bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the reliability and applicability of human unbound brain-to-plasma concentration ratios
Authors: Fagerholm Urban
Published: November 2022

Background

Blood-brain barrier permeability (BBB Pe) and unbound brain-to-plasma concentration ratio (Kp,uu,brain) are relevant parameters describing the brain uptake potential of compounds. BBB efflux by transporter proteins, mainly MDR-1 and BCRP, is an essential factor determining Kp,uu,brain. Kp,uu,brain-values are commonly estimatedin vivoin rats and monkeys and predicted usingin silicomethodology. Such estimates can be used to predict corresponding human clinical values.

Objective

The objective of the study was to evaluate the reliability and applicability of human clinical Kp,uu,brain-data for understanding and predictions of brain uptake in man.

Methodology

Kp,uu,brainin rats, monkeys and humans, measured andin silicopredicted MDR-1 and BCRP substrate specificities andin silicopredicted passive Pewere used for the analysis.In silicopredictions were done using the ANDROMEDA by Prosilico ADME/PK-prediction software.

Results and Discussion

Rat and monkey Kp,uu,brain-values were highly correlated (R^2=0.74; n=17). Based on this finding a correlation between rat and human Kp,uu,brainwas expected. However, no correlation between rat and human Kp,uu,brainwas found (R^2=0.01; n=13). There was no (as also anticipated) correlation between passive Peand human Kp,uu,brain(R^2=0.04; n=16) and compounds with measured or predicted efflux did not have lower Kp,uu,brainthan compounds without efflux. The compound with highest Kp,uu,brainin man (2.8) is effluxed and predicted to have high passive Peand has no apparent efflux at the rat BBB. The MDR-1 substrate with highest Kp,uu,brainin rat (2.4) has very low Kp,uu,brainin man (0.15) is predicted to have high passive Pe.

Conclusion

Results indicate that available human Kp,uu,brain-data are too uncertain to be applicable for validation of predictions and understanding of clinical brain uptake of drugs and drug candidates.
The impact of a gamified intervention on daily steps in real-life conditions: a retrospective analysis of 4800 individuals
Authors: Mazéas Alexandre , Forestier Cyril , Harel Guillaume , Duclos Martine , Chalabaev Aïna
Published: November 2022

Background

Digital interventions integrating gamification features hold promise to promote daily steps. However, results regarding the effectiveness of this type of intervention are heterogeneous and not yet confirmed in real-life contexts.

Objective

This study aimed to examine the effectiveness of a gamified intervention and its potential moderators in a large sample using real-world data. Specifically, we tested (1) whether a gamified intervention enhanced daily steps during the intervention and follow-up periods compared to baseline, (2) whether this enhancement was higher in participants to the intervention than in nonparticipants, and (3) what participants’ characteristics or intervention parameters moderated the effect of the program.

Methods

Data from 4819 individuals who registered for a mHealth Kiplin program between 2019 and 2022 were retrospectively analyzed. In this intervention, participants could take part in one or several games where their daily step count was tracked, allowing individuals to play with their overall activity. Nonparticipants are people who registered to the program but did not take part in the intervention and were considered as a control group. Daily step counts were measured via accelerometers embedded in either commercial wearables or smartphones of the participants. Exposure to the intervention, the intervention content, and participants’ characteristics were included in multilevel models to test the study objectives.

Results

Participants in the intervention group demonstrated a significantly greater increase in mean daily steps from baseline compared to nonparticipants (p<.0001). However, intervention effectiveness depended on participants’ initial physical activity. Whereas the daily steps of participants with <7500 baseline daily steps significantly improved from baseline both during the Kiplin intervention (+3291 daily steps) and during follow-up periods (+945 daily steps), participants with a higher baseline had no improvement or significant decreases in daily steps after the intervention. Age (p<.0001) and exposure (p<.0001) positively moderated the intervention effect.

Conclusions

In real-world settings and among a large sample, the Kiplin intervention was significantly effective to increase the daily steps of participants from baseline, during intervention and follow-up periods, compared to nonparticipants. Interestingly, responses to the intervention differed based on participant’ initial steps with the existence of a plateau effect. Drawing on the insights of the self-determination theory, we can assume that the effect of gamification could depend of the initial motivation and activity of participants.
Factors associated with release relief of Long COVID symptoms at 12-Months and their impact on daily life
Authors: Salmon Dominique , Slama Dorsaf , Linard Françoise , Dumesges Nicolas , Lebaut Valérie , Hakim Florence , Oustric Pauline , Seyrat Emilie , Thoreux Patricia , Marshall Esaie
Published: November 2022

Introduction

Our purpose was to describe the course of Long COVID symptoms after 12-month follow-up, their impact on daily life and the factors associated with the relief of symptoms.

Methods

A cross-sectional survey was conducted within an out-patient clinic for Long COVID patients. Participants, who had experienced their initial COVID-19 episode between January, 15 2020 and May 21, 2021, were contacted 12-months post onset. Their characteristics, symptom course at initial COVID-19 episode, Long COVID phase and one year follow-up along with remission status were collected through a questionnaire and a specific post COVID remission scale from complete remission to persistence of symptoms and dependence in daily life activities.

Results

Among the 231 long COVID participants who answered the 12-month follow-up questionnaire, 63.2% had developed SARS-CoV-2 antibodies before COVID-19 vaccination. At 12-month follow-up, only 8.7% of the participants felt in complete remission while 28.6% noted a significant improvement of their symptoms. The prevalence rate of most symptoms remained high at 12 months: asthenia 83.1%, neurocognitive and neurological symptoms 91.8%, cardiothoracic symptoms 77.9%, musculoskeletal 78.8%. During Long COVID phase, 62.2% had to stop working at least once and only 32.5% resumed professional activities full time at one year follow-up. The presence of SARS-CoV-2 antibodies before COVID-19 vaccination was associated with an increased probability of significant improvement at one year (aPRR: 1.60, p=0.028) while ageusia at initial Long COVID phase was associated with a lower probability of improvement (aPRR: 0.38, p=0.007).

Conclusion

While observing a trend towards some improvement in a majority of long COVID patients at a 12-month follow-up, fatigue, musculoskeletal pain, cardiothoracic symptoms and neurocognitive impairment persisted in most of them. Having developed SARS-CoV-2 antibodies was associated with a better prognosis while persistent ageusia at long COVID phase seems to be associated with the persistence of symptoms.
Maternally-derived antibody titer dynamics and risk of hospitalised infant dengue disease
Authors: O’Driscoll Megan , Buddhari Darunee , Huang Angkana , Waikman Adam , Kaewhirun Surachai , Iamsirithaworn Sopon , Khampaen Direk , Farmer Aaron , Fernandez Stefan , Rodriguez-Barraquer Isabel , Srikiatkhachorn Anon , Thomas Stephen , Endy Timothy , Rothman Alan L. , Anderson Kathryn , Cummings Derek A.T. , Salje Henrik
Published: November 2022

Dengue virus (DENV) immunity is complex. Maternally-derived DENV antibodies initially provide protection against infection, however, as antibodies decay they can enhance disease severity upon infection. Quantifying antibody titers that are associated with disease risk is complicated by their dynamic nature and imperfect measurement processes. It also remains unknown whether long-term trends in birth rates, population-level infection risks, and maternal ages have altered immune profiles in child-bearing women, leading to shifts in age-specific infant disease risks. Here, we analyse DENV antibody data from two infant cohorts (N=165 infants with 665 blood draws) and 40 years of infant dengue hospitalisation data from Thailand. We use mathematical models to reconstruct maternally-derived antibody dynamics and estimate hospitalisation risk by titer. We find the relative risk of dengue hospitalisation ranges from 0.13 (0.00-0.89) in 1 month olds to 3.52 (3.25-3.79) in 8 month olds, compared to the risk in 12 month olds. We estimate the highest risk of infant dengue hospitalisation occurs at PRNT50titers of 6.0 (5.7-6.6). Our inferred titer-related risk estimates are consistent with previously identified titer-based correlates of severe disease among older individuals experiencing secondary DENV infections, suggesting a common mechanism of risk enhancement from pre-existing antibodies. Finally, we describe how the shifting epidemiology of dengue in Thailand, combined with declining birth rates, have decreased the absolute risk of infant dengue disease by 64% over a 40 year period while having minimal impact on the mean age of infant hospital-attended dengue disease.
Mapping the African Tobacco Control Network
Authors: Leischow Scott J. , Ayo-Yusuf Olalekan , Okamoto Janet , Warner Mary , Twesten Jenny E. , Stecher Chad , Valente Thomas W. , Parascandola Mark
Published: November 2022

Background

To understand the state of tobacco control efforts across Africa, a first-ever survey was implemented to assess the nature and activities of tobacco control stakeholders across the African continent.

Methods

A survey in English, Arabic, and French was made available to individuals and organizations to assess the types and scope of tobacco control efforts and experience with tobacco control programs based on FCTC articles/MPOWER components.

Results

There were 219 respondents from 32 African and 6 non-African countries. Research and advocacy were the most reported activities, and several organizations emerged as network nodes for connecting tobacco control efforts across multiple African countries. The most common FCTC articles/MPOWER components worked on were (W) warning about the dangers of tobacco (58%), (M) monitor tobacco use and policies (49%), and (P) protection against secondhand smoke exposure (47%). Significant between-country differences were also found on some FCTC articles/MPOWER components: (1) (R) price and tax measures [Articles 6 and 15] (F=1.57, p=0.048), (2) industry interference [Article 5.3] (F=1.62, p=0.038), and (3) economically viable alternatives to tobacco growing [Article 17] (F=1.94, p=0.007).

Discussion

This study found a broad and robust tobacco control network across Africa, with multiple organizations serving those networks and having overlapping collaborations. There is considerable variability in tobacco control priorities and networking, and multiple barriers were identified to expanding the network and to fostering increased tobacco control efforts. The results point to important directions for increasing collaboration across FCTC articles/MPOWER components to improve tobacco control efforts; potential research opportunities, including an analysis of tobacco industry activities, an exploration of ways to help people quit tobacco, and approaches to elevate the cost of tobacco; and a solid tobacco control network foundation on which to build. However, exploring creative approaches to increase research most relevant to specific countries and their cultural characteristics is essential.
Longitudinal analysis at three oral sites links oral microbiota to clinical outcomes in allogeneic hematopoietic stem-cell transplant
Authors: Heidrich Vitor , Knebel Franciele H. , Bruno Julia S. , de Molla Vinícius C. , Miranda-Silva Wanessa , Asprino Paula F. , Tucunduva Luciana , Rocha Vanderson , Novis Yana , Fregnani Eduardo R. , Arrais-Rodrigues Celso , Camargo Anamaria A.
Published: November 2022

Background

Allogeneic hematopoietic stem-cell transplant (allo-HSCT) is a potentially curative therapy for several hematological disorders. Before stem-cell infusion, recipients undergo a conditioning regimen with chemo/radiotherapy and immunosuppressants, requiring the use of antibiotics to treat and prevent infections. This regimen promotes drastic alterations in the recipient’s microbiotas, including the oral microbiota, which have been associated with allo-HSCT complications and poor outcomes. However, long-term longitudinal studies on the oral microbiota of allo-HSCT recipients are scarce and disregard the existence of distinct microbiotas within the oral cavity. Here, we used 16S rRNA gene sequencing to characterize the microbiota dynamics (during and after allo-HSCT) of 31 allo-HSCT recipients at 3 oral sites (gingival crevicular fluid, oral mucosa, and supragingival biofilm).

Results

Analysis of the oral microbiota dynamics during allo-HSCT revealed a significant decline in bacterial diversity and major shifts in microbiota composition in all oral sites, including blooms of potentially pathogenic genera. These blooms in some cases preceded respiratory infections caused by the blooming genera. We also noticed that differences in microbiota diversity and composition between oral sites were lost during allo-HSCT. Overall, oral microbiotas returned to their preconditioning state after engraftment. However, the ability to recover the initial bacterial composition varied between patients. After stratifying patients based on their ability to recover their preconditioning microbiota composition, we found that recovery of the oral mucosa microbiota composition was not associated with antibiotic usage but was associated with higher preconditioning diversity and earlier reconstitution of normal leukocyte counts. Most notably, oral mucosa microbiota composition recovery was an independent biomarker of better allo-HSCT outcomes.

Conclusion

We observed clear patterns of microbiota dysbiosis in all three oral sites during allo-HSCT, however each oral site responded differently to the perturbations associated with allo-HSCT. Oral microbiota injury and recovery patterns were associated with allo-HSCT complications and outcomes. This study highlights the potential clinical impact of the oral microbiota in the allo-HSCT setting and the clinical value of tracking oral microbiota changes during allo-HSCT.
The Effect of Intracerebroventricular Fibroblast Growth Factor 23 on gene expression in the Rats’ Hypothalamus
Authors: Ursem Stan R , Diepenbroek Charlene , Kool Tess , Eggels Leslie , Heijboer Annemieke C , la Fleur Susanne E
Published: November 2022

Fibroblast growth factor 23 (FGF23) is a key regulator of systemic phosphate homeostasis, but also an interplay with glucose metabolism has been suggested. Several studies implicate a function of FGF23 in the brain, and indeed we have recently identified FGF23 protein in several brain areas in rats, such as the hypothalamus, third ventricle and choroid plexus. In the current study, we aimed to determine the effect of an intracerebroventricular (icv) injection of FGF23 in the third ventricle of rats on hypothalamic genes involved in glucose regulation. In addition, we assessed whether glycerol can be used safely for icv injections as glycerol is used as a stabilizing compound for FGF23 protein.

Adult Wistar rats received an icv injection of recombinant rat FGF23 or vehicle. Dose dependent behavioral changes, suggestive of stress, were observed directly after infusion of FGF23. After 60 min animals were sacrificed and the arcuate nucleus, lateral hypothalamus and choroid plexus were isolated. In these brain regions gene expression was determined of the FGF23 receptor complex (FGFR1, αKlotho), NPY, POMC, phosphate transporters (SLC20 and SLC34 families) and markers of cellular ER stress (ATF4 and the ratio of spliced/unspliced XBP1).

We showed that glycerol is well tolerated as stabilizer for icv injections. In FGF23-treated animals, cellular ER stress markers were increased in the arcuate nucleus. FGF23 injection did not affect expression of its receptor complex, NPY, POMC, or phosphate transporters. Future studies are warranted to investigate the effect of FGF23 in the brain on the protein level and on neuronal activation.
Polystyrene-colonizing bacteria are enriched for long-chain alkane degradation pathways
Authors: Hsueh Shu Wei , Jian You-Hua , Fugmann Sebastian D. , Yang Shu Yuan
Published: November 2022

One of the most promising strategies for the management of plastic waste is microbial biodegradation, but efficient degraders for many types of plastics are still lacking, including for polystyrene (PS). Genomics has emerged as a powerful tool for mining environmental microbes that may have the ability to degrade different types of plastics. In this study, we use 16S sequencing to analyze the microbiomes for multiple PS samples collected from sites with different vegetation in Taiwan to reveal potential common properties between species that have exhibit growth advantages on PS surfaces. Phylum enrichment analysis identified Cyanobacteria and Deinococcus-Thermus as being the most over-represented groups on PS, and both phyla include species known to reside in extreme environments and could encode unique enzymes that grant them properties suitable for colonization on PS surfaces. Investigation of functional enrichment in PS-enriched species highlighted carbon metabolic pathways, especially those related to hydrocarbon degradation. This is corroborated by the finding that genes encoding long-chain alkane hydroxylases such as AlmA are more prevalent in the genomes of PS-associated bacteria. Our analyses illustrate how plastic in the environment support the colonization of different microbes compared to surrounding soil. In addition, our results point to the possibility that alkane hydroxylases could confer growth advantages of microbes on PS.
Reference genome sequences of the oriental armyworm,Mythimna separata(Lepidoptera: Noctuidae)
Authors: Yokoi Kakeru , Furukawa Seiichi , Zhou Rui , Jouraku Akiya , Bono Hidemasa
Published: November 2022

Lepidopteran insects are an important group of animals, among which some are used as biochemical and physiological model species in the insect and silk industries, whereas others are major agricultural pests. Therefore, genome sequences of several lepidopteran insects have been reported thus far. The oriental armyworm,Mythimna separata, is an agricultural pest commonly used to study insect immune reactions and interactions with parasitoid wasps as hosts. To improve our understanding of these research topics, reference genome sequences were constructed in the present study. Using long-read and short-read sequence data,de novoassembly and polishing were performed, and haplotigs were purged. Subsequently, gene predictions and functional annotations were performed. To search for orthologs of the Toll and immune deficiency (IMD) pathways and C-type lectins, annotation data analysis, BLASTp, and Hummer scans were performed. TheM. separatagenome is 682 Mbp; its contig N50 was 2.7 Mbp with 21,970 genes and 24,452 coding sites predicted. All orthologs of the core components of the Toll and IMD pathways and 105 C-type lectins were identified. These results suggest that the genome data were of sufficient quality as reference genome data and could contribute to promotingM. separataand lepidopteran research at the molecular and genome levels.

Simple Summary

The oriental armyworm,Mythimna separata, an agricultural pest, is commonly used to study insect immune reactions and interactions with parasitoid wasps. To promote such studies, a reference genome was constructed. TheM. separatagenome is 682Mbp long—a size comparable to that of other lepidopteran insects. The contig N50 value of the genome is 2.7 Mb, which indicates sufficient quality to be used as reference genome data. Gene set data were constructed using genome and RNA-sequencing data; a total of 21,970 genes and 24,452 coding sites were predicted. Functional gene annotation was performed using the predicted amino acid sequences and reference gene set data of the model organism and other insect species as well as Unigene and Pfam datasets. Consequently, 45–80% of the amino acid sequences were annotated using these data sets. Using these data, most of the orthologs of core components in the Toll and immune deficiency (IMD) pathways were identified, suggesting the presence of these two pathways inM. separata. Additionally, 105 C-type lectins were identified in theM. separatagenome, which were more numerous than those in other insect species, suggesting that these genes may be duplicated.
Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis
Authors: Mota-Gómez Irene , Rodríguez Juan Antonio , Dupont Shannon , Lao Oscar , Jedamzick Johanna , Kuhn Ralf , Lacadie Scott , García-Moreno Sara Alexandra , Hurtado Alicia , Acemel Rafael D. , Capel Blanche , Marti-Renom Marc A. , Lupiáñez Darío G.
Published: November 2022

Mammalian sex is determined by opposing networks of ovarian and testicular genes that are well characterized. However, its epigenetic regulation is still largely unknown, thus limiting our understanding of a fundamental process for species propagation. Here we explore the 3D chromatin landscape of sex determinationin vivo, by profiling FACS-sorted embryonic mouse gonadal populations, prior and after sex determination, in both sexes. We integrate Hi-C with ChIP-seq experiments usingMETALoci, a novel genome spatial auto-correlation analysis that identifies 3D enhancer hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination, affecting the enhancer hubs of hundreds of genes that display temporal- and sex-specific expression. Moreover, the identification of the 3D enhancer hubs allows the reconstruction of regulatory networks, revealing key transcription factors involved in sex determination. By combining predictive approaches and validations in transgenic mice we identify a novelFgf9regulatory hub, deletion of which results in male-to-female sex reversal with the upregulation of ovarian-specific markers and the initiation of meiosis. Thus, spatial auto-correlation analysis is an effective strategy to identify regulatory networks associated to biological processes and to further characterize the functional role of the 3D genome.
Modulation of TRPV4 Protects against Degeneration Induced by Sustained Loading and Promotes Matrix Synthesis in the Intervertebral Disc
Authors: Easson Garrett W.D. , Savadipour Alireza , Anandarajah Akila , Iannucci Leanne E. , Lake Spencer P. , Guilak Farshid , Tang Simon Y.
Published: November 2022

While it is well-known that mechanical signals can either promote or disrupt intervertebral disc (IVD) homeostasis, the molecular mechanisms for transducing mechanical stimuli are not fully understood. The transient receptor potential vanilloid 4 (TRPV4) ion channel activated in isolated IVD cells initiates extracellular matrix (ECM) gene expression, while TRPV4 ablation reduces cytokine production in response to circumferential stretching. However, the role of TRPV4 on ECM maintenance during tissue-level mechanical loading remains unknown. Using an organ culture model, we modulated TRPV4 function over both short-(hours) and long-term (days) and evaluated IVDs’ response. Activating TRPV4 with the agonist GSK101 resulted in a Ca2+flux propagating across the cells within the IVD. NF-κB signaling in the IVD peaked at 6 hours following TRPV4 activation that subsequently resulted in higher IL-6 production at 7 days. These cellular responses were concomitant with the accumulation of glycosaminoglycans and increased hydration in the nucleus pulposus that culminated in higher stiffness of the IVD. Sustained compressive loading of the IVD resulted in elevated NF-κB activity, IL-6 and VEGF-A production, and degenerative changes to the ECM. TRPV4 inhibition using GSK205 during loading mitigated the changes in inflammatory cytokines, protected against IVD degeneration, and but could not prevent ECM disorganization due to mechanical damage in the annulus fibrosus. These results indicate TRPV4 plays an important role in both short-and long-term adaptations of the IVD to mechanical loading. The modulation of TRPV4 may be a possible therapeutic for preventing load-induced IVD degeneration.
Subcellular proteome of radial glia reveals non-muscle myosins control basal endfeet to mediate interneuron organization
Authors: D’Arcy Brooke R , Lennox Ashley L , Musso Camila Manso , Bracher Annalise , Escobar-Tomlienovich Carla , Perez-Sanchez Stephany , Silver Debra L
Published: November 2022

Radial glial cells (RGCs) are essential for the generation and organization of neurons in the cerebral cortex. RGCs have an elongated bipolar morphology with basal and apical endfeet which reside in distinct niches. Yet, how this subcellular compartmentalization of RGCs controls cortical development is largely unknown. Here, we employin vivoproximity labeling using unfused BirA to generate the first subcellular proteome of RGCs and uncover new principles governing local control of cortical development. We discover a cohort of proteins that are significantly enriched in RGC basal endfeet, with MYH9 and MYH10 among the most abundant.Myh9andMyh10transcripts also localize to endfeet with distinct temporal dynamics. Although they each encode isoforms of non-muscle myosin II heavy chain,Myh9andMyh10have drastically different requirements for RGC integrity.Myh9loss from RGCs decreases branching complexity and causes endfoot protrusion through the basement membrane. In contrast,Myh10controls endfoot adhesion, as mutants have unattached apical and basal endfeet. Finally, we show thatMyh9- andMyh10-mediated regulation of RGC complexity and endfoot position non-cell autonomously controls interneuron number and organization in the marginal zone. Our study demonstrates the utility ofin vivoproximity labeling for dissecting local control of complex systems, and reveals new mechanisms for dictating RGC integrity and cortical architecture.
Inter-species stimulus enhancement: Herring gulls (Larus argentatus) read human behaviour during foraging
Authors: Feist Franziska , Smith Kiera , Graham Paul
Published: November 2022

Herring gulls are one of the few species that thrive in anthropogenic landscapes and their familiarity with people makes them an excellent target for studies of inter-species social cognition. Urban gulls pay attention to human behaviour in food-related contexts and we set out to investigate whether such cues can be used to redirect a gull’s attention to potential food items in their environment. Herring gulls were given free choice of two differently coloured anthropogenic food items in the presence of a demonstrator, who was either sitting still or pretending to eat food from an item that matched one of the secondary food items. We found that a demonstrator mimicking eating significantly increased the likelihood of an approach or peck. Furthermore, 95% of pecks were directed towards the secondary food item which colour-matched the demonstrator’s food item. The results show situation-dependent attentional modulation in gulls, whereby gulls are able to use human cues for stimulus enhancement and foraging decisions. Given the relatively recent history of urbanisation in herring gulls, this cross-species social information transfer is likely to be a by-product of the cognitive flexibility inherent in kleptoparasitic species.
Phencyclidine disrupts neural coordination and cognitive control by dysregulating translation
Authors: Park Eun Hye , Kao Hsin-Yi , Jourdi Hussam , van Dijk Milenna , Carrillo-Segura Simón , Tunnell Kayla W. , Gutierrez Jeffrey , Wallace Emma J. , Troy-Regier Matthew , Radwan Basma , Lesburguères Edith , Alarcon Juan Marcos , Fenton André A
Published: November 2022

Background

Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist impairs cognition remains unknown.

Methods

The effects of PCP were investigated i) on hippocampal CA1 ensemble action potential dischargein vivoin urethane-anesthetized rats and during awake behavior in mice; ii) on synaptic responses inex vivomouse hippocampus slices; iii) in mice on a hippocampus-dependent active place avoidance task that requires cognitive control; and iv) on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects to the effects of inhibitors of protein synthesis, group-1-type metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs.

Results

Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity, and impaired active place avoidance, despite learning the task before PCP. Consistent with metabotropic actions, PCP exaggerated protein-synthesis dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression (LTD). Pretreatment with anisomycin or the mGluR1/5-antagonist MPEP, both of which repress translation, prevented the PCP-induced discoordination, and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR-antagonist NVP-AAM077 unbalanced translation that engages the AKT, mTOR and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not.

Conclusions

PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, leading to the neural discoordination that is central to the cognitive and sensorimotor impairments.
CSF1R inhibition by PLX5622 reduces pulmonary fungal infection by depleting MHCIIhiinterstitial lung macrophages
Authors: Mohamed Sally H. , Vanhoffelen Eliane , Fu Man Shun , Cosway Emilie , Anderson Graham , Velde Greetje Vande , Drummond Rebecca A.
Published: November 2022

PLX5622 is a small molecular inhibitor of the CSF1 receptor (CSF1R) and is widely used to deplete macrophages within the central nervous system (CNS). However, recent reports have indicated that PLX5622 may affect myeloid cells in other organs including the bone marrow and spleen. We investigated the impact of PLX5622 treatment in wild-type C57BL/6 mice and discovered that one-week treatment with PLX5622 was sufficient to deplete interstitial macrophages in the lung and brain-infiltrating Ly6Clowpatrolling monocytes, in addition to CNS-resident macrophages. These cell types were previously indicated to act as infection reservoirs for the pathogenic fungusCryptococcus neoformans. We therefore took advantage of PLX5622-mediated depletion of these myeloid cell subsets to examine their functional role inC. neoformanslung infection and extrapulmonary dissemination. We found that PLX5622-treated mice had significantly reduced fungal lung infection and reduced extrapulmonary dissemination to the CNS but not to the spleen or liver. Fungal lung infection mapped to MHCIIhiinterstitial lung macrophages, which underwent significant expansion during infection following monocyte replenishment and not local division. Although PLX5622 depleted CNS infiltrating patrolling monocytes, these cells did not accumulate in the fungal-infected CNS following pulmonary infection. In addition, Nr4a1-deficient mice, which lack patrolling monocytes, had similar control and dissemination ofC. neoformansinfection to wild-type controls. Our data demonstrate that PLX5622 may have a beneficial effect in the control of intracellular replicating pathogenic fungi that utilise CSF1R-dependent myeloid cells as infection reservoirs.
Compensation and conversation in autism: atypical connectivity supports typical behavior
Authors: Jasmin Kyle , Martin Alex , Gotts Stephen J.
Published: November 2022

Background

It is well-established that individuals with autism show atypical functional brain connectivity. However, the role this plays in behavior, especially in naturalistic social settings, has remained unclear. Some atypical patterns may reflect core deficits, while others may instead compensate for deficits and promote adaptive behavior. Distinguishing these possibilities requires measuring the ‘typicality’ of spontaneous behavior and determining which connectivity patterns correlate with it.

Methods

Thirty-nine male participants (19 autism, 20 typically-developed) engaged in 115 spontaneous conversations with an experimenter during fMRI scanning (Jasmin, et al., 2019, Brain). A classifier algorithm was trained to distinguish participants by diagnosis based on 81 semantic, affective and linguistic dimensions derived from their use of language. The algorithm’s certainty that a participant was in either the autism or typical group was used as a measure of task performance and compared with functional connectivity levels.

Results

The algorithm accurately classified participants (74%,P= .002), and its scores correlated with clinician-observed autism signs (ADOS) (rs= .56,P= .03). In support of a compensatory role, greater functional connectivity, most prominently between left-hemisphere social communication regions and right inferior frontal cortex, correlated with more typical language behaviour, only for the autism group (rs= .56,P= .01).

Conclusion

We report a simple and highly generalizable method for quantifying behavioral performance and neural compensation during complex spontaneous social behavior, without the need for ana prioribenchmark. The findings suggest that functional connectivity increases in autism during communication reflect a neural compensation strategy.
Cell density-dependent death triggered by viral palindromic DNA sequences
Authors: Robins William P , Meader Bradley T , Toska Jonida , Mekalanos John J
Published: November 2022

Defense systems that recognize viruses have provided not only the tools of molecular biology but also important insights into other mechanisms that can induce immunity to these or other infectious agents including transmissible plasmids and chromosomal genetic elements. Several systems that trigger cell death upon viral infection have recently been recognized but the signals that activate these abortive infection systems remain largely unknown. Here we characterize one such system inVibrio choleraethat we found was responsible for triggeringcell-densitydependentdeath (CDD) of bacterial cells in response to the presence of certain genetic elements. The key components of the CDD system include quorum-regulated components DdmABC and the host factor PriA. Our analysis indicates that the plasmid and phage signals that trigger CDD were palindromic DNA sequences that are predicted to form stem-loop hairpin structures from single-stranded DNA during stalled replication. Our results further suggest that other agents that generate damaged DNA can also trigger DdmABC/PriA activation and cell death probably through activation of a nuclease domain present in the DdmA protein. Thus, any infectious process that results in damaged DNA, particularly during DNA replication, can in theory trigger cell death through the DdmABC/PriA abortive infection system.
Defense systems are pervasive across chromosomally integrated mobile genetic elements and are inversely correlated to virulence and antimicrobial resistance
Authors: Botelho João
Published: November 2022

Mobile genetic elements (MGEs) are key promoters of microbial evolution. These elements can be located extrachromosomally or integrated into the chromosome. Well-known examples of chromosomally integrated MGEs (ciMGEs) are integrative and conjugative/mobilizable elements (ICEs and IMEs), and most studies to date have focused on the biological mechanisms that shape their lifestyle. It is crucial to profile the diversity and understand their distribution across the microbial community, as the number of genome sequences increases exponentially. Herein, I scanned a collection of more than 20000 bacterial and archaeal non-redundant genomes and found over 13000 ciMGEs across multiple phyla, representing a massive increase in the number of ciMGEs available in public databases (<1000). Although ICEs are the most important ciMGEs for the accretion of defense systems, virulence, and antimicrobial resistance (AMR) genes, IMEs outnumbered ICEs. Moreover, defense systems, AMR, and virulence genes were negatively correlated in both ICEs and IMEs. Multiple ciMGEs form heterogeneous communities and challenge inter-phylum barriers. Finally, I observed that the functional landscape of ICEs was populated by uncharacterized proteins. Altogether, this study provides a comprehensive catalog of nucleotide sequences and associated metadata for ciMGEs from 34 phyla across the bacterial and archaeal domains.
Geometry of population activity in spiking networks with low-rank structure
Authors: Cimesa Ljubica , Ciric Lazar , Ostojic Srdjan
Published: November 2022

Recurrent network models are instrumental in investigating how behaviorally-relevant computations emerge from collective neural dynamics. A recently developed class of models based on low-rank connectivity provides an analytically tractable framework for understanding of how connectivity structure determines the geometry of low-dimensional dynamics and the ensuing computations. Such models however lack some fundamental biological constraints, and in particular represent individual neurons in terms of abstract units that communicate through continuous firing rates rather than discrete action potentials. Here we examine how far the theoretical insights obtained from low-rank rate networks transfer to more biologically plausible networks of spiking neurons. Adding a low-rank structure on top of random excitatory-inhibitory connectivity, we systematically compare the geometry of activity in networks of integrate-and-fire neurons to rate networks with statistically equivalent low-rank connectivity. We show that the mean-field predictions of rate networks allow us to identify low-dimensional dynamics at constant population-average activity in spiking networks, as well as novel non-linear regimes of activity such as out-of-phase oscillations and slow manifolds. We finally exploit these results to directly build spiking networks that perform nonlinear computations.

Author summary

Behaviorally relevant information processing is believed to emerge from interactions among neurons forming networks in the brain, and computational modeling is an important approach for understanding this process. Models of neuronal networks have been developed at different levels of detail, with typically a trade off between analytic tractability and biological realism. The relation between network connectivity, dynamics and computations is best understood in abstract models where individual neurons are represented as simplified units with continuous firing activity. Here we examine how far the results obtained in a specific, analytically-tractable class of rate models extend to more biologically realistic spiking networks where neurons interact through discrete action potentials. Our results show that abstract rate models provide accurate predictions for the collective dynamics and the resulting computations in more biologically faithful spiking networks.
The RNF220 domain nuclear factor Teyrha-Meyrha (Tey) regulates the migration and differentiation of specific visceral and somatic muscles inDrosophila
Authors: Frasch Manfred , Ismat Afshan , Reim Ingolf , Raufer Jasmin
Published: November 2022

The development of the visceral musculature of theDrosophilamidgut encompasses a closely coordinated sequence of migration events of cells from the trunk and caudal visceral mesoderm, respectively, that underlies the formation of the stereotypic orthogonal pattern of circular and longitudinal midgut muscles. Our current study focuses on the last step of migration and morphogenesis of the longitudinal visceral muscle precursors derived from the caudal mesoderm. We show that these multinucleated muscle precursors utilize dynamic filopodial extensions to migrate in dorsal and ventral directions over the forming midgut tube. The establishment of maximal dorsoventral distances from one another and subsequent alignment with their anteroposterior neighbors leads to the equidistant coverage of the midgut with longitudinal muscle fibers. We identify Teyrha-Meyhra (Tey), a tissue-specific nuclear factor related to the RNF220 domain protein family, as a crucial regulator of this process of muscle migration and morphogenesis that is further required for proper differentiation of the longitudinal visceral muscles. In addition, Tey is expressed in a single type of somatic muscle founder cell in each hemisegment. Tey regulates the migration of this founder cell and is required for the proper pathfinding of its developing myotube to specific myotendinous attachment sites.
A single extracellular loop of FoxA controls ligand specificity, uptake, and signaling inPseudomonas aeruginosa
Authors: Chan Derek C. K. , Josts Inokentijs , Koteva Kalinka , Wright Gerard D. , Tidow Henning , Burrows Lori L.
Published: November 2022

The outer membrane of Gram-negative bacteria prevents many antibiotics from reaching intracellular targets. However, some antimicrobials can take advantage of iron import transporters to cross this barrier. We showed previously that the thiopeptide antibiotic, thiocillin, exploits the nocardamine (ferrioxamine E) xenosiderophore transporter, FoxA, of the opportunistic pathogenPseudomonas aeruginosafor uptake. Here we show that FoxA also transports the xenosiderophore bisucaberin and describe at 2.5 Å resolution the first crystal structure of bisucaberin bound to FoxA. Bisucaberin is distinct from other siderophores because it forms a 3:2 rather than 1:1 siderophore-iron complex. Mutations in a single extracellular loop of FoxA differentially affected nocardamine, thiocillin, and bisucaberin binding, uptake, and signal transduction. These results show that in addition to modulating ligand binding, the extracellular loops of siderophore transporters are of fundamental importance for controlling ligand uptake and its regulatory consequences, which has implications for the development of siderophore-antibiotic conjugates to treat difficult infections.
Sensory Reweighting: A Common Mechanism for Subjective Visual Vertical and Cybersickness Susceptibility
Authors: Chung William , Barnett-Cowan Michael
Published: November 2022

The malaise symptoms of cybersickness are thought to be related to the sensory conflict present in the exposure to virtual reality (VR) content. When there is a sensory mismatch in the process of sensory perception, the perceptual estimate has been shown to change based on a reweighting mechanism between the relative contributions of the individual sensory signals involved. In this study, the reweighting of vestibular and body signals was assessed before and after exposure to different typical VR experiences and sickness severity was measured to investigate the relationship between susceptibility to cybersickness and sensory reweighting. Participants reported whether a visually presented line was rotated clockwise or counterclockwise from vertical while laying on their side in a subjective visual vertical (SVV) task. Task performance was recorded prior to VR exposure and after a low and high intensity VR game. The results show that the SVV was significantly shifted away from the body representation of upright and towards the vestibular signal after exposure to the high intensity VR game. Cybersickness measured using the fast motion sickness (FMS) scale found that sickness severity ratings were higher in the high intensity compared to the low intensity experience. The change in SVV from baseline after each VR exposure modelled using a simple 3-parameter gaussian regression fit was found to explain 49.5% of the variance in the FMS ratings. These results highlight the aftereffects of VR for sensory perception and suggests a potential relationship between the susceptibility to cybersickness and sensory reweighting.
Dendritic excitability controls overdispersion
Authors: Friedenberger Zachary , Naud Richard
Published: November 2022

The brain is an intricate assembly of intercommunicating neurons whose input-output function is only partially understood. The role of active dendrites in shaping spiking responses, in particular, is unclear. Although existing models account for active dendrites and spiking responses, they are too complex to analyze analytically and demand long stochastic simulations. Here we combined cable and renewal theory to describe how input fluctuations shape the response of neuronal ensembles with active dendrites. We found that dendritic input readily and potently controls interspike interval dispersion. This phenomenon can be understood by considering that neurons display three fundamental operating regimes: one mean-driven regime and two fluctuation-driven regimes. We show that these results are expected to appear for a wide range of dendritic properties and verify the predictions of the model in experimental data. These findings have implications for the role of interspike interval dispersion in learning and for theories of attractor states.
Thermoconforming rays of the star-nosed mole
Authors: Tattersall Glenn J. , Campbell Kevin L.
Published: November 2022

The star-nosed mole (Condylura cristata) is well known for its unique star-like rostrum (‘star’) which is formed by 22 nasal appendages highly specialised for tactile sensation. As a northerly distributed insectivorous mammal occupying both aquatic and terrestrial habitats, this sensory appendage is regularly exposed to cold water and thermally conductive soil, leading us to ask whether the surface temperature, a proxy for blood flow to the star, conforms to the local ambient temperature to conserve body heat. Alternatively, given the high functioning and sensory nature of the star, we posited it was possible that the rays may be kept continually warm when foraging, with augmented peripheral blood flow serving the metabolic needs of this tactile sensory organ. To test these ideas, we remotely monitored the surface temperatures of the star and other uninsulated appendages in response to changes in local water or ground temperature in captive, wild-caught star-nosed moles. While the tail responded to increasing heat load through vasodilation, the surface temperature of the star consistently thermoconformed, varying passively in surface temperature, suggesting little evidence for thermoregulatory vasomotion. This thermoconforming response may have evolved as a compensatory response related to the high costs of heat dissipation to water or soil in this actively foraging insectivore.

Summary Statement (for JEB Submission)

The highly mechanosensitive nasal rays of the star-nosed mole conform closely with ambient temperature thereby minimizing heat loss without apparent changes in sensory performance.