bluuebunny/crossref_metadata_2025 huggingface dataset:
Reference Values for Dopamine Transporter Imaging With 99mTc-TRODAT-1 in Healthy Subjects and Parkinson’s Disease Patients
Authors: Pitella Felipe Arriva , Trevisan Ana Carolina , Alexandre-Santos Leonardo , Kato Mery , Macruz Brito Manuelina Mariana Capellari , Tumas Vitor , Wichert-Ana Lauro
Published: June 2022

Purpose

The aim of this study was to evaluate different quantitative indexes of striatum dopamine transporter density in healthy subjects and patients with PD.

Patients and Methods

Sixty-seven patients, 23 healthy (8 male; 59 ± 11 years old) and 44 age-matched patients (29 male; 59 ± 7 years old), with various degrees of severity of idiopathic PD (duration of symptoms, 10 ± 6 years; Hoehn and Yahr Scale, 2.16 ± 0.65; UPDRS-3, 29.74 ± 17.79). All patients performed 99mTc-TRODAT-1 SPECT. Binding potential indexes (BPIs) of striatum and subregions, asymmetry index (AI), and putamen/caudate ratio (P/C) were calculated.

Results

Binding potential index was lower in the PD than in healthy subjects. A BPI cutoff for striatum and putamen ranging from 0.73 to 0.78 showed 95% to 100% sensitivity and 84% to 88% specificity. For the caudate nucleus, a BPI threshold of 0.8 to 0.88 revealed 100% sensitivity and 77% to 84% specificity. The BPI’s respective areas under the curve ranged from 0.92 to 0.98. For AI and P/C, the area under the curve was less than 0.70. Binding potential index intraclass correlation coefficient was close to 1.0 in the intraobserver evaluation and 0.76 to 0.87 in the interobserver assessment. Intraclass correlation coefficient for AI and P/C was inferior to 0.75 in the intraobserver and interobserver evaluations.

Conclusions

Different semiquantitative indices differentiated PD and healthy subjects and may help the differential diagnosis of other entities involving the dopaminergic system. Asymmetry index and P/C performances were lower than BPI, including their intraobserver and interobserver reliability, and therefore should be used with caution.
Genomic architecture of supergenes: connecting form and function
Authors: Berdan Emma L. , Flatt Thomas , Kozak Genevieve M. , Lotterhos Katie E. , Wielstra Ben
Published: June 2022

Supergenes are tightly linked sets of loci that are inherited together and control complex phenotypes. While classical supergenes—governing traits such as wing patterns in
Heliconius
butterflies or heterostyly in
Primula
—have been studied since the Modern Synthesis, we still understand very little about how they evolve and persist in nature. The genetic architecture of supergenes is a critical factor affecting their evolutionary fate, as it can change key parameters such as recombination rate and effective population size, potentially redirecting molecular evolution of the supergene in addition to the surrounding genomic region. To understand supergene evolution, we must link genomic architecture with evolutionary patterns and processes. This is now becoming possible with recent advances in sequencing technology and powerful forward computer simulations. The present theme issue brings together theoretical and empirical papers, as well as opinion and synthesis papers, which showcase the architectural diversity of supergenes and connect this to critical processes in supergene evolution, such as polymorphism maintenance and mutation accumulation. Here, we summarize those insights to highlight new ideas and methods that illuminate the path forward for the study of supergenes in nature.

This article is part of the theme issue ‘Genomic architecture of supergenes: causes and evolutionary consequences’.
Inversion invasions: when the genetic basis of local adaptation is concentrated within inversions in the face of gene flow
Authors: Schaal Sara M. , Haller Benjamin C. , Lotterhos Katie E.
Published: June 2022

Across many species where inversions have been implicated in local adaptation, genomes often evolve to contain multiple, large inversions that arise early in divergence. Why this occurs has yet to be resolved. To address this gap, we built forward-time simulations in which inversions have flexible characteristics and can invade a metapopulation undergoing spatially divergent selection for a highly polygenic trait. In our simulations, inversions typically arose early in divergence, captured standing genetic variation upon mutation, and then accumulated many small-effect loci over time. Under special conditions, inversions could also arise late in adaptation and capture locally adapted alleles. Polygenic inversions behaved similarly to a single supergene of large effect and were detectable by genome scans. Our results show that characteristics of adaptive inversions found in empirical studies (e.g. multiple large, old inversions that are
F
ST
outliers, sometimes overlapping with other inversions) are consistent with a highly polygenic architecture, and inversions do not need to contain any large-effect genes to play an important role in local adaptation. By combining a population and quantitative genetic framework, our results give a deeper understanding of the specific conditions needed for inversions to be involved in adaptation when the genetic architecture is polygenic.

This article is part of the theme issue ‘Genomic architecture of supergenes: causes and evolutionary consequences’.
Supergene potential of a selfish centromere
Authors: Finseth Findley , Brown Keely , Demaree Andrew , Fishman Lila
Published: June 2022

Selfishly evolving centromeres bias their transmission by exploiting the asymmetry of female meiosis and preferentially segregating to the egg. Such female meiotic drive systems have the potential to be supergenes, with multiple linked loci contributing to drive costs or enhancement. Here, we explore the supergene potential of a selfish centromere (
D
) in
Mimulus guttatus
, which was discovered in the Iron Mountain (IM) Oregon population. In the nearby Cone Peak population,
D
is still a large, non-recombining and costly haplotype that recently swept, but shorter haplotypes and mutational variation suggest a distinct population history. We detected
D
in five additional populations spanning more than 200 km; together, these findings suggest that selfish centromere dynamics are widespread in
M. guttatus
. Transcriptome comparisons reveal elevated differences in expression between driving and non-driving haplotypes within, but not outside, the drive region, suggesting large-scale
cis
effects of
D
's spread on gene expression. We use the expression data to refine linked candidates that may interact with drive, including Nuclear Autoantigenic Sperm Protein (NASP
SIM3
), which chaperones the centromere-defining histone CenH3 known to modify
Mimulus
drive. Together, our results show that selfishly evolving centromeres may exhibit supergene behaviour and lay the foundation for future genetic dissection of drive and its costs.

This article is part of the theme issue ‘Genomic architecture of supergenes: causes and evolutionary consequences’.
Pseudomonas petroselini sp. nov., a pathogen causing bacterial rot of parsley in Japan
Authors: Sawada Hiroyuki , Fujikawa Takashi , Osada Shigeru , Satou Mamoru
Published: June 2022

Phytopathogenic bacterial strains (MAFF 311094T, MAFF 311095, MAFF 311096 and MAFF 311097), which were isolated from rot lesions of parsley (Petroselinum crispum) sampled in Miyagi, Japan, were subjected to polyphasic characterization to determine their taxonomic position. The cells were Gram-reaction-negative, aerobic, non-spore-forming, motile with one or two polar flagella and rod-shaped. The 16S rRNA gene sequences analyses revealed that the strains belong to the genus

Pseudomonas

, exhibiting the highest sequence similarity to

Pseudomonas sivasensis

P7T (99.93% sequence similarity),

Pseudomonas cyclaminis

MAFF 301449T (99.93 %),

Pseudomonas extremaustralis

14-3T (99.86 %),

Pseudomonas kitaguniensis

MAFF 212408T (99.86 %) and

Pseudomonas antarctica

CMS 35T (99.79 %). The genomic DNA G+C content was 60.1 mol%, and the major cellular fatty acids (>5 % of the total fatty acids) were C16:0, summed feature 3 (C16:1
ω7c/C16:1
ω6c), summed feature 8 (C18:1
ω7c/C18:1
ω6c) and C17:0 cyclo. The rpoD sequence-based phylogenetic and whole genome-based phylogenomic analyses demonstrated that the strains are a member of the

Pseudomonas fluorescens

subgroup, but their phylogenetic position does not match those of any members of this subgroup. The average nucleotide identity and digital DNA–DNA hybridization values between the strains and their closely related species were ≤90.64% and ≤41.9 %, respectively, which were below the thresholds for prokaryotic species delineation (95–96 and 70%, respectively). Phenotypic characteristics, pathogenicity toward parsley and cellular fatty acid composition could differentiate the strains from their closest relatives. The phenotypic, chemotaxonomic and genotypic data presented in this study revealed that the strains constitute a novel

Pseudomonas

species, for which we propose the name Pseudomonas petroselini sp. nov., with MAFF 311094T (=ICMP 24279T) being the type strain.
Network-based multi-omics integration reveals metabolic at-risk profile within treated HIV-infection
Authors: Mikaeloff Flora , Gelpi Marco , Benfeitas Rui , Knudsen Andreas D. , Vestad Beate , Høgh Julie , Hov Johannes R. , Benfield Thomas , Murray Daniel , Giske Christian G , Mardinoglu Adil , Trøseid Marius , Nielsen Susanne D. , Neogi Ujjwal
Published: June 2022

Multiomics technologies improve the biological understanding of health status in people living with HIV on antiretroviral therapy (PLWHART). Still, a systematic and in-depth characterization of metabolic risk profile during successful long-term treatment is lacking. Here, we used multi-omics (plasma lipidomic and metabolomic, and fecal 16s microbiome) data-driven stratification and characterization to identify the metabolic at-risk profile within PLWHART. Through network analysis and similarity network fusion (SNF), we identified three groups of PLWHART (SNF-1 to 3). The PLWHART at SNF-2 (45%) was a severe at-risk metabolic profile with increased visceral adipose tissue, BMI, higher incidence of metabolic syndrome (MetS), and increased di- and triglycerides despite having higher CD4+ T-cell counts than the other two clusters. However, the healthy-like and severe at-risk group had a similar metabolic profile differing from HC, with dysregulation of amino acid metabolism. At the microbiome profile, the healthy-like group had a lower α-diversity, a lower proportion of MSM, and was enriched in Bacteroides. In contrast, in at-risk groups, there was an increase in Prevotella, with a high proportion of men who have sex with men (MSM) confirming the influence of sexual orientation on the microbiome profile The multi-omics integrative analysis reveals a complex microbial interplay by microbiome-derived metabolites in PLWHART. PLWHART those are severely at-risk clusters may benefit from personalized medicine and lifestyle intervention to improve their metabolic profile.

Significance

The network and factorization-based integrative analysis of plasma metabolomics, lipidomics, and microbiome profile identified three different diseases’ state -omics phenotypes within PLWHART driven by metabolomics, lipidomics, and microbiome that a single omics or clinical feature could not explain. The severe at-risk group has a dysregulated metabolic profile that potentiates metabolic diseases that could be barriers to healthy aging. The at-risk group may benefit from personalized medicine and lifestyle intervention to improve their metabolic profile.
Cdh5-lineage independent origin of dermal lymphatic vessels revealed by temporally restricted lineage tracing
Authors: Zhang Yan , Ortsäter Henrik , Martinez-Corral Ines , Mäkinen Taija
Published: June 2022

The developmental origins of lymphatic endothelial cells (LECs) have been under intense research after a century-long debate. Although previously thought to be of solely venous endothelial origin, additional sources of LECs were recently identified in multiple tissues in mice. Here, we investigated the regional differences in the origin(s) of the dermal lymphatic vasculature by lineage tracing using the pan-endothelial Cdh5-CreERT2 line. Tamoxifen-induced labeling of blood ECs at E9.5, prior to initiation of lymphatic development, traced the majority of dermal LECs but with lower efficiency in the lumbar compared with cervical skin. By contrast, when used at E9.5 but not at E11.5, 4-hydroxytamoxifen, the active metabolite of tamoxifen that provides a tighter window of Cre activity, revealed low labeling frequency of LECs, and lymphvasculogenic clusters in the lumbar skin in particular. Temporally restricted lineage tracing thus reveals contribution of LECs of Cdh5-lineage independent origin to dermal lymphatic vasculature. Our results further highlight the Cre induction strategy as a critical parameter in defining the temporal window for stage-specific lineage tracing during early developmental stages of rapid tissue differentiation.
Genetic conflicts between sex chromosomes drive expansion and loss of sperm nuclear basic protein genes in Drosophila
Authors: Chang Ching-Ho , Malik Harmit S.
Published: June 2022

Many animal species employ short, positively charged proteins, called sperm nuclear basic proteins (SNBPs) or protamines, for tighter packaging of genomes in sperm. SNBP repertoires differ dramatically across animal lineages and signatures of rapid evolution have been reported in mammals. Both sperm competition and meiotic drive between sex chromosomes have been proposed as causes of SNBP innovation. We used a phylogenomic approach to investigate SNBP diversification and its underlying causes in Drosophila species. We found unambiguous signatures of positive selection in most SNBP genes except for genes essential for male fertility in D. melanogaster. Unexpectedly, evolutionarily young SNBP genes are more likely to encode essential functions for fertility than ancient, conserved SNBP genes like CG30056, which we found is dispensable for male fertility despite universal retention in Drosophila species. We found 19 independent amplification events involving eight SNBP genes that occurred preferentially on sex chromosomes in 78 Drosophila species. Conversely, we found that otherwise-conserved SNBP genes were lost in the montium group of Drosophila species, coincident with an X-Y chromosomal fusion. Furthermore, SNBP genes that became linked to sex chromosomes via chromosomal fusions are prone to degenerate or relocate back to autosomes. We hypothesize that SNBP genes ancestrally encoded by autosomes suppress meiotic drive, whereas sex-chromosomal SNBP expansions directly participate in meiotic drive. X-Y fusions in the montium group render autosomal SNBPs dispensable by making X-versus-Y meiotic drive obsolete or costly. We conclude that SNBP rapid evolution is driven by genetic conflicts between sex chromosomes during spermatogenesis in Drosophila species.
The incubation period for monkeypox cases confirmed in the Netherlands, May 2022
Authors: Miura Fuminari , van Ewijk Catharina Else , Backer Jantien A. , Xiridou Maria , Franz Eelco , de Coul Eline Op , Brandwagt Diederik , van Cleef Brigitte , van Rijckevorsel Gini , Swaan Corien , van den Hof Susan , Wallinga Jacco
Published: June 2022

In May 2022 outbreaks of monkeypox have been reported in countries where the monkeypox virus is not endemic. We estimate the incubation period for monkeypox, using the reported time of exposure and symptom onset for 18 confirmed cases detected in the Netherlands up to 31st May 2022. The mean incubation period was 8.5 days, ranging from 4.2 to 17.3 days (5th to 95th percentiles). These findings underpin 21 days for monitoring or quarantining of case contacts.
A new Oprm1-Cre mouse line enables detailed molecular characterization of μ-opioid receptor cell types
Authors: Mengaziol Juliet , Dunn Amelia D. , Crues-Muncunill Jordi , Eacret Darrell , Chen Chongguang , Bland Kathryn , Liu-Chen Lee-Yuan , Ehrlich Michelle E. , Blendy Julie A.
Published: June 2022

Key targets of both the therapeutic and abused properties of opioids are μ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the cellular mechanisms underlying opioid addiction. Given that addictive opioids such as morphine, oxycodone, heroin, and fentanyl all activate MORs, and current therapies such as naloxone and buprenorphine block this activation, the availability of tools to mechanistically investigate opioid-mediated cellular and behavioral phenotypes are necessary. Therefore, we derived, validated, and applied a novel MOR-specific Cre mouse line, inserting the Cre coding sequence into the MOR 3’UTR to generate a bicistronic gene. As intended, there were no differences in behavioral responses to morphine when compared to wild type mice, nor are there any alterations in Oprm1 gene expression or receptor density. To assess Cre recombinase activity, MOR-Cre mice were crossed with the floxed GFP-reporters, RosaLSLSun1-sfGFP or RosaLSL-GFP-L10a. The latter allowed for cell type specific RNA sequencing via TRAP (Translating Ribosome Affinity Purification) of striatal MOR+ neurons following opioid withdrawal. This new tool will facilitate the study of opioid biology under varying conditions.
Human norovirus efficiently replicates in differentiated 3D-human intestinal enteroids
Authors: Mirabelli Carmen , Santos-Ferreira Nanci , Gillilland Merritt G. , Cieza Roberto J. , Colacino Justin A. , Sexton Jonathan Z. , Taube Stefan , Rocha-Pereira Joana , Wobus Christiane E.
Published: June 2022

Human norovirus (HNoV) accounts for one fifth of all acute viral gastroenteritis worldwide and an economic burden of ∼$60 billion globally. The lack of treatment options against HNoV is in part due to the lack of cultivation systems. Recently, a model of infection in biopsies-derived human intestinal enteroids (HIE) has been described: 3D-HIE are first dispersed in 2D-monolayers and differentiated prior to infection, resulting in a labor-intensive, time-consuming procedure. Here, we present an alternative protocol for HNoV infection of 3D-HIE. We found that 3D-HIE differentiate as efficiently as 2D-monolayers. In addition, immunofluorescence-based quantification of UEA-1, a lectin that stains the villus brush border, revealed that over 90% of differentiated 3D-HIE spontaneously undergo polarity inversion, allowing for viral infection without the need for microinjection. Infection with HNoV GII.4-positive stool samples attained a fold-increase over inoculum of ∼2 Log10 at 2 days post infection or up to 3.5 Log10 when ruxolitinib, a JAK1/2-inhibitor, was added. Treatment of GII.4-infected 3D-HIE with the polymerase inhibitor 2’-C-Methylcytidine (2CMC), other antivirals, or with a HNoV-neutralizing antibody showed a reduction in viral infection, suggesting that 3D-HIE are an excellent platform to test anti-infectives. The host response to HNoV was then investigated by RNA sequencing in infected versus uninfected 3D-HIE, in the presence of ruxolitinib to focus on viral-associated signatures. The analysis revealed upregulated hormones and neurotransmitter signal transduction pathways and downregulated inflammatory pathways upon HNoV infection. Overall, 3D-HIE have proven to be a more robust model to study HNoV infection, screen antivirals and investigate host response to HNoV infection.

Importance

Human norovirus (HNoV) clinical and socio-economic impact calls for immediate actions in the development of anti-infectives. Physiologically-relevant in vitro models are hence needed to study HNoV biology, tropism and mechanism of viral-associated disease but also as a platform to identify antiviral agents. Biopsy-derived human intestinal enteroids are a biomimetic of the intestine and recently described as a model that supports HNoV infection. The established protocol is time-consuming and labor-intensive. Therefore, we sought to develop a simplified and robust alternative model of infection in 3D enteroids that undergo differentiation and spontaneous polarity inversion. Advantages of this model are the shorter experimental time, better infection yield and spatial integrity of the intestinal epithelium. This model is potentially suitable for the study of pathogens that infect intestinal cells from the apical surface but also for unraveling the interactions between intestinal epithelium and indigenous bacteria of the human microbiome.
SARS-CoV-2 type I Interferon modulation by nonstructural proteins 1 and 2
Authors: Lacasse Émile , Dubuc Isabelle , Gudimard Leslie , Gravel Annie , Allaeys Isabelle , Boilard Éric , Flamand Louis
Published: June 2022

Since the beginning of the COVID-19 pandemic, enormous efforts were devoted to understanding how SARS-CoV-2 escapes the antiviral response. Yet, modulation of type I interferons (IFNs) by this virus is not completely understood. Using in vitro and in vivo approaches, we have characterized the type I IFN response during SARS-CoV-2 infection as well as immune evasion mechanisms. The transcriptional and translational expression of IFNs, cytokines and chemokines were measured in lung homogenates of Wuhan-like, Beta, and Delta SARS-CoV-2 K18-ACE2 transgenic mice. Using in vitro experiments, we measured SARS-CoV-2 and its non-structural proteins 1 and 2 (Nsp1-2) to modulate expression of IFNβ and interferon-stimulated genes (ISG). Our data show that infection of mice with Wuhan-like virus induces robust expression of Ifna and Ifnb1 mRNA and limited type I production. In contrast, Beta and Delta variant infected mice failed to activate and produce IFNα. Using in vitro systems, Ifnβ gene translation inhibition was observed using an Nsp1 expression vector. Conversely, SARS-CoV-2 and its variants induce robust expression of NF-κB-driven genes such as those encoding CCL2 ans CXCL10 chemokines. We also identified Nsp2 as an activator of NF-κB that partially counteracts the inhibitory actions of Nsp1. In summary, our work indicates that SARS-CoV-2 skews the antiviral response in favor of an NF-κB-driven inflammatory response, a hallmark of acute COVID-19, and that Nsp2 is partly responsible for this effect.

Importance

Several studies suggest that SARS-CoV-2 possess multiple mechanisms aimed shunting the type I interferon response. However, few studies have studied type I IFN modulation in the context of infection. Our work indicates that mice and human cells infected with SARS-CoV-2 produce sufficient type I IFN to activate an antiviral response, despite Nsp1 translational blockade of IFNΒ1 mRNA. In contrast to Wuhan-like virus, Beta and Delta variants failed to induce Ifna gene expression. Our work also showcases the importance of studying protein functions in the context of infection, as demonstrated by the partial antagonizing properties of the Nsp2 protein on the activities of Nsp1. Our studies also highlight that the innate immune response triggered by SARS-CoV-2 is chiefly driven by NF-κB responsive genes for which Nsp2 is partially responsible.
Media coverage and speculation about the impact of the COVID-19 pandemic on suicide: A content analysis of UK news
Authors: Marzano Lisa , Hawley Monica , Fraser Lorna , Lainez Yasmine , Marsh James , Hawton Keith
Published: June 2022

Objectives

Since the start of the COVID-19 pandemic, there has been much concern and speculation about rises in suicide rates, despite evidence that suicides did not in fact increase in the first year of the pandemic in most countries with real-time suicide data. This public narrative is potentially harmful, as well as misleading, and is likely to be perpetuated by sensational news coverage.

Method

We conducted a systematic analysis of UK news coverage (including opinion pieces) on the impact of COVID-19 on suicidality, to examine the content and quality of such reporting as the pandemic developed, and as different coronavirus restrictions were imposed.

Results

We identified 372 stories about COVID-19 and suicidality in online and print news between the first UK lockdown (March 2020) and May 2021 (when restrictions were significantly eased in the UK). Throughout this period, over a third of articles (39.2%) and headlines (41.4%) claimed or predicted a rise in suicide, often attributed to feelings of entrapment and poor mental health (especially amongst young people), and fueled by expert commentary and speculation. Almost a third of reports were rated as being of poor overall quality (116, 31.2%), and at least half included no signposting to help and support. However, reporting improved in phases of less stringent COVID-19 restrictions and over time, with later articles and headlines including fewer negative statements and predictions about rises in suicides, and greater reliance on academic evidence.

Conclusions

As the longer-term consequences of the pandemic develop, and other national and global events unfold, it is increasingly important that the media, and the wider community of experts shaping its narratives, strive for a positive and evidence-informed approach to news coverage of suicide.

Strengths and Limitations of this Study

This is the first systematic analysis of UK news coverage on the impact of COVID-19 on suicidality.

Findings are based on a well-established, evidence-informed news monitoring database.

However, this analysis cannot account for the impact of news coverage on different audiences, nor for its reach

Our focus did not extend to broadcasts or other media formats.
Optical Control of Neuronal Activities with Photoswitchable Nanovesicles
Authors: Xiong Hejian , Alberto Kevin A. , Youn Jonghae , Taura Jaume , Morstein Johannes , Li Xiuying , Wang Yang , Trauner Dirk , Slesinger Paul A. , Nielsen Steven O. , Qin Zhenpeng
Published: June 2022

Precise modulation of neuronal activity by neuroactive molecules is essential for understanding brain circuits and behavior. However, tools for highly controllable molecular release are lacking. Here, we developed a photoswitchable nanovesicle with azobenzene-containing phosphatidylcholine (azo-PC), coined ‘azosome’, for neuromodulation. Irradiation with 365 nm light triggers thetrans-to-cisisomerization of azo-PC, resulting in a disordered lipid bilayer with decreased thickness and cargo release. Irradiation with 455 nm light induces reverse isomerization and switches the release off. Real-time fluorescence imaging shows controllable and repeatable cargo release within seconds (< 3 s). Importantly, we demonstrate that SKF-81297, a dopamine D1-receptor agonist, can be released from the azosome to activate cultures of primary striatal neurons. Azosome shows promise in precise optical control over the molecular release and can be a valuable tool for molecular neuroscience studies.
MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors
Authors: Kilian Michael , Sheinin Ron , Tan Chin Leng , Kraemer Christopher , Friedrich Mirco , Kaminitz Ayelet , Sanghvi Khwab , Lindner Katharina , Cichon Frederik , Jung Stafanie , Jaehne Kristine , Ratliff Miriam , Prins Robert , von Deimling Andreas , Wick Wolfgang , Madi Asaf , Bunse Lukas , Platten Michael
Published: June 2022

Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of nuclear factor of activated T cells (Nfat)2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.
New model of glucose-insulin regulation characterizes effects of physical activity and facilitates personalized treatment evaluation in children and adults with type 1 diabetes
Authors: Deichmann Julia , Bachmann Sara , Burckhardt Marie-Anne , Pfister Marc , Szinnai Gabor , Kaltenbach Hans-Michael
Published: June 2022

Accurate treatment adjustment to physical activity (PA) remains a challenging problem in type 1 diabetes (T1D) management. Exercise-driven effects on glucose metabolism depend strongly on duration and intensity of the activity, and are highly variable between patients. In-silico evaluation can support the development of improved treatment strategies, and can facilitate personalized treatment optimization. This requires models of the glucose-insulin system that capture relevant exercise-related processes. We developed a model of glucose-insulin regulation that describes changes in glucose metabolism for moderate- to high-intensity PA of short and prolonged duration. In particular, we incorporated the insulin-independent increase in glucose uptake and production, including glycogen depletion, and the prolonged rise in insulin sensitivity. The model further includes meal absorption and insulin kinetics, allowing simulation of everyday scenarios. The model accurately predicts glucose dynamics for varying PA scenarios in a range of independent validation data sets, and full-day simulations with PA of different timing, duration and intensity agree with clinical observations. We personalized the model on data from a multi-day free-living study of children with T1D by adjusting a small number of model parameters to each child. To assess the use of the personalized models for individual treatment evaluation, we compared subject-specific treatment options for PA management in replay simulations of the recorded data with altered meal, insulin and PA inputs.

Author summary

Exercise represents a cornerstone of diabetes management. Yet, many people with type 1 diabetes restrain from exercising, since it increases the risk for hypoglycemia and requires adjusted insulin treatment. The effect of exercise on blood glucose levels depends on exercise duration and intensity, but also varies strongly between individuals, making accurate adjustment a challenge. Mathematical models can help to better understand exercise physiology and to devise new treatment strategies. Here, we propose a model of glucose-insulin regulation that captures the effects of exercise on glucose metabolism and personalize it to individual children with type 1 diabetes, allowing subject-specific treatment assessment.
Mutation of theDrosophilaserotonin transporter dSERT disrupts courtship and feeding and increases both daytime and nighttime sleep
Authors: Knapp Elizabeth M. , Kaiser Andrea , Arnold Rebecca C. , Sampson Maureen M. , Ruppert Manuela , Xu Li , Anderson Matthew I. , Bonanno Shivan L. , Scholz Henrike , Donlea Jeffrey M. , Krantz David E.
Published: June 2022

The Serotonin Transporter (SERT) regulates extracellular serotonin levels and is the target of most current drugs used to treat depression. The mechanisms by which inhibition of SERT activity influences behavior are poorly understood. To address this question in the model organismDrosophila melanogaster, we developed new loss of function mutations inDrosophila SERT(dSERT).Previous studies in both flies and mammals have implicated serotonin as an important neuromodulator of sleep, and our newly generateddSERTmutants show an increase in total sleep and altered sleep architecture. Differences in daytime vs. nighttime sleep architecture as well as genetic rescue experiments unexpectedly suggest that distinct serotonergic circuits may modulate daytime versus nighttime sleep.dSERTmutants also show defects in copulation and food intake, akin to the clinical side effects of SSRIs. Starvation did not overcome the sleep drive in the mutants. Additionally in males, but not femaledSERTmutants, the drive to mate also failed to overcome sleep drive.dSERTmay be used to further explore the mechanisms by which serotonin regulates sleep and its interplay with other complex behaviors.

Author Summary

Many medications used to treat depression and anxiety act by changing serotonin levels in the brain. Fruit flies also use serotonin and can be used as a model to study the brain. We have made a fly mutant for the serotonin transporter (SERT), which is the target of antidepressants in humans. The mutants sleep more, eat less, and have a decreased sex drive. These flies can be used to study the neuronal pathways by which serotonin regulates sleep, eating and sexual behaviors and may help us to understand the behavioral effects of antidepressants.
Learning better by learning together: dyadic visual perceptual learning on orientation discrimination
Authors: Zhang Yifei , Li Jian , Wang Yizhou , Fang Fang
Published: June 2022

The belief that learning can be modulated by social context is mainly supported by high-level value-based learning studies. However, whether social context can even modulate low-level learning such as visual perceptual learning (VPL) is still unknown. Unlike traditional VPL studies in which participants were trained singly, here we developed a novel dyadic VPL paradigm in which paired participants were trained with the same orientation discrimination task and they could monitor each other’s performance. We found that the social context (i.e., dyadic training) led to a greater behavioral performance improvement and a faster learning speed, compared with the single training. Interestingly, the facilitating effects could be modulated by the performance difference between paired participants. Functional magnetic resonance imaging (fMRI) results showed that, compared with the single training, social cognition areas including bilateral parietal cortex and dorsolateral prefrontal cortex displayed a different spatial activity pattern and enhanced functional connectivities to early visual cortex during the dyadic training. Furthermore, the dyadic training resulted in more refined orientation representation in primary visual cortex (V1), which was closely associated with the greater behavioral performance improvement. Taken together, we demonstrate that the social context, learning with a partner, can remarkably augment the plasticity of low-level visual information process by means of reshaping the neural activities in early visual cortex and social cognition areas, as well as their functional interplays.
The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice
Authors: Ullah Irfan , Beaudoin-Bussières Guillaume , Symmes Kelly , Cloutier Marc , Ducas Eric , Tauzin Alexandra , Laumaea Annemarie , Bégin Philippe , Mothes Walther , Kumar Priti , Bazin Renée , Finzi Andrés , Uchil Pradeep D.
Published: June 2022

COVID-19 convalescent plasmas (CCPs) are chosen for plasma therapy based on neutralizing titers and anti-Spike immunoglobulin levels. However, specific CCP characteristics that promote SARS-CoV-2 control in recipients are complex and incompletely defined. Using an in vivo imaging approach, we demonstrate that CCPs with low neutralizing and high Fc-effector activity, in contrast to those with poor Fc-function, afford effective prophylaxis and therapy in K18-hACE2 mice lethally challenged with SARS-CoV-2-nLuc. Macrophages and neutrophils significantly contributed to CCP effects during therapy but to a reduced extent under prophylaxis. Both IgG and Ig(M+A) were required during therapy, but the IgG fraction alone was sufficient during prophylaxis. Finally, despite neutralizing poorly, SARS-CoV-2 Wuhan-elicited CCPs delayed Delta and Beta variants of concern (VOC)-induced mortality in mice illustrating the contribution of polyclonal Fc-effector functions in immunity against VOCs. Thus, in addition to neutralization, Fc-effector activity is a significant criterion for CCP selection for therapeutic applications.
Distinguishing discrete and continuous behavioral variability using warped autoregressive HMMs
Authors: Costacurta Julia C. , Duncker Lea , Sheffer Blue , Gillis Winthrop , Weinreb Caleb , Markowitz Jeffrey E. , Datta Sandeep R. , Williams Alex H. , Linderman Scott W.
Published: June 2022

A core goal in systems neuroscience and neuroethology is to understand how neural circuits generate naturalistic behavior. One foundational idea is that complex naturalistic behavior may be composed of sequences of stereotyped behavioral syllables, which combine to generate rich sequences of actions. To investigate this, a common approach is to use autoregressive hidden Markov models (ARHMMs) to segment video into discrete behavioral syllables. While these approaches have been successful in extracting syllables that are interpretable, they fail to account for other forms of behavioral variability, such as differences in speed, which may be better described as continuous in nature. To overcome these limitations, we introduce a class of warped ARHMMs (WARHMM). As is the case in the ARHMM, behavior is modeled as a mixture of autoregressive dynamics. However, the dynamics under each discrete latent state (i.e. each behavioral syllable) are additionally modulated by a continuous latent “warping variable.” We present two versions of warped ARHMM in which the warping variable affects the dynamics of each syllable either linearly or nonlinearly. Using depth-camera recordings of freely moving mice, we demonstrate that the failure of ARHMMs to account for continuous behavioral variability results in duplicate cluster assignments. WARHMM achieves similar performance to the standard ARHMM while using fewer behavioral syllables. Further analysis of behavioral measurements in mice demonstrates that WARHMM identifies structure relating to response vigor.
Neuroanatomy of stomatopod central complexes offers putative neural substrate for oriented behaviors in crustaceans
Authors: Chou Alice , Sayre Marcel E. , Lin Chan , Cronin Thomas W.
Published: June 2022

All insects studied to date possess a centrally located group of neuropils, known collectively as the central complex, that has been implicated in sensory integration and motor action selection. Among the functions prescribed to the central complex, none is perhaps as intriguing as its role in orientation and navigation. Neurobiological correlates of both current and desired headings have been described in insect CXs. Despite the diversity of arthropods, understanding of the CX as a navigational center originates entirely from terrestrial insects. Stomatopod crustaceans, commonly referred to as mantis shrimps, form an order of predatory marine crustaceans with intricate and diverse visual systems that maintain the distinction of being the only fully aquatic animal known to utilize the navigational strategy of path integration. They utilize idiothetic, celestial, and landmark cues to orient in the benthos. Here, we investigate the neuroanatomy of adult and developing mantis shrimp central complexes and associated neuropils to begin understanding this brain region in a sensorially and behaviorally complex crustacean.
Can deep learning provide a generalizable model for dynamic sound encoding in auditory cortex?
Authors: Pennington Jacob R. , David Stephen V.
Published: June 2022

Convolutional neural networks (CNNs) can provide powerful and flexible models of neural sensory processing. However, the utility of CNNs in studying the auditory system has been limited by their requirement for large datasets and the complex response properties of single auditory neurons. To address these limitations, we developed a population encoding model: a CNN that simultaneously predicts activity of several hundred neurons recorded during presentation of a large set of natural sounds. This approach defines a shared spectro-temporal space and pools statistical power across neurons. Population models of varying architecture performed consistently better than traditional linear-nonlinear models on data from primary and non-primary auditory cortex. Moreover, population models were highly generalizable. The output layer of a model pre-trained on one population of neurons could be fit to novel single units, achieving performance equivalent to that of neurons in the original fit data. This ability to generalize suggests that population encoding models capture a general set of computations performed by auditory cortex.
MetaboDirect: An Analytical Pipeline for the processing of FTICR-MS-based Metabolomics Data
Authors: Ayala-Ortiz Christian , Graf-Grachet Nathalia , Freire-Zapata Viviana , Fudyma Jane , Hildebrand Gina , AminiTabrizi Roya , Howard-Varona Cristina , Corilo Yuri E. , Hess Nancy , Duhaime Melissa , Sullivan Matthew , Tfaily Malak
Published: June 2022

Background

Microbiomes are now recognized as main drivers of ecosystem function ranging from the oceans and soils to humans and bioreactors. However, a grand challenge in microbiome science is to characterize and quantify the chemical currencies of organic matter (i.e. metabolites) that microbes respond to and alter. Critical to this has been the development of Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS), which has drastically increased molecular characterization of complex organic matter samples, but challenges users with hundreds of millions of data points where readily available, user-friendly, and customizable software tools are lacking.

Results

Here, we build on years of analytical experience with diverse sample types to develop MetaboDirect, an open-source, command-line based pipeline for the analysis, visualization, and presentation of metabolomics data by direct injection FTICR-MS after molecular formula assignment has been performed. When compared to all other available FTICR software, MetaboDirect is superior with respect to its compute time as it only requires a single line of code that launches a fully automated framework for the generation and visualization of a wide range of plots, with minimal coding experience required. Among the tools evaluated, MetaboDirect is also uniquely able to automatically generate biochemical transformation networks (ab initio) based on mass differences that provide a comprehensive experimental assessment of metabolite connectives within a given sample or a complex metabolic system, thereby providing important information about the nature of the samples and the set of the microbial reactions or pathways that gave rise to them. Finally, for more experienced users, MetaboDirect allows users to customize plots, outputs, and analyses.

Conclusion

Application of MetaboDirect to FTICR-MS-based metabolomics datasets from a marine phage-bacterial infection experiment and aSphagnumleachate microbiome incubation experiment showcase the exploration capabilities of the pipeline that will enable the FTICR-MS research community to evaluate and interpret their data in greater depth and in less time. It will further advance our knowledge of how microbial communities influence and are influenced by the chemical makeup of the surrounding system. Source code and User’s guide of MetaboDirect are freely available through (https://github.com/Coayala/MetaboDirect) and (https://metabodirect.readthedocs.io/en/latest/) respectively.
Edge-based growth control inArabidopsisinvolves two cell wall-associated Receptor-Like Proteins
Authors: Elliott Liam , Kalde Monika , Schuerholz Ann-Kathrin , Wolf Sebastian , Moore Ian , Kirchhelle Charlotte
Published: June 2022

Morphogenesis of multicellular organs requires coordination of cellular growth. In plants, 3D growth is driven by undirected turgor pressure, whereas growth directionality is controlled by cell wall mechanical properties at 2D cell faces. Their shared cell wall also fixes cells in their position, and plants thus have to integrate tissue-scale mechanical stresses arising due to growth in a fixed tissue topology. This implies a need to monitor cell wall mechanical and biochemical status and to adapt growth accordingly. Here, we propose that plant cells use their 1D cell edges to monitor cell wall status. We describe two Receptor-Like Proteins, RLP4 and RLP4-L1, which occupy a unique polarity domain at cell edges established through a targeted secretory transport pathway. We show that at cell edges, RLP4s associate with the cell wall via their extracellular domain, and contribute to directional growth control inArabidopsis.
Multiple memory systems for efficient temporal order memory
Authors: Jafarpour Anna , Lin Jack J. , Knight Robert T. , Buffalo Elizabeth A.
Published: June 2022

We report the distinct contribution of multiple memory systems to retrieval of the temporal order of events. The neural dynamics related to retrieval of movie scenes revealed that recalling the temporal order of close events elevates hippocampal theta power, like that observed for recalling close spatial relationships. In contrast, recalling far events elevates beta power in the orbitofrontal cortex, reflecting recall based on the overall movie structure.
Asymmetric retinal direction tuning predicts optokinetic eye movements across stimulus conditions
Authors: Harris Scott C. , Dunn Felice A.
Published: June 2022

Across species, the optokinetic reflex (OKR) stabilizes vision during self-motion. OKR occurs when ON direction-selective retinal ganglion cells (oDSGCs) detect slow, global image motion on the retina. How oDSGC activity is integrated centrally to generate behavior remains unknown. Here, we discover mechanisms that contribute to motion encoding in vertically-tuned oDSGCs, and leverage these findings to empirically define signal transformation between retinal output and vertical OKR behavior. We demonstrate that motion encoding in vertically-tuned oDSGCs is contrast-sensitive and asymmetric for oDSGC types that prefer opposite directions. These phenomena arise from the interplay between spike threshold nonlinearities and differences in synaptic input weights, including shifts in the balance of excitation and inhibition. In behaving mice, these neurophysiological observations, along with a central subtraction of oDSGC outputs, accurately predict the trajectories of vertical OKR across stimulus conditions. Thus, asymmetric tuning across competing sensory channels can critically shape behavior.