bluuebunny/crossref_metadata_2025 huggingface dataset:
The timid invasion: behavioural adjustments and range expansion in a non-native rodent
Authors: Eccard Jana A. , Mazza Valeria , Holland Celia , Stuart Peter
Published: July 2023

Animal behaviour can moderate biological invasion processes, and the native fauna's ability to adapt. The importance and nature of behavioural traits favouring colonization success remain debated. We investigated behavioural responses associated with risk-taking and exploration, both in non-native bank voles (
Myodes glareolus
,
N
= 225) accidentally introduced to Ireland a century ago, and in native wood mice (
Apodemus sylvaticus
,
N
= 189), that decline in numbers with vole expansion. We repeatedly sampled behavioural responses in three colonization zones: established bank vole populations for greater than 80 years (2 sites), expansion edge vole populations present for 1–4 years (4) and pre-arrival (2). All zones were occupied by wood mice. Individuals of both species varied consistently in risk-taking and exploration. Mice had not adjusted their behaviour to the presence of non-native voles, as it did not differ between the zones. Male voles at the expansion edge were initially more risk-averse but habituated faster to repeated testing, compared to voles in the established population. Results thus indicate spatial sorting for risk-taking propensity along the expansion edge in the dispersing sex. In non-native prey species the ability to develop risk-averse phenotypes may thus represent a fundamental component for range expansions.
When perfection isn't enough: host egg signatures are an effective defence against high-fidelity African cuckoo mimicry
Authors: Lund Jess , Dixit Tanmay , Attwood Mairenn C. , Hamama Silky , Moya Collins , Stevens Martin , Jamie Gabriel A. , Spottiswoode Claire N.
Published: July 2023

Most mimicry systems involve imperfect mimicry, whereas perfect and high-fidelity mimicry are rare. When the fidelity of mimicry is high, mimics might be expected to have the upper hand against their antagonists. However, in coevolving systems, diversification of model phenotypes may provide an evolutionary escape, because mimics cannot simultaneously match all model individuals in the population. Here we investigate high-fidelity mimicry in a highly specialized, Afrotropical brood parasite–host system: the African cuckoo and fork-tailed drongo. Specifically, we test whether host egg polymorphisms are an effective defence against such mimicry. We show, using a combination of image analysis, field experiments and simulations, that: (1) egg colour and pattern mimicry of fork-tailed drongo eggs by African cuckoos is near-perfect on average; (2) drongos show fine-tuned rejection of foreign eggs, exploiting unpredictable pattern differences between parasitic eggs and their own; and (3) the high degree of interclutch variation (polymorphic egg ‘signatures’) exhibited by drongos gives them the upper hand in the arms race, with 93.7% of cuckoo eggs predicted to be rejected, despite cuckoos mimicking the full range of drongo egg phenotypes. These results demonstrate that model diversification is a highly effective defence against mimics, even when mimicry is highly accurate.
Two reasons to kill: predation and kin discrimination in myxobacteria
Authors: Kaimer Christine , Weltzer Michael L. , Wall Daniel
Published: July 2023

Myxobacteria are social microbial predators that use cell–cell contacts to identify bacterial or fungal prey and to differentiate kin relatives to initiate cellular responses. For prey killing, they assemble Tad-like and type III-like secretion systems at contact sites. For kin discrimination (KD), they assemble outer membrane exchange complexes composed of the TraA and TraB receptors at contacts sites. A type VI secretion system and Rhs proteins also mediate KD. Following cellular recognition, these systems deliver appropriate effectors into target cells. For prey, this leads to cell death and lysis for nutrient consumption by myxobacteria. In KD, a panel of effectors are delivered, and if adjacent cells are clonal cells, resistance ensues because they express a cognate panel of immunity factors; while nonkin lack complete immunity and are intoxicated. This review compares and contrasts recent findings from these systems in myxobacteria.
Correlation analysis of heart rate variations and glucose fluctuations during sleep
Authors: Kajisa Taira , Kuroi Toshiya , Hara Hiroyuki , Sakai Toshiyuki
Published: July 2023

Objective

The body’s glucose concentration is influenced by carbohydrate intake, insulin-induced carbohydrate reduction, and hepatic glycogen breakdown induced by stress hormones. This study investigated the potential of employing glucose fluctuations as a measure of stress by examining the relationship between heart rate variability (HRV) data and glucose levels during sleep in healthy subjects.

Methods

In this cross-sectional study, a chest-worn electrocardiogram (ECG) and continuous glucose monitoring device (CGM) were respectively used to monitor the heart rate intervals and glucose fluctuations of five subjects (two males, three females) during sleep. A time-series correlation analysis was performed on the HRV data extracted from heart rate intervals and the corresponding glucose fluctuation data.

Results

The time-series analysis of ECG and CGM data collected from subjects during sleep (n = 25 nights) revealed a moderate negative correlation between glucose levels and HRV, with a cross-correlation coefficient of r = –0.453.

Conclusion

Similar to HRV, changes in stress levels can be detected by observing glucose fluctuations, particularly during sleep when the impact of food intake can be eliminated. Our findings highlight a significant correlation between glucose levels and HRV, indicating that glucose fluctuations can be used as an indicator of autonomic nervous system activity.
GENDERED GAPS TO TB PREVENTION AND CARE IN KENYA: A POLITICAL ECONOMY ANALYSIS STUDY
Authors: Abdullahi Leila , Oketch Sandra , Komen Henry , Mbithi Irene , Millington Kerry , Mulupi Stephen , Chakaya Jeremiah , Zulu Eliya
Published: July 2023

Background

Tuberculosis (TB) remains a public health concern despite the massive global efforts towards ending TB. Kenya is among the high burdened countries globally with the TB prevention and care efforts hampered by poor health systems, resource limitations and other socio-political contexts that inform policy and implementation. Notably, TB cases are much higher in men than women, and therefore, the political economy analysis study provides in-depth contexts and understanding of the gender gaps to access and successful treatment for TB infection.

Methods

The Political Economy Analysis (PEA) adopted a qualitative in-depth approach that targeted 16 Key Informant Interviews (KIIs). The Key Informant Interviews (KIIs) were distributed among government entities, academia, non-state actors, and community TB groups.

Results

The themes identified were mapped onto the applied PEA analysis framework domains. The contextual and institutional issues included gender concerns related to the disconnect between TB policies and gender inclusion aspects, such as low prioritization for TB programs, limited use of evidence to inform decisions and poor health system structures. The broad barriers influencing the social contexts for TB programs were social stigma and cultural norms such as traditional interventions that negatively impact health-seeking behaviors. The themes around the economic situation were poverty and unemployment, food insecurity, and malnutrition. The political context centered around the systemic and governance gaps in the health system from the national and devolved health functions.

Conclusion

Overall, broad contextual factors identified from the political economy analysis widens the disparity in targeted gender efforts toward men. Following the development of effective TB policies and strategies, it is important to have well-planned gendered responsive interventions with a clear implementation plan and monitoring system to enhance access to TB prevention and care.

Strength and limitations

The study provides insights into the political, economic, and social contexts influencing TB prevention and care efforts. Additionally, to the best of our knowledge, this will be the first PEA to evaluate the TB program from a gendered perspective.

As a limitation, the study is missing the voices and lived experiences of men leaving with TB as this was not part of the study scope. As such, we do not have their perspectives as they may better articulate some barriers faced with access and uptake of TB prevention and management programs.
Delay Discounting and Family History of Psychopathology in Children Ages 9-11: Results from the ABCD Study
Authors: Sloan Matthew E. , Sanches Marcos , Tanabe Jody , Gowin Joshua L.
Published: July 2023

Delay discounting is a tendency to devalue delayed rewards compared to immediate rewards. Evidence suggests that steeper delay discounting is associated with psychiatric disorders across diagnostic categories, but it is unclear whether steeper delay discounting is a risk factor for these disorders. We examined whether children at higher risk for psychiatric disorders, based on family history, would demonstrate steeper delay discounting behavior. We examined the relationship between delay discounting behavior and family history of psychopathology using data from the Adolescent Brain Cognitive Development (ABCD) study, a nationally representative sample of 11,878 children. Participants completed the delay discounting task between the ages of 9 and 11. We computed Spearman’s correlations between family pattern density of psychiatric disorders and delay discounting behavior. We conducted mixed effects models to examine associations between family pattern density of psychiatric disorders and delay discounting while accounting for sociodemographic factors. Correlations between family history of psychopathology and delay discounting behavior were small, ranging from ρ = –0.02 to 0.04. In mixed effects models, family history of psychopathology was not associated with steeper delay discounting behavior. Sociodemographic factors played a larger role in predicting delay discounting behavior than family history of psychopathology. Race, ethnicity, sex, parental education, and marital status were all significantly associated with delay discounting behavior. These results do not support the hypothesis that children with greater risk for psychopathology display steeper delay discounting behavior. Sociodemographic factors play a larger role in determining delay discounting behavior in this age group.
Socio-cultural practices, dietary and nutrition patterns, economic and vitamin-D deficiency status of pulmonary tuberculosis patients (PTB) of tribal and urban population of India: An Explanatory Model Interview Catalogue (EMIC)
Authors: Barik Sushanta Kumar , Turuk Jyotirmayee , Singh Meenu , Giri Sidhartha , Pati Sanghamitra
Published: July 2023

This study emphasizes on the implication and benefits of an Explanatory Model Interview Catalogue (EMIC) on the collective information of the socio-cultural status, diet and nutrition pattern, economic status, and treatment options through proper counselling of pulmonary tuberculosis patients (PTB) during the acquiring of the tuberculosis (TB) in tribal and urban population. TB is one of leading cause of death in India. It is necessary to find out progression of PTB associated with socio-cultural practices, dietary and nutrition patterns, economic status, and Vitamin-D deficiency among TB patients of tribal and urban population for better management of tuberculosis patients.

Therefore, EMIC developed will be applied for collection of details on diet and nutrition, types of occupation, social status, types of complementary consumable additives, economic status, types of community and languages, Vitamin-D status, treatment details, quality of life in newly diagnosed PTB patients in state level, district level hospitals and medical research institutions.
scPathoQuant: A tool for efficient alignment and quantification of pathogen sequence reads from 10x single cell sequencing data sets
Authors: Whitmore Leanne S. , Tisoncik-Go Jennifer , Gale Michael
Published: July 2023

Currently there is a lack of efficient computational pipelines/tools for conducting simultaneous genome mapping of pathogen-derived and host reads from single cell RNA sequencing (scRNAseq) output from pathogen-infected cells. Contemporary options include processes involving multiple steps and/or running multiple computational tools, increasing user operations time. To address the need for new tools to directly map and quantify pathogen and host sequence reads from within an infected cell from scRNAseq data sets in a single operation, we have built a python package, called scPathoQuant. scPathoQuant extracts sequences that were not aligned to the primary host genome, maps them to a pathogen genome of interest, here as demonstrated for viral pathogens, quantifies total reads mapping to the entire pathogen, quantifies reads mapping to individual pathogen genes, and finally reintegrates pathogen sequence counts into matrix files that are used by standard single cell pipelines for downstream analyses with only one command. We demonstrate that scPathoQuant provides a scRNAseq viral and host genome-wide sequence read abundance analysis that can differentiate and define multiple viruses in a single sample scRNAseq output.
IL-15 enhances anti-tumor immunity of sipuleucel-T by activating lymphocyte subsets and reversing immunoresistance
Authors: Saeed Muhammad A. , Peng Bo , Kim Kevin , Borkowski Ariel , Tine Brian Van , Sheikh Nadeem , Vu Tuyen , Thorek Daniel LJ , Fehniger Todd , Pachynski Russell K.
Published: July 2023

Engineered cell therapies have emerged as a potent therapeutic option for the hematologic malignancies, however solid tumor responses to similar approaches have been modest. The outlier is Sipuleucel-T (sip-T), an FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report the first high dimensional cellular analyses of sip-T using mass cytometry (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B-cells, and natural killer (NK) and NKT cells.

We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate cancer. Of cytokines tested, IL-15 treated sip-T showed the most significant activation and proliferation of effector lymphocytes, as well as augmentation of tumor cytotoxicity in vitro. Co-culture of sip-T with IL-15 and control or prostate-relevant antigens showed significant activation and expansion of CD8 T and NKT cells in an antigen-specific manner. Adoptive transfer of IL-15 treated sip-T into NSG mice resulted in potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2 to 14-fold higher influx of sip-T and a significant increase in interferon (IFN)-γ producing CD8+ T and NKT cells within the tumor microenvironment (TME) in the IL-15 group. In conclusion, we put forward the first evidence that IL-15 treatment can enhance the functional anti-tumor efficacy of sip-T, providing rationale for combining IL-15 or IL-15 agonists with sip-T to treat mCRPC patients.

Graphical Abstract

One sentence summary

IL-15 treatment can enhance the efficacy/anti-tumor immunity of sipuleucel-T by modulating CD8+ T-cell and CD56+ NKT subsets.
Skyline fossilized birth-death model is robust to violations of sampling assumptions in total-evidence dating
Authors: Zhang Chi , Ronquist Fredrik , Stadler Tanja
Published: July 2023

Several total-evidence dating studies under the fossilized birth-death (FBD) model have produced very old age estimates, which are not supported by the fossil record. This phenomenon has been termed “deep root attraction (DRA)”. For two specific data sets, involving divergence time estimation for the early radiations of ants, bees and wasps (Hymenoptera) and of placental mammals (Eutheria), it has been shown that the DRA effect can be greatly reduced by accommodating the fact that extant species in these trees have been sampled to maximize diversity, so called diversified sampling. Unfortunately, current methods to accommodate diversified sampling only consider the extreme case where it is possible to identify a cut-off time such that all splits occurring before this time are represented in the sampled tree but none of the younger splits. In reality, the sampling bias is rarely this extreme, and may be difficult to model properly. Similar modeling challenges apply to the sampling of the fossil record. This raises the question of whether it is possible to find dating methods that are more robust to sampling biases. Here, we show that the skyline FBD (SFBD) process, where the diversification and fossil-sampling rates can vary over time in a piecewise fashion, provides age estimates that are more robust to inadequacies in the modeling of the sampling process and less sensitive to DRA effects. In the SFBD model we consider, rates in different time intervals are either considered to be independent and identically distributed, or assumed to be autocorrelated following an Ornstein-Uhlenbeck (OU) process. Through simulations and reanalyses of the Hymenoptera and Eutheria data, we show that both variants of the SFBD model unify age estimates under random and diversified sampling assumptions. The SFBD model can resolve DRA by absorbing the deviations from the sampling assumptions into the inferred dynamics of the diversification process over time. Although this means that the inferred diversification dynamics must be interpreted with caution, taking sampling biases into account, we conclude that the SFBD model represents the most robust approach available currently for addressing DRA in total-evidence dating.
Microglia Regulate Sleep via Calcium-Dependent Modulation of Norepinephrine Transmission
Authors: Ma Chenyan , Li Bing , Silverman Daniel , Ding Xinlu , Li Anan , Xiao Chi , Huang Ganghua , Worden Kurtresha , Muroy Sandra , Chen Wei , Xu Zhengchao , Tso Chak Foon , Huang Yixuan , Zhang Yufan , Luo Qingming , Saijo Kaoru , Dan Yang
Published: July 2023

Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia – the resident immune cells in the brain – remains poorly understood. Here we show that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca2+signaling, and suppression of norepinephrine transmission. Chemogenetic activation of microglia Gi signaling strongly promoted sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors decreased sleep. Two-photon imaging showed that P2Y12/Gi activation elevated microglia intracellular Ca2+, and blockade of this Ca2+elevation largely abolished the Gi-induced sleep increase. Microglia Ca2+level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine. Furthermore, imaging of norepinephrine activity with its biosensor showed that microglia P2Y12/Gi activation significantly reduced norepinephrine, partly by increasing the adenosine concentration. Thus, microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.
Microglial cannabinoid receptor type 1 mediates social memory deficits produced by adolescent THC exposure and 16p11.2 duplication
Authors: Hasegawa Yuto , Kim Juhyun , Ursini Gianluca , Jouroukhin Yan , Zhu Xiaolei , Miyahara Yu , Xiong Feiyi , Madireddy Samskruthi , Obayashi Mizuho , Lutz Beat , Sawa Akira , Brown Solange P. , Pletnikov Mikhail V. , Kamiya Atsushi
Published: July 2023

Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.
ERBB signalling contributes to immune evasion in KRAS-driven lung adenocarcinoma
Authors: Laing Sarah , Kruspig Björn , Shaw Robin , Officer-Jones Leah , Edwards Sarah , McKinven Danielle , Hsieh Ya-Ching , Powley Ian , Brady Nicola , Pennie Rachel , Kwan Ryan , Lima Anthony , Myrta Szymon , Periyasamy Manikandan , Dye Isabel C , Nixon Colin , Clark Graeme , Junttila Melissa R. , Maddalo Danilo , Miller Crispin , Ali Simak , Fuchter Matthew J. , Nickles Dorothee , Kirschner Kristina , Brown Robert B. , Le Quesne John , Strathdee Douglas , Coffelt Seth B. , Roberts Ed , Murphy Daniel J.
Published: July 2023

Immunotherapy is increasingly viewed as treatment of choice for lung cancer, however, clinical responses to immune checkpoint blockade remain highly unpredictable and are largely transient. A deeper mechanistic understanding of the dynamics of tumour:immune interactions is needed to drive rational development of improved treatment strategies. Progress is hampered by a paucity of autochthonous model systems in which to interrogate the 2-way interactions of immune responses to evolving tumours and vice-versa. Specifically, commonly used genetically engineered mouse models typically lack the genetic diversity needed to drive an adaptive immune response. APOBEC mutagenesis signatures are prominent in lung cancer and APOBEC activity is predicted to drive immune visibility through Cytidine deaminase activity, coupled with inaccurate DNA-repair responses. We therefore generated a CRE-inducibleAPOBEC3Ballele, interbred with multiple oncogenic drivers of lung adenocarcinoma, and used the resulting mice to investigate the response to PD1 blockade at single cell resolution.

SIGNIFICANCE

Using our novel immune-visible model of KRas-driven autochthonous lung adenocarcinoma, we uncovered a surprising increase in tumour-cell expression of EGFR/ERBB ligands following treatment with α-PD1 and present evidence that transient ERBB blockade can restore immune surveillance in KRas mutant LuAd and combine effectively with immune checkpoint blockade.
Macroecological patterns in experimental microbial communities
Authors: Shoemaker William R. , Sánchez Álvaro , Grilli Jacopo
Published: July 2023

Ecology has historically benefited from the characterization of statistical patterns of biodiversity within and across communities, an approach known as macroecology. Within microbial ecology, macroecological approaches have identified universal patterns of diversity and abundance that can be captured by effective models. Experimentation has simultaneously played a crucial role, as the advent of high-replication community time-series has allowed researchers to investigate underlying ecological forces. However, there remains a gap between experiments performed in the laboratory and macroecological patterns documented in natural systems, as we do not know whether these patterns can be recapitulated in the lab and whether experimental manipulations produce macroecological effects. This work aims at bridging the gap between experimental ecology and macroecology. Using high-replication time-series, we demonstrate that microbial macroecological patterns observed in nature exist in a laboratory setting, despite controlled conditions, and can be unified under the Stochastic Logistic Model of growth (SLM). We find that demographic manipulations (e.g., migration) impact observed macroecological patterns. By modifying the SLM to incorporate said manipulations alongside experimental details (e.g., sampling), we obtain predictions that are consistent with macroecological outcomes. By combining high-replication experiments with ecological models, microbial macroecology can be viewed as a predictive discipline.
Copy Number Variants and heritability estimates on UKBiobank data
Authors: Boulahfa Jawad , Floch Edith Le , Pierre-Jean Morgane , Deleuze Jean-François , Dandine-Roulland Claire
Published: July 2023

Copy Number Variants (CNVs) are sometimes used to perform association studies. The aim of this paper was to study the use of CNVs in another context: heritability estimation. We wanted to assess the impact of using CNVs in these estimates, either alone, or in conjunction with Single Nucleotide Polymorphisms (SNPs). Using real SNP and CNV data from UK Biobank, we simulated phenotypes depending either on one or the two type(s) of data. We showed that mixed models, usually used for estimating heritability on SNP data, were also capable of estimating CNV heritability and to properly decipher between CNV and SNP heritabilities when phenotypes depend on both types of data. However CNV heritability estimation becomes more challenging when it is only supported by the few relatively common CNVs. Finally we estimated CNV and SNP heritabilities for two real phenotypes from UK Biobank (height and hypertension) but only hypertension showed a small but non-null CNV heritability of about 1.7%.
Venom tradeoff shapes interspecific interactions, physiology and reproduction
Authors: Surm Joachim M. , Birch Sydney , Macrander Jason , Jaimes-Becerra Adrian , Fridrich Arie , Aharoni Reuven , Rozenblat Rotem , Sharabany Julia , Appelbaum Lior , Reitzel Adam M. , Moran Yehu
Published: July 2023

The ability of an animal to effectively capture prey and defend against predators is pivotal for its survival. Venom, a mixture of many toxin proteins, shapes predator-prey interactions. Here, we use the sea anemoneNematostella vectensisto test how toxin genotypes impact predator-prey interactions. We developed a new genetic manipulation tool which significantly reduces both RNA and protein levels of Nv1, a major neurotoxin. In concert we recently discovered a native population ofNematostellathat has lost Nv1.We demonstrate that these anemones lacking Nv1, have reduced ability to defend themselves against grass shrimp, a native predator. Additionally, secreted Nv1 can act indirectly in defense by attracting mummichog fish, which are known to prey on grass shrimp. This unravels a tritrophic interaction acting in animal defense at the molecular level. Additionally, our work reveals an evolutionary tradeoff, as the reduction of Nv1 levels causes faster growth and increased sexual and asexual reproductive rates.
Disease-specific tau filaments assemble via polymorphic intermediates
Authors: Lövestam Sofia , Li David , Wagstaff Jane L. , Kotecha Abhay , Kimanius Dari , McLaughlin Stephen H. , Murzin Alexey G. , Freund Stefan M.V. , Goedert Michel , Scheres Sjors H.W.
Published: July 2023

Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention. However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here, we use time-resolved electron cryo-microscopy (cryo-EM) to study thein vitroassembly of recombinant truncated tau (amino acids 297-391) into paired helical filaments of Alzheimer’s disease or into filaments of chronic traumatic encephalopathy. We report the formation of a shared first intermediate amyloid (FIA), with an ordered core comprising amino acids 302-316. Nuclear magnetic resonance indicates that the same amino acids adopt rigid, β-strand-like conformations in monomeric tau. At later time points, the FIAs disappear and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of novel therapies.
Impaired cholesterol transport from aged astrocytes to neurons can be rescued by cannabinoids
Authors: Allende Leandro G. , Natalí Lautaro , Cragnolini Andrea B. , Musri Melina M. , Mendoza Diego de , Martín Mauricio G.
Published: July 2023

Cholesterol is crucial for the proper functioning of eukaryotic cells, especially neurons, which rely on cholesterol to maintain their complex structure and facilitate synaptic transmission. However, brain cells are isolated from peripheral cholesterol by the blood-brain barrier and mature neurons primarily uptake the cholesterol synthesized by astrocytes for proper function. This study aimed to investigate the effect of aging on cholesterol trafficking in astrocytes and its delivery to neurons. Using in vitro and in vivo models of aging, we found that aged astrocytes accumulated high levels of cholesterol in the lysosomal compartment, and this cholesterol buildup can be attributed to the simultaneous occurrence of two events: decreased levels of the ABCA1 transporter which impairs ApoE-cholesterol export from astrocytes, and reduced expression of NPC1, which hinders cholesterol release from lysosomes. We show that these two events are accompanied by increased microR33 in aged astrocytes, which is known to downregulate ABCA1 and NPC1. In addition, we demonstrate that the microR33 increase is triggered by oxidative stress, one of the hallmarks of aging.

By co-culture experiments we also show that aging in vitro impairs the cholesterol delivery from astrocytes to neurons. Remarkably, we found that this altered transport of cholesterol could be alleviated through treatment with endocannabinoids as well as cannabidiol or CBD. Given that reduced neuronal cholesterol affects synaptic plasticity, the ability of cannabinoids to restore cholesterol transport from aged astrocytes to neurons holds significant implications in the field of aging.
Denoising Diffusion MRI: Considerations and implications for analysis
Authors: Manzano-Patron Jose-Pedro , Moeller Steen , Andersson Jesper L.R. , Ugurbil Kamil , Yacoub Essa , Sotiropoulos Stamatios N.
Published: July 2023

Development of diffusion MRI (dMRI) denoising approaches has experienced considerable growth over the last years. As noise can inherently reduce accuracy and precision in measurements, its effects have been well characterised both in terms of uncertainty increase in dMRI-derived features and in terms of biases caused by the noise floor, the smallest measurable signal given the noise level. However, gaps in our knowledge still exist in objectively characterising dMRI denoising approaches in terms of both of these effects and assessing their efficacy. In this work, we reconsider what a denoising method should and should not do and we accordingly define criteria to characterise the performance. We propose a comprehensive set of evaluations, including i) benefits in improving signal quality and reducing noise variance, ii) gains in reducing biases and the noise floor and improving, iii) preservation of spatial resolution, iv) agreement of denoised data against a gold standard, v) gains in downstream parameter estimation (precision and accuracy), vi) efficacy in enabling noise-prone applications, such as ultra-high-resolution imaging. We further provide newly acquired complex datasets (magnitude and phase) with multiple repeats that sample different SNR regimes to highlight performance differences under different scenarios. Without loss of generality, we subsequently apply a number of exemplar patch-based denoising algorithms to these datasets, including Non-Local Means, Marchenko-Pastur PCA (MPPCA) in the magnitude and complex domain and NORDIC, and compare them with respect to the above criteria and against a gold standard complex average of multiple repeats. We demonstrate that all tested denoising approaches reduce noise-related variance, but not always biases from the elevated noise floor. They all induce a spatial resolution penalty, but its extent can vary depending on the method and the implementation. Some denoising approaches agree with the gold standard more than others and we demonstrate challenges in even defining such a standard. Overall, we show that dMRI denoising performed in the complex domain is advantageous to magnitude domain denoising with respect to all the above criteria.
CellSNAP: A fast, accurate algorithm for 3D cell segmentation in quantitative phase imaging
Authors: Raj Piyush , Paidi Santosh , Conway Lauren , Chatterjee Arnab , Barman Ishan
Published: July 2023

Quantitative phase imaging (QPI) has rapidly emerged as a complementary tool to fluorescence imaging, as it provides an objective measure of cell morphology and dynamics, free of variability due to contrast agents. In particular, three-dimensional (3D) tomographic imaging of live cells has opened up new directions of investigation by providing systematic and correlative analysis of various cellular parameters without limitations of photobleaching and phototoxicity. While current QPI systems allow the rapid acquisition of tomographic images, the pipeline to analyze these raw 3D tomograms is not well-developed. This work focuses on a critical, yet often underappreciated, step of the analysis pipeline, that of 3D cell segmentation from the acquired tomograms. The current method employed for such tasks is the Otsu-based 3D watershed algorithm, which works well for isolated cells; however, it is very challenging to draw boundaries when the cells are clumped. This process is also memory intensive since the processing requires computation on a 3D stack of images. We report the CellSNAP (Cell Segmentation via Novel Algorithm for Phase Imaging) algorithm for the segmentation of QPI images, which outstrips the current gold standard in terms of speed, robustness, and implementation, achieving cell segmentation under 2 seconds per cell on a single-core processor. The implementation of CellSNAP can easily be parallelized on a multi-core system for further speed improvements. For the cases where segmentation is possible with the existing standard method, our algorithm displays an average difference of 5% for dry mass and 8% for volume measurements. We also show that CellSNAP can handle challenging image datasets where cells are clumped and marred by interferogram drifts, which pose major difficulties for all QPI-focused segmentation tools. We envision our work will lead to the broader adoption of QPI imaging for high-throughput analysis, which has, in part, been stymied by a lack of suitable image segmentation tools.
Primary human lung fibroblasts exhibit trigger- but not disease-specific cellular senescence and impair alveolar epithelial cell progenitor function
Authors: Bramey Nora , Melo-Narvaez Maria Camila , See Fenja , Ballester-Lllobell Beatriz , Steinchen Carina , Jain Eshita , Hafner Kathrin , Yildirim Ali Önder , Königshoff Melanie , Lehmann Mareike
Published: July 2023

Aging is the main risk factor for chronic lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging such as cellular senescence are increased in different cell types such as fibroblasts in the lungs of these patients. However, whether the senescent phenotype of fibroblasts derived from IPF or COPD differs is still unknown. Therefore, we characterized senescence at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, and TGF-β1) in cultured primary human lung fibroblasts (phLF) from control donors, IPF, or COPD patients. We found that phLF from different disease-origins have a low baseline senescence. H2O2and bleomycin treatment induced a senescent phenotype in phLF whereas TGF-β1 only had a pro-fibrotic effect. Interestingly, we did not observe any differences in susceptibility to senescence induction in phLF based on disease origin. However, exposure to different stimuli resulted in different senescent programs in phLF. Moreover, senescent phLF reduced colony formation efficiency of alveolar epithelial progenitor cells. In conclusion, the senescent phenotype of phLF is mainly determined by the senescence inducer and impairs alveolar epithelial progenitor capacityin vitro.
How does fertilization impact the wild blueberry microbiome ?
Authors: Morvan Simon , Paré Maxime C. , Lafond Jean , Hijri Mohamed
Published: July 2023

Wild blueberries production is regarded as less intensive than other agricultural systems, although several agricultural practices are commonly implemented to increase crop yields and to mitigate pets and pathogen attacks. Fertilization, organic or mineral, is used to increase soil nutrient availability and improve fruit yield. Wild blueberry plants are also known to depend on their microbiome to overcome the lack of nutrient availability in the soil and their symbiosis with ericoid mycorrhizal fungi is thought to be crucial in that regard. As fertilization can alter crop microbial communities, our study aimed to measure the impact of this practice in a wild blueberry setting, focusing on the bacterial and fungal communities found in the roots and rhizosphere ofVaccinium angustifoliumAit., both at the time of application and more than year later during the harvest season. Our study indicates that fertilization, whether mineral or organic, has a minimal effect on microbial communities. One year after application, fertilization does not seem to have a negative repercussion on the ericoid mycorrhizal (ErM) fungal community as no significant differences were observed in terms of relative abundance on known and putative ErM taxa between the control and the two fertilizer treatments. The fact that fertilization is applied at a low rate could explain this absence of effect on the microbial communities. However, longer-term studies are needed to ensure that repeated fertilization does not cause any shifts in microbial communities that could be detrimental to the wild blueberry nutrition.

Importance

This study examines the impact of fertilization, whether organic or mineral, on microbial communities in the roots and rhizosphere of wild blueberry (Vaccinium angustifoliumAit.). both Fertilization is commonly used to enhance soil nutrient availability and improve fruit yield, but its effects on the plant’s microbiome, particularly on the ericoid mycorrhizal fungi (ErM), are not well understood. The samples were taken both during the pruning season, 3 months after the treatment, and one year later, during harvest season. The results suggest that fertilization has minimal impact on the microbial communities. One year after application, no significant differences were observed in the relative abundance of known and putative ErM taxa between the control group and the two fertilizer-treated groups. The low amount of fertilization applied could explain these results. However, longer-term research are needed to ensure that repeated fertilization does not lead to detrimental shifts in microbial communities affecting wild blueberry nutrition.
Predictive Systems Biology Modeling: Unraveling Host Metabolic Disruptions and Potential Drug Targets in Acute Viral Infections
Authors: Li Gong-Hua , Han Feifei , Luo Rong-Hua , Li Peng , Chang Chia-Jung , Xu Weihong , Long Xin-Yan , Huang Jing-Fei , Zheng Yong-Tang , Kong Qing-Peng , Xiao Wenzhong
Published: July 2023

Background

Host response is critical to the onset, progression, and outcome of viral infections. Since viruses hijack the host cellular metabolism for their replications, we hypothesized that restoring host cell metabolism can efficiently reduce viral production.

Results

Here, we present a viral-host Metabolic Modeling (vhMM) method to systematically evaluate the disturbances in host metabolism in viral infection and computationally identify targets for modulation by integrating genome-wide precision metabolic modeling and cheminformatics. We applied vhMM to SARS-CoV-2 infections and identified consistent changes in host metabolism and gene and endogenous metabolite targets between the original SARS-COV-2 and different variants (Alpha, Delta, and Omicron). Among six compounds predicted for repurposing,methotrexate, cinnamaldehyde, anddeferipronewere testedin vitroand effective in inhibiting viral production with IC50 less than 4uM. Further, an analysis of real-world patient data showed that cinnamon usage significantly reduced the SARS-CoV-2 infection rate with an odds ratio of 0.65 [95%CI: 0.55∼0.75].

Conclusions

These results demonstrated that vhMM is an efficient method for predicting targets and drugs for viral infections.
Gas vesicle-blood interactions enhance ultrasound imaging contrast
Authors: Ling Bill , Ko Jeong Hoon , Stordy Benjamin , Zhang Yuwei , Didden Tighe F. , Malounda Dina , Swift Margaret B. , Chan Warren C.W. , Shapiro Mikhail G.
Published: July 2023

Gas vesicles (GVs) are genetically encoded, air-filled protein nanostructures of broad interest for biomedical research and clinical applications, acting as imaging and therapeutic agents for ultrasound, magnetic resonance, and optical techniques. However, the biomedical applications of GVs as a systemically injectable nanomaterial have been hindered by a lack of understanding of GVs’ interactions with blood components, which can significantly impactin vivoperformance. Here, we investigate the dynamics of GVs in the bloodstream using a combination of ultrasound and optical imaging, surface functionalization, flow cytometry, and mass spectrometry. We find that erythrocytes and serum proteins bind to GVs and shape their acoustic response, circulation time, and immunogenicity. We show that by modifying the GV surface, we can alter these interactions and thereby modify GVs’in vivoperformance. These results provide critical insights for the development of GVs as agents for nanomedicine.
The long non-coding RNA LINC00941 modulates MTA2/NuRD occupancy to suppress premature human epidermal differentiation
Authors: Morgenstern Eva , Schwartz Uwe , Graf Johannes , Bruckmann Astrid , Kretz Markus
Published: July 2023

Numerous long non-coding RNAs (lncRNAs) were shown to have functional impact on cellular processes such as human epidermal homeostasis. However, the mechanism of action for many lncRNAs remains unclear to date. Here, we report that lncRNA LINC00941 regulates keratinocyte differentiation on an epigenetic level through association with the NuRD complex, one of the major chromatin remodelers in cells. We find that LINC00941 interacts with NuRD-associated MTA2 in human primary keratinocytes. LINC00941 perturbation changes MTA2/NuRD occupancy at bivalent chromatin domains in close proximity to transcriptional regulator genes, including theEGR3gene coding for a transcription factor regulating epidermal differentiation. Notably, LINC00941 depletion resulted in reduced NuRD occupancy at theEGR3gene locus, increased EGR3 expression in human primary keratinocytes, as well as increased abundance of EGR3-regulated epidermal differentiation genes in cells and human organotypic epidermal tissue. Our results therefore indicate a role for LINC00941/NuRD in repressing EGR3 expression in non-differentiated keratinocytes, consequentially preventing premature differentiation of human epidermal tissue.
Same same but different – The global response ofEscherichia colito five different LpxC inhibitors
Authors: Möller Anna-Maria , Vázquez-Hernández Melissa , Kutscher Blanka , Brysch Raffael , Brückner Simon , Marino Emily , Kleetz Julia , Senges Christoph HR , Schäkermann Sina , Bandow Julia E , Narberhaus Franz
Published: July 2023

A promising but yet clinically unexploited antibiotic target in difficult-to-treat Gram-negative bacteria is LpxC, the key enzyme in the biosynthesis of lipopolysaccharides (LPS), which are the major constituents of the outer membrane. To gain insights into the mode of action of five different LpxC inhibitors, we conducted a comparative phenotypic and proteomic analysis. All five compounds bound to purified LpxC fromEscherichia coli. Treatment ofE. coliwith these compounds changed the cell shape and stabilized LpxC suggesting that the FtsH-mediated turnover is impaired. LpxC inhibition sensitizedE. colito the cell wall antibiotic vancomycin, which typically does not cross the outer membrane. Four of the five compounds led to an accumulation of lyso-PE, a cleavage product of phosphatidylethanolamine (PE), generated by the phospholipase PldA. The combined results suggested an imbalance in phospholipid (PL) and LPS biosynthesis, which was corroborated by the global proteome response to treatment with the LpxC inhibitors. Apart from LpxC itself, FabA and FabB responsible for the biosynthesis of unsaturated fatty acids, were consistently upregulated. Our work also shows that antibiotics targeting the same enzyme do not necessarily elicit identical cellular responses. Compound-specific marker proteins belonged to different functional categories, like stress responses, nucleotide or amino acid metabolism and quorum sensing. These findings provide new insights into common and distinct cellular defense mechanisms against LpxC inhibition. Moreover, they support a delicate balance between LPS and PL biosynthesis with great potential as point of attack for antimicrobial intervention.

Importance

The alarming spread of antimicrobial resistance among Gram-negative bacteria calls for novel intervention strategies. Inhibitors of LpxC, the first committed enzyme of lipopolysaccharide biosynthesis have been recognized as promising broad-spectrum antibiotics against Gram-negative pathogens. Despite the development of dozens of chemically diverse LpxC inhibitor molecules, it is essentially unknown how bacteria counteract LpxC inhibition. Our study provides comprehensive insights into the bacterial defense strategies against five different LpxC inhibitors. We show that the cellular response ofEscherichia coliis compound-specific but shares a common pattern. Inhibition of LpxC is toxic, disrupts membrane integrity, and elicits a stress response, including upregulation of fatty acid biosynthesis proteins. Pre-treatment ofE. coliwith low doses of LpxC inhibitors increased the sensitivity to the cell wall antibiotic vancomycin suggesting new directions in combination therapies.
Comprehensive catalogs for microbial genes and metagenome-assembled genomes of the swine lower respiratory tract microbiome identify the relationship of microbial species with lung lesions
Authors: Li Jingquan , Huang Fei , Zhou Yunyan , Huang Tao , Tong Xinkai , Zhang Mingpeng , Chen Jiaqi , Zhang Zhou , Du Huipeng , Liu Zifeng , Zhou Meng , Xiahou Yiwen , Ai Huashui , Chen Congying , Huang Lusheng
Published: July 2023

Understanding the community structure and functional capacity of the lower respiratory tract microbiome is crucial for elucidating its roles in respiratory tract diseases. However, there are few studies about it owing to the difficulty in obtaining microbial samples from the lower respiratory tract. Here we collected 745 microbial samples from the porcine lower respiratory tract by harvesting 675 pigs, and constructed a gene catalog containing 10,337,194 nonredundant genes, of which only 30% could be annotated taxonomically. We obtained 397 metagenome-assembled genomes (MAGs) including 111 MAGs with high-quality. These 397 MAGs were further clustered into 292 species-level genome bins (SGBs), among which 56% SGBs are unknown with current databases. Combining with the lung lesion phenotype, we found thatMycoplasma hyopneumoniaestrains and the adhesion-related virulence factors harboring in their genomes were significantly associated with porcine lung lesions, implying the role of adhesion and overgrowth of pathogenicM. hyopneumoniaein host lung diseases. This study provided important resources for the study of porcine lower respiratory tract microbiome and lung health.