2025 huggingface dataset:
Vaccination strategies impact the probability of outbreak extinction: a case study of COVID-19 transmission
Authors: Jitsuk Natcha C. , Chadsuthi Sudarat , Modchang Charin
Published: July 2022

Mass vaccination has been one of the effective control measures for mitigating infectious disease transmission. Several vaccination strategies have been introduced throughout history to control infections and terminate the outbreak. Here, we employed the coronavirus disease 2019 (COVID-19) transmission as a case study and constructed a stochastic age-structured compartmental model to investigate the effectiveness of different vaccination strategies. We estimated the outbreak extinction probability under different vaccination scenarios in homogeneous and heterogeneous populations. We found that population heterogeneity could enhance the likelihood of outbreak extinction at various vaccine coverage. In addition, prioritizing vaccines for people with higher infection risk could maximize the outbreak extinction probability and reduce more infections. In contrast, allocating vaccines to individuals with higher mortality risk provides better results in reducing deaths. We also found that as the vaccine effectiveness wane over time, a booster dose of vaccine could significantly enhance the extinction probability and mitigate disease transmission.
Identification of individual differences in response to methadone, buprenorphine, and naltrexone in animal models of opioid use disorder
Authors: Kallupi Marsida , de Guglielmo Giordano , Conlisk Dana , Brennan Molly , Tieu Lani , Sedighim Sharona , Boomhower Brent , Smith Lauren C , Shankar Kokila , Carrette Lieselot LG , Simpson Sierra , Avelar Alicia , Maturin Lisa , Martinez Angelica , Qiao Ran , Dirik Selen , Crook Caitlin , Bonnet-Zahedi Selene , Iyer Mohini R. , Blucher Corrine E. , Fannon McKenzie J , Woods Leah C. Solberg , Palmer Abraham A. , George Olivier
Published: July 2022

Rationale

Current medications for opioid use disorder include buprenorphine, methadone, and naltrexone. While these medications show significant efficacy in reducing craving and opioid use, there are substantial individual differences in response to these treatments in humans. The reason for such difference is poorly known.

Objectives

Here, we tested the hypothesis that similar individual differences may be observed in a large population of heterogenous stock rats, that have been bred to maximize genetic diversity, using a behavioral paradigm relevant to opioid use disorder.

Methods

Over 500 rats were given intermittent (4d/week) and extended access (12h/day) to oxycodone self-administration for 14 sessions to establish oxycodone dependence and escalation of intake. We then measured the effect of buprenorphine (0.5mg/kg), methadone (3mg/kg) and naltrexone (3mg/kg) on the motivation to self-administer oxycodone by using a progressive ratio schedule of reinforcement.

Results

We found that naltrexone and buprenorphine significantly decreased motivation to oxycodone rewards. While naltrexone reduced oxycodone intake in both males and females, systemic administration with buprenorphine reduced progressive ratio responses only in males. Methadone reduced motivation to oxycodone self-administration in nearly 25% of the population, without reaching statical significance. Our results showed that the efficacy of these medications depends on the severity of addiction like behaviors, indicated by the addiction index.

Conclusions

These results demonstrate individual differences in response to medications to treat opioid use disorder in a genetically diverse population of rats.
Differential effects of oxytocin receptor antagonist on social rank and other social behavior in male mice
Authors: Nasukawa Daiki , Yamada Kota , Ujihara Yusuke , Hirakata Haruka , Tamura Ryuto , Yatagai Saya , Hayashi Kazuko , Toda Koji
Published: July 2022

Social rank within a group is essential for survival in many animals. Rank in the community helps to avoid unnecessary conflicts and establish stable relationships with others. Oxytocin has received increasing attention for its function in social behavior. However, the causal relationship between oxytocin levels and social rank has remained unclear. Here, we examined the effects of intraperitoneal injection of the oxytocin receptor antagonist L-368-899 on (1) social rank, (2) sex preference, (3) social preference, and (4) dyadic interaction in male mice. In the tube test, injection of the oxytocin receptor antagonist had no effect on first-rank mice, but caused fluctuation of the rank in second-rank mice, suggesting that the function of oxytocin in the maintenance of the social rank is rank-dependent. Second, injection of the oxytocin receptor antagonist dose-dependently impaired the sex preference of the male mice, confirming that oxytocin is essential in sexual behavior. Third, injection of the oxytocin receptor antagonist had no effect on social preference and dyadic interaction between the male mice, suggesting that oxytocin is not necessary in direct social interaction. Taken together, these results demonstrate that the role of the oxytocin in male mice is limited to a specific context of social behavior.

Highlights

The stable social rank of the male mice in their cages was clearly observed in the tube test.

Administration of an oxytocin receptor antagonist to first-rank mice caused no change in social rank.

Administration of an oxytocin receptor antagonist to second-rank mice caused fluctuation of social rank.

Sex preference, but not social preference and dyadic interactions, were impaired after the injection of the oxytocin receptor antagonist.
Sampling bias and the robustness of ecological metrics for plant-damage-type association networks
Authors: Swain Anshuman , Azevedo-Schmidt Lauren E. , Maccracken S. Augusta , Currano Ellen D. , Dunne Jennifer , Labandeira Conrad C. , Fagan William F.
Published: July 2022

Plants and their insect herbivores have been a dominant component of the terrestrial ecological landscape for the past 410 million years and feature intricate evolutionary patterns and co-dependencies. A complex systems perspective allows for both detailed resolution of these evolutionary relationships as well as comparison and synthesis across systems. Using proxy data of insect herbivore damage (denoted by the damage type or DT) preserved on fossil leaves, functional bipartite network representations provide insights into how plant–insect associations depend on geological time, paleogeographical space, and environmental variables such as temperature and precipitation. However, the metrics measured from such networks are prone to sampling bias. Such sensitivity is of special concern for plant–DT association networks in paleontological settings where sampling effort is often severely limited. Here, we explore the sensitivity of functional bipartite network metrics to sampling intensity and identify sampling thresholds above which metrics appear robust to sampling effort. Across a broad range of sampling efforts, we find network metrics to be less affected by sampling bias and/or sample size than richness metrics, which are routinely used in studies of fossil plant–DT interactions. These results provide reassurance that cross-comparisons of plant–DT networks offer insights into network structure and function and support their widespread use in paleoecology. Moreover, these findings suggest novel opportunities for using plant–DT networks in neontological terrestrial ecology to understand functional aspects of insect herbivory across geological time, environmental perturbations, and geographic space.
Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein mediated neurodegeneration
Authors: Yu Meigen , Ye Hui , De-Paula Ruth B. , Mangleburg Carl Grant , Wu Timothy , Li Yarong , Duong Duc , Allen Genevera I. , Seyfried Nicholas T. , Al-Ramahi Ismael , Botas Juan , Shulman Joshua M.
Published: July 2022

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson’s disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 88 conserved fly homologs of 38 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, following knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles support dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of 2 genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced brain structural degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurodegeneration.
Identification of a microbial sub-community from the feral chicken gut that reducesSalmonellacolonization and improves gut health in a gnotobiotic chicken model
Authors: Wongkuna Supapit , Kumar Roshan , Ghimire Sudeep , Drescher Samara Mattiello , Maji Abhijit , Ambat Achuthan , Antony Linto , Chankhamhaengdecha Surang , Janvilisri Tavan , Nelson Eric , Doerner Kinchel C. , Behr Melissa , Scaria Joy
Published: July 2022

A complex microbial community in the gut generally prevent the colonization of enteric pathogens such asSalmonella. Because of the high complexity, several species or combination of species in the gut can confer colonization resistance. To gain a better understanding of the colonization resistance againstSalmonella enterica, we isolated a library of 1,300 bacterial strains from feral chicken gut microbiota which represented a total of 51 species. Using a co-culture assay, we screened the representative species from this library and identified 30 species that inhibitedSalmonella entericaTyphimurium. To improve theSalmonellainhibition capacity, from a pool of fast-growing species, we formulated 66 bacterial blends, each of which composed of 10 species. Bacterial blends were more efficient in inhibitingSalmonellaas compared to individual species. The blend that showed maximum inhibition (Mix10) also inhibited other serotypes ofSalmonellafrequently found in poultry. Thein vivoeffect of Mix10 was examined in a gnotobiotic and conventional chicken model. The Mix10 consortium reducedSalmonellacolonization, intestinal tissue damage and inflammation in both models. Cell free supernatant of Mix10 did not showSalmonellainhibition, indicating that Mix10 inhibitsSalmonellathrough either nutritional competition or reinforcement of host immunity. Out of ten species, three species in Mix10 did not colonize while three species constituted more than 70% of the community. Two of these species represents previously uncultured bacteria. Our approach could be used as a high-throughput screening system to identify additional bacterial sub-communities that confer colonization resistance against enteric pathogens and its effect on the host.

Importance

Salmonellacolonization in chicken and human infections originating fromSalmonella-contaminated poultry is a significant problem. Poultry has been identified as the most common food linked to enteric pathogen outbreaks in the United States. Since multi-drug resistantSalmonellaoften colonize chicken and cause human infections, methods to controlSalmonellacolonization in poultry are needed. The method we describe here could form the basis of developing gut microbiota-derived bacterial blends as a microbial ecosystem therapeutic againstSalmonella.
Angiogenesis precedes myogenesis during regeneration following biopsy injury in skeletal muscle
Authors: Jacobsen Nicole L. , Morton Aaron B. , Segal Steven S.
Published: July 2022

Background

Acute injury to skeletal muscle damages myofibers and fragments capillaries, impairing contractile function and local perfusion. Myofibers and microvessels regenerate from satellite cells and from surviving microvessel fragments, respectively, to restore intact muscle. However, it is unknown whether myofiber regeneration and microvascular regeneration reflect interdependent processes or may proceed sequentially.

Methods

To investigate the temporal relationship between myogenesis and angiogenesis during regeneration, a punch biopsy (diameter, 2 mm) was performed through the center of the gluteus maximus (GM) muscle. Complete removal of all tissue components created a void into which regeneration was evaluated through 21 days post injury (dpi). Confocal imaging and histological analyses of whole-mount GM preparations and GM cross sections assessed the growth of microvessels and myofibers into the wound. Regeneration of perfused microvessels was evaluated in vivo by injecting fluorescent dextran into the circulation during intravital imaging.

Results

A provisional matrix filled with PDGFRα+ and CD45+ cells spanned the wound within 1 dpi. Regenerating microvessels advanced into the matrix by 7 dpi. At 10 dpi, sprouting and intussusceptive angiogenesis produced disorganized microvascular networks and spanned the wound with perfusion by 14 dpi. In striking contrast, the wound remained devoid of myofibers at 7 and 10 dpi. Myogenesis into the wound began by 14 dpi with nascent myofibers traversing the wound by 21 dpi. Regenerating myofibers and microvessels were less well organized than in the surrounding (uninjured) muscle.

Conclusions

Angiogenesis precedes myogenesis following punch biopsy injury of adult skeletal muscle. Regenerating microvessels encompass the wound and become perfused with blood prior to colocalization with regenerating myofibers. These findings infer that a microvascular supply supports the metabolic demands of regenerating skeletal muscle. Finding that regenerated microvascular networks and myofibers are disorganized within the biopsy site suggests that loss of guidance cues upon complete tissue removal impairs re-establishment of canonical skeletal muscle structure.
FHL5 controls vascular disease-associated gene programs in smooth muscle cells
Authors: Wong Doris , Auguste Gaëlle , Lino Cardenas Christian L. , Turner Adam W. , Chen Yixuan , Ma Lijiang , Perry R. Noah , Aherrahrou Redouane , Kuppusamy Maniselvan , Yang Chaojie , Mosquera Jose Verdezoto , Dube Collin J. , Khan Mohammad Daud , Palmore Meredith , Kavousi Maryam , Peyser Patricia A. , Matic Ljubica , Hedin Ulf , Manichaikul Ani , Sonkusare Swapnil K. , Civelek Mete , Kovacic Jason C. , Björkegren Johan L.M. , Malhotra Rajeev , Miller Clint L.
Published: July 2022

Background

Genome-wide association studies (GWAS) have identified hundreds of loci associated with common vascular diseases such as coronary artery disease (CAD), myocardial infarction (MI), and hypertension. However, the lack of mechanistic insights for a majority of these loci limits translation of these findings into the clinic. Among these loci with unknown functions is UFL1-FHL5 (chr6q16.1), a locus that reached genome-wide significance in a recent CAD/MI GWAS meta-analysis. In addition to CAD/MI, UFL1-FHL5 is also implicated to coronary calcium, intracranial aneurysm, and migraine risk, consistent with the widespread pleiotropy observed among other GWAS loci.

Methods

We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and imaging of human coronary artery tissues to implicate Four-and-a-half LIM domain 5 (FHL5) as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments.

Results

We prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through eQTL colocalization methods. FHL5 gene expression was enriched in the SMC and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating SMC contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream CAD/MI loci, such as FOXL1 and FN1 that have roles in vascular remodeling.

Conclusion

Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling loci. These trans-acting mechanisms may account for a portion of the heritable risk for complex vascular diseases.
Rapid BCMA downmodulation on myeloma cells upon CAR T cell contact is mediated by trogocytosis and BCMA internalization
Authors: Camviel Nicolas , Wolf Benita , Croce Giancarlo , Gfeller David , Zoete Vincent , Arber Caroline
Published: July 2022

Background

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) on multiple myeloma (MM) produces fast but not long-lasting responses. Reasons for treatment failure are poorly understood. CARs simultaneously targeting two antigens may represent an alternative. Here, we (1) designed and characterized novel A proliferation inducing ligand (APRIL) based dual-antigen targeting CARs, and (2) investigated mechanisms of resistance to CAR T cells with three different BCMA-binding moieties (APRIL, single-chain-variable-fragment, heavy-chain-only).

Methods

Three new APRIL-CARs were designed and characterized. Human APRIL-CAR T cells were evaluated for their cytotoxic function in vitro and in vivo, for their polyfunctionality, immune synapse formation, memory, exhaustion phenotype and tonic signaling activity. To investigate resistance mechanisms, we analyzed BCMA levels and cellular localization and quantified CAR T cell - target cell interactions by live microscopy. Impact on pathway activation and tumor cell proliferation was assessed in vitro and in vivo.

Results

APRIL-BBζ CAR T cells in a trimeric ligand binding conformation conferred the best polyfunctionality, immune synapse formation and fast anti-tumor function in vivo in two different mouse xenograft models. Upon CAR T cell – myeloma cell contact, we found rapid BCMA downmodulation on target cells with all three evaluated binding moieties. CAR T cells acquired BCMA on their cell surface by trogocytosis, and BCMA on MM cells was rapidly internalized. Since trogocytosis can lead to CAR T cell exhaustion and presence of CAR T cells does not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell – MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo.

Conclusion

We designed and characterized distinct APRIL-CAR T cells for dual-antigen targeting of MM. Rapid BCMA downmodulation occurred upon CAR T cell – tumor cell encounter independently of whether an APRIL or antibody-based binding moiety was used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. Our study sheds light on the mechanisms underlying CAR T cell failure in MM and can inform the development of improved treatment strategies.
Phosphorylation Determines Whether Neuroligin-3 is at Excitatory or Inhibitory Synapses in Different Regions of the Brain
Authors: Altas Bekir , Tuffy Liam P. , Patrizi Annarita , Dimova Kalina , Soykan Tolga , Romanowski Andrea J. , Robertson Colin D. , Khim Saovleak N. , Bunce Garrett W. , Ambrozkiewicz Mateusz C. , Yagensky Oleksandr , Krueger-Burg Dilja , Hammer Matthieu , Hsiao He-Hsuan , Laskowski Pawel R. , Dyck Lydia , Sassoè-Pognetto Marco , Chua John J.E. , Urlaub Henning , Jahn Olaf , Brose Nils , Poulopoulos Alexandros
Published: July 2022

Neuroligin-3 is a postsynaptic adhesion molecule involved in development, function, and pathologies of synapses in the brain. It is a genetic cause of autism and a potent component of the tumor microenvironment in gliomas. There are four Neuroligins that operate at distinct synapse types, selectively interacting with presynaptic adhesion and postsynaptic scaffold proteins. We investigated the subcellular localization and scaffold specificities of synaptic Neuroligin-3 and demonstrate an unexpected pattern of localization to excitatory synapses in cortical areas, and inhibitory synapses in subcortical areas. Using phosphoproteomics, we identify Neuroligin-3-specific serine phosphorylation in cortex and hippocampus that obstructs a key binding site for inhibitory synapse scaffolds. Using in utero CRISPR/Cas9 knockout and replacement with phosphomimetic mutants, we demonstrate that phosphorylation at this site determines excitatory versus inhibitory synapse localization of Neuroligin-3 in vivo. Our data reveal a mechanism that differentially regulates the balance of Neuroligin-3 between excitatory and inhibitory synapses, adding to our emerging understanding of their role in the development of brain connectivity and associated pathologies.
Ranking species based on sensitivity to perturbations under non-equilibrium community dynamics
Authors: Medeiros Lucas P. , Allesina Stefano , Dakos Vasilis , Sugihara George , Saavedra Serguei
Published: July 2022

Managing ecological communities requires fast detection of species that are sensitive to perturbations. Yet, the focus on recovery to equilibrium has prevented us from assessing species responses to perturbations when abundances fluctuate over time. Here, we introduce two data-driven approaches (expected sensitivity and eigenvector rankings) based on the time-varying Jacobian matrix to rank species over time according to their sensitivity to perturbations on abundances. Using several population dynamics models, we demonstrate that we can infer these rankings from time-series data to predict the order of species sensitivities. We find that the most sensitive species are not always the ones with the most rapidly changing or lowest abundance, which are typical criteria used to monitor populations. Finally, using two empirical time series, we show that sensitive species tend to be harder to forecast. Our results suggest that incorporating information on species interactions can improve how we manage communities out of equilibrium.
Cell-free Trim-Away reveals the mechanism of antibody-mediated protein degradation by TRIM21
Authors: Mevissen Tycho E.T. , Prasad Anisa V. , Walter Johannes C.
Published: July 2022

TRIM21 is a cytosolic antibody receptor and E3 ubiquitin ligase that promotes destruction of a broad range of pathogens. TRIM21 also underlies the antibody-dependent protein targeting method Trim-Away. Current evidence suggests that TRIM21 binding to antibodies leads to formation of a self-anchored K63 ubiquitin chain on the N-terminus of TRIM21 that triggers the destruction of TRIM21, antibody, and target protein. Here, we report that addition of antibody and TRIM21 to Xenopus egg extracts promotes efficient degradation of endogenous target proteins, establishing cell-free Trim-Away as a powerful tool to interrogate protein function. Chemical methylation of TRIM21 had no effect on target proteolysis, whereas deletion of all lysine residues in targets abolished their ubiquitination and proteasomal degradation. These results demonstrate that target protein but not TRIM21 polyubiquitination is required for Trim-Away, and they suggest that current models of TRIM21 function should be fundamentally revised.
Predicting the specific substrate for transmembrane transport proteins using BERT language model
Authors: Ataei Sima , Butler Gregory
Published: July 2022

Transmembrane transport proteins play a vital role in cells’ metabolism by the selective passage of substrates through the cell membrane. Metabolic network reconstruction requires transport reactions that describe the specific substrate transported as well as the metabolic reactions of enzyme catalysis. In this paper, we apply BERT (Bidirectional Encoder Representations from Transformers) language model for protein sequences to predict one of 12 specific substrates. Our UniProt-ICAT-100 dataset is automatically constructed from UniProt using the ChEBI and GO ontologies to identify 4,112 proteins transporting 12 inorganic anion or cation substrates. We classified this dataset using three different models including Logistic Regression with an MCC of 0.81 and accuracy of 97.5%; Feed-forward Neural Networks classifier with an MCC of 0.88 and accuracy of 98.5%. Our third model utilizes a Fine-tuned BERT language model to predict the specific substrate with an MCC of 0.95 and accuracy of 99.3% on an independent test set.
Chronic Prestress Regulation of Micro-Heart Muscle Physiology
Authors: Simmons Daniel W. , Schuftan David R. , Guo Jingxuan , Oguntuyo Kasoorelope , Ramahdita Ghiska , Munsell Mary K. , Kandalaft Brennan , Pear Missy , Huebsch Nathaniel
Published: July 2022

Engineered heart tissues have been created to study cardiac biology and disease in a setting that more closely mimicsin-vivoheart muscle than 2D monolayer culture. Previously published studies suggest that geometrically anisotropic micro-environments are crucial for inducing “in vivo-like” physiology from immature cardiomyocytes. We hypothesized that such anisotropic tissue geometries regulate tissue prestress, and that in turn this prestress is a major factor regulating cardiomyocytes’ electrophysiological development. Thus, we studied the effects of tissue geometry on electrophysiology of micro-heart muscle arrays (μHM) engineered from human induced pluripotent stem cells (iPSC). Geometries predicted to increase tissue prestress not only affected cardiomyocyte structure, but also had profound effects on electrophysiology.

Elongated geometries led to adaptations that yielded increased calcium intake during each contraction cycle. Strikingly, pharmacologic studies revealed a prestress threshold is required for sodium channel function, whereas L-type calcium and rapidly-rectifying potassium channels were largely insensitive. Analysis of RNA and protein levels suggest sodium channel activity changes were related to post-transcriptional, and potentially post-translational, changes. μHM formed from Plakophilin 2 (PKP2) knockout iPSC had a cellular structure similar to isogenic controls.

However, these tissues exhibited no functional sodium current and an overall lesser degree of electrical remodeling in response to prestress. These results suggest that PKP2, a key component of the nascent desmosome, is crucial to transducing tissue prestress into physiologically beneficial electrical remodeling via activation of sodium channels.
Exploring Relationships between Functional Network Connectivity and Cognition with an Explainable Clustering Approach
Authors: Ellis Charles A. , Sancho Martina Lapera , Miller Robyn , Calhoun Vince
Published: July 2022

The application of clustering algorithms to fMRI functional network connectivity (FNC) data has been extensively studied over the past decade. When applied to FNC, these analyses assign samples to an optimal number of groups without a priori assumptions. Through these groupings, studies have provided insights into the dynamics of network connectivity through the identification of different brain states and have identified subgroups of individuals with unique brain activity. However, the manner in which underlying brain networks influence the identified groups is yet to be fully understood. In this study, we apply k-means clustering to resting-state fMRI-based static FNC data collected from 37,784 healthy individuals. We identified 2 groups of individuals with statistically significant differences in cognitive performance in several test metrics. Then, by applying two different versions of G2PC, a global permutation feature importance approach, and logistic regression with elastic net regularization, we were able to identify the relative importance of brain network pairs and their underlying features to the resulting groups. Through these approaches, together with the visualization of centroids’ connectivity matrices, we were able to explain the observed differences in cognition in terms of specific key brain networks. We expect that our results will shed further light upon the effect of underlying brain networks on encountered cognitive differences between groups with unique brain activity.
Identification of pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration and identification of a causal role of short-chain fatty acids in addiction-like behaviors
Authors: Simpson Sierra , Kimbrough Adam , Peters Gregory , Wellmeyer Emma , Mclellan Rio , Walker Natalie , Jia Haoyu , Hu Sharon , Iyer Mohini , Sathish Varshini , Sedighim Sharona , Kallupi Marsida , Brennan Molly , Maturin Lisa , Hughes Talyn , Xie Tristin , Espinoza Veronika , Carrette Lieselot , Smith Lauren C. , Seaman Jonathan , Solberg Woods Leah C. , Palmer Abraham A. , DeGuglielmo Giordano , George Olivier
Published: July 2022

The gut brain axis is thought to play a role in behavior and physiological responses through chemical, immunological, and metabolite signaling. Antibiotics, diet, and drugs can alter the transit time of gut contents as well as the makeup of the microbiome. Heterogeneity in genetics and environment are also well-known factors involved in the initiation and perpetuation of substance use disorders. Few viable genetic or biological markers are available to identify individuals who are at risk of escalating opioid intake. Primarily, the addiction field has focused on the nervous system, limiting the discovery of peripheral factors that contribute to addiction. To address this gap, we characterized the microbiome before and after drug exposure, and after antibiotics depletion in male and female heterogenous stock rats to determine if microbiome constituents are protective of escalation. We hypothesized that individuals that are prone to escalation of opioid self-administration will have distinct microbial and metabolic profiles. The fecal microbiome and behavioral responses were measured over several weeks of oxycodone self-administration and after antibiotic treatment. Antibiotic treatment reduces circulating short-chain fatty acids (SCFA) by depleting microbes that ferment fiber into these essential signaling molecules for the gut-brain axis. Depletion of the microbiome increased oxycodone self-administration in a subpopulation of animals (Responders). Supplementation of SCFAs in antibiotic depleted animals decreased elevated oxycodone self-administration. Phylogenetic functional analysis reveals distinct metabolic differences in the subpopulations of animals that are sensitive to antibiotic depletion and animals rescued by SCFA supplementation. In conclusion, this study identifies pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration, demonstrates that escalation of oxycodone self-administration dysregulates the microbiome and metabolic landscape, and identifies a causal role of short-chain fatty acids in addiction-like behaviors.
Efficient precision genome editing ofChlamydomonas reinhardtiiwith CRISPR/Cas
Authors: Nievergelt Adrian P. , Diener Dennis R. , Bogdanova Aliona , Pigino Gaia
Published: July 2022

CRISPR/Cas genome engineering in the unicellular green algal modelChlamydomonas reinhardtiihas until now only been applied to targeted gene disruption, whereas scar-less knock-in transgenesis has generally been considered infeasible. We have developed highly efficient homology-directed knock-in mutagenesis in cell-walled strains ofChlamydomonas. Our method allows scarless integration of fusion tags and sequence modifications of near arbitrary proteins without need for a preceding mutant line.
Exploring structural determinants and the role of nucleolin in formation of the long-range interaction between untranslated regions of p53 mRNA
Authors: Kiliszek Agnieszka , Rypniewski Wojciech , Błaszczyk Leszek
Published: July 2022

p53 protein is a key regulator of cellular homeostasis by coordinating framework of anti-proliferative pathways as a response to various stress factors. Although the main mechanism of stress-dependent induction of p53 protein relies on posttranslational modifications influencing its stability and activity, a growing number of evidences suggest that complex regulation of p53 expression occurs also at the mRNA level. This study explore structural determinants of long-range RNA-RNA interaction in p53 mRNA, crucial for stress-dependent regulation of p53 protein translation. We demonstrate that the eight nucleotide bulge motif plays a key structural role in base pairing of complementary sequences from the 5’ and 3’ untranslated regions of p53 mRNA. We also show that one of the p53 translation regulators, nucleolin, displays an RNA chaperone activity and facilitates the association of sequences involved in the formation of long-range interaction in p53 mRNA. Mutational analysis reveal that all four RNA recognition motifs are indispensable for optimal RNA chaperone activity of nucleolin. These observations help to decipher the unique mechanism of p53 protein translation regulation pointing bulge motif and nucleolin as the critical factors during intramolecular RNA-RNA recognition in p53 mRNA.
Chlamydomonas Mutants Null for Chloroplast Triose Phosphate Transporter3 are Metabolically Compromised and Light Sensitive
Authors: Huang (黄伟超) Weichao , Krishnan Anagha , Plett Anastasija , Meagher Michelle , Linka Nicole , Wang Yongsheng , Ren Bijie , Findinier Justin , Redekop Petra , Fakhimi Neda , Kim Rick G. , Karns Devin A. , Boyle Nanette , Posewitz Matthew C. , Grossman Arthur R.
Published: July 2022

Modulation of export of photoassimilates from the chloroplast is essential for controlling the distribution of fixed carbon in the cell and maintaining optimum photosynthetic rates. In this study we identified chloroplast triose phosphate/phosphate translocators 2 and 3 (CreTPT2 and CreTPT3) in the green algaChlamydomonas reinhardtiithat exhibited similar substrate specificities but were differentially expressed over the diel cycle. We focused mostly on analyzing CreTPT3 because of its high level of expression and the severe phenotype exhibited bytpt3relative to thetpt2mutants. Null mutants for CreTPT3 had a pleiotropic phenotype that impacted growth, photosynthetic activities, metabolite profiles, carbon partitioning, and organelle-specific accumulation of H2O2. These analyses demonstrated that CreTPT3 is a dominant conduit on the chloroplast envelope for the transport of photoassimilate. In addition, CreTPT3 can serve as a safety valve that moves excess reductant out of the chloroplast and appears to be essential for preventing the cells from experiencing oxidative stress and accumulating of reactive oxygen species, even under low/moderate light intensities. Finally, our studies indicate subfunctionalization of the CreTPT transporters and suggest that there are differences in managing the export of photoassimilates from the chloroplasts of Chlamydomonas and vascular plants.
Open ocean and coastal strains of the N2-fixing cyanobacterium UCYN-A have distinct transcriptomes
Authors: del Carmen Muñoz-Marín María , Magasin Jonathan D. , Zehr Jonathan P.
Published: July 2022

Decades of research on marine N2fixation focused onTrichodesmium, which are generally free-living cyanobacteria, but in recent years the endosymbiotic cyanobacteriumCandidatusAtelocyanobacterium thalassa (UCYN-A) has received increasing attention. However, few studies have shed light on the influence of the host versus the habitat on UCYN-A N2fixation and overall metabolism. Here we compared transcriptomes from natural populations of UCYN-A from oligotrophic open-ocean versus nutrient-rich coastal waters, using a microarray that targets the full genomes of UCYN-A1 and UCYN-A2 and known genes for UCYN-A3. We found that UCYN-A2, usually regarded as adapted to coastal environments, was transcriptionally very active in the open ocean and appeared to be less impacted by habitat change than UCYN-A1. Across habitats and sublineages, genes for N2fixation and energy production had high transcript levels, and, intriguingly, were among the minority of genes that kept the same schedule of diel expression. This might indicate different regulatory mechanisms for genes that are critical to the symbiosis for the exchange of nitrogen for carbon from the host. Our results underscore the importance of N2fixation in UCYN-A symbioses across habitats, with consequences for community interactions and global biogeochemical cycles.
Analyzing relative export competitiveness of Indian agricultural food products: a study of fresh and processed fruits and vegetables
Authors: Sharma Ashpreet , Kathuria Lalit Mohan , Kaur Tanveen
Published: July 2022

Purpose

Given the dominant share of India in global production of fruits and vegetables, this paper intends to analyze the export competitiveness of India and other major food exporters in the world trade. The purpose of this study is to examine export structure, substitutability and complementarity of selected fresh and processed fruits and vegetables of top ten food exporters for the period 2010-20.

Design/methodology/approach

Balassa’s (1965) revealed comparative advantage (RCA) index was used to measure RCA indices of selected fruits and vegetables under study. Also, revealed symmetric comparative advantage (RSCA) and normalized RCA (NRCA) indices have been calculated. Further, Spearman rank correlation coefficients were computed to analyze changes over the study period for India and other competing countries. The export data have been sourced from UN Comtrade, an electronic database of United Nations, as well as World Trade Statistical Review, a database of World Trade Organization. The analysis was undertaken at Harmonized System (HS) four-digit classification for the period 2010-20.

Findings

The results disclosed an improvement in India’s comparative advantage over the period of 2010-20 in HS 07 product category, whereas the advantage ceded to other competitive nations in HS 08 product category. Further, Spearman rank correlation coefficients revealed that India faces competition from countries like China, Indonesia, Brazil, Thailand, Argentina and European Union for HS 07 product category, while countries like Mexico, Indonesia, Brazil and Thailandare the major competitors of India in HS 08 product category.

Originality/value

The paper expands the existing agricultural trade literature in three ways. First, it is one of the very few studies that have analyzed RCA for Indian fresh and processed fruits and vegetables using three different types of indices, namely, Balassa’s RCA, RSCA and NRCA. Second, the authors provide a number of comparisons related to RCA for Indian fruits and vegetables with other top food exporters in the world for a period of 10 years (2010-20). Third, the authors contribute to agricultural trade literature by assessing the substitutability or complementarity of India in the export of fruits and vegetables with other competing nations by using Spearman rank correlation coefficients.
Spatiotemporal connectivity dynamics in spatially structured populations
Authors: Drake Joseph , Lambin Xavier , Sutherland Chris
Published: July 2022

Connectivity is a fundamental concept linking dispersal to the emergent dynamics and persistence of spatially structured populations. Functional measures of connectivity typically seek to integrate aspects of landscape structure and animal movement to describe ecologically meaningful connectedness at the landscape and population scale.

Despite this focus on function, traditional measures of landscape connectivity assume it is a static property of the landscape, hence abstracting out the underlying spatiotemporal population dynamics. Connectivity is, arguably, a dynamic property of landscapes, and is inherently related to the spatial distribution of individuals and populations across the landscape. Static representations of connectivity potentially overlook this variation and therefore adopting a dynamic approach should offer improved insights about connectivity and associated ecological processes.

Using a large‐scale, long‐term time series of occupancy data from a metapopulation of water volesArvicola amphibius, we tested competing hypotheses about how considering the dynamic nature of connectivity improves the ability of spatially explicit occupancy models to recover population dynamics. Iteratively relaxing standing assumptions of connectivity metrics, these models ranged from spatially and temporally fixed connectivity metrics that are widely applied, to the more flexible, but lesser used model that allowed temporally varying connectivity measures that incorporate spatiotemporally dynamic patch occupancy states.

Our results provide empirical evidence that demographic weighting using patch occupancy dynamics and temporal variability in connectivity measures are important for describing metapopulation dynamics.

We highlight the implications of commonly held assumption in connectivity modelling and demonstrate how they result in different and highly variable predictions of metapopulation capacity. Thus, we argue that the concept of connectivity and its potential applications would benefit from recognizing inherent spatiotemporal variation in connectivity that is explicitly linked to underlying ecological state variables.
Leaf enzyme plays a more important role in leaf nitrogen resorption efficiency than soil properties along an elevation gradient
Authors: Liu Bai , Gao Decai , Chang Qing , Liu Ziping , Fan Xianlei , Meng Di , Bai Edith
Published: July 2022

Nitrogen (N) resorption is a strategy for plant N conservation through which plants withdraw N from senescing leaves prior to litterfall and its underlying mechanisms are important for better understanding of N cycling. However, most current studies focused on the impacts of soil and leaf nutrients on leaf N resorption efficiency (NRE), and plant physiological regulation that is species dependent is still unclear.

Here, we conducted a field experiment to investigate the variations of leaf NRE along an altitudinal gradient in a temperate forest of Northeastern China.

Results showed that leaf NRE of Quercus mongolica and Fraxinus mandshurica increased with altitude, while leaf NRE of Tilia amurensis, Acer mono and Acer pseudosieboldianum exhibited an opposite trend, although the relationships were not significant for F. mandshurica and A. mono. The inconsistent responses of leaf NRE of different species to increasing altitude were primarily due to the effect of leaf Glutamate dehydrogenase (GDH), an enzyme responsible for N translocation. Leaf GDH activity in senescing leaves explained the variation of NRE more than soil and climate factors did, suggesting that different plant species had different physiological regulation strategies for their N conservation under similar environment.

Synthesis. Our study highlights the role of leaf enzyme as a pivotal regulator of leaf NRE and helps us better understand and predict N cycling under climate change in forest ecosystems.
Modelling emotion, perfecting heart: disassembling technologies of affect with an android bodhisattva in Japan
Authors: White Daniel , Katsuno Hirofumi
Published: July 2022

As part of a surge in technologies with so‐called ‘artificial emotional intelligence’, robotics engineers and Buddhist monks in Japan have developed an android bodhisattva to deliver teachings at a popular Zen temple. Like many recent robots in Japan, the android is designed to impact visitors’ feelings. For this reason, it can be called a ‘technology of affect’. In order to communicate how new affective technologies are facilitating intimacy in human‐machine relations in Japan, we employ the concept of ‘disassembling’. By conceptuallydisassemblingtechnologies of affect and placing them in performative contexts, we show how technologies of affect alsodisassembleestablished associations between artificial agents and the feelings they evoke in popular imaginaries. We argue that identifying these disassembling processes helps demonstrate how emerging AI technologies can engender social change at the level of affect through evocative depictions of machine emotion.
Current and prior human papillomavirus (HPV) type and cytology results enable risk assessment for triage to colposcopy
Authors: Feldman Sarah
Published: July 2022

Linked article: This is a mini commentary on Gustafson et al., pp. 2132–2141. in this issue. To view this article visit https://doi.org/10.1111/1471‐0528.17200
BmMD‐2A responds to 20‐hydroxyecdysone and regulates Bombyx mori silkworm innate immunity in larva‐to‐pupa metamorphosis
Authors: Zhang Ruonan , Chen Xue , Wang Yuan , Bai Xu , Yang Qiong , Zhong Yangjin , Yu Xiao‐Qiang , Jin Fengliang , Yang Wanying
Published: July 2022

20E‐hydroxyecdysone (20E) plays important roles in larval molting and metamorphosis in insects and is also involved in the insect innate immune response. Insect metamorphosis is a highly successful strategy for environmental adaptation and is the most vulnerable stage during which the insect is susceptible to various pathogens. 20E regulates a series of antimicrobial peptides (AMPs) through the immunodeficiency (IMD) pathway activation in Drosophila; nevertheless, whether other immune pathways are involved in 20E‐regulated insect immunity is unknown. Our previous studies showed that BmMD‐2A is a member of the MD‐2‐related lipid recognition (ML) family of proteins that are involved in the Bombyx mori innate immunity Toll signaling pathway. In this study, we further demonstrate that BmMD‐2A is also positively regulated by 20E, and the BmMD‐2A neutralization experiment suggested that 20E activates some downstream immune effect factors, the AMP genes against Escherichia coli and Staphylococcus aureus, through the regulation of BmMD‐2A in larval metamorphosis, implying that B. mori may use the Toll‐ML signaling pathway to maintain innate immune balance in the larval‐pupal metamorphosis stage, which is a different innate immunity pathway regulated by 20E compared to the IMD pathway in Drosophila.
Do Audit Teams Affect Audit Production and Quality? Evidence from Audit Teams' Industry Knowledge*
Authors: Cahan Steven F. , Che Limei , Knechel W. Robert , Svanström Tobias
Published: July 2022

We examine how the extent and distribution of industry knowledge within an audit team affect audit outcomes. While prior research examining the role of auditors' industry knowledge focuses mainly on audit firms, audit offices, and audit partners, audits are conducted by audit teams. Using an audit framework and proprietary data from a Big 4 firm that includes audit hours for each team member, we find that Big 4 audit teams with higher average industry knowledge are associated with more audit effort. In contrast, we find mixed evidence on the relation between the average hourly internal cost rate and team knowledge. Furthermore, we find that balanced teams, which have at least one team member who qualifies as an industry specialist at both the senior rank and junior rank, produce higher‐quality audits than teams that have no specialists. In contrast, the audit quality of unbalanced teams, which have a specialist at the senior rank but not the junior rank or vice versa, is not statistically different than teams with no specialists. Overall, our evidence suggests that both the extent and distribution of industry knowledge within a team matter for audit production and that industry knowledge is utilized more effectively when it is spread throughout the team. The findings have useful implications for audit firms and regulators regarding how team composition and industry knowledge affect audit outcomes.