bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergence of the reproduction matrix in epidemic forecasting
Authors: Gorji Hossein , Stauffer Noé , Lunati Ivan
Published: July 2024

During the recent COVID-19 pandemic, the instantaneous reproduction number,
R
(
t
), has surged as a widely used measure to target public health interventions aiming at curbing the infection rate. In analogy with the basic reproduction number that arises from the linear stability analysis,
R
(
t
) is typically interpreted as a threshold parameter that separates exponential growth (
R
(
t
) > 1) from exponential decay (
R
(
t
) < 1). In real epidemics, however, the finite number of susceptibles, the stratification of the population (e.g. by age or vaccination state), and heterogeneous mixing lead to more complex epidemic courses. In the context of the multidimensional renewal equation, we generalize the scalar
R
(
t
) to a reproduction matrix,

R
(
t
)

, which details the epidemic state of the stratified population, and offers a concise epidemic forecasting scheme. First, the reproduction matrix is computed from the available incidence data (subject to some
a priori
assumptions), then it is projected into the future by a transfer functional to predict the epidemic course. We demonstrate that this simple scheme allows realistic and accurate epidemic trajectories both in synthetic test cases and with reported incidence data from the COVID-19 pandemic. Accounting for the full heterogeneity and nonlinearity of the infection process, the reproduction matrix improves the prediction of the infection peak. In contrast, the scalar reproduction number overestimates the possibility of sustaining the initial infection rate and leads to an overshoot in the incidence peak. Besides its simplicity, the devised forecasting scheme offers rich flexibility to be generalized to time-dependent mitigation measures, contact rate, infectivity and vaccine protection.
Random walks with spatial and temporal resets can explain individual and colony-level searching patterns in ants
Authors: Lecheval Valentin , Robinson Elva J. H. , Mann Richard P.
Published: July 2024

Central place foragers, such as many ants, exploit the environment around their nest. The extent of their foraging range is a function of individual movement, but how the movement patterns of large numbers of foragers result in an emergent colony foraging range remains unclear. Here, we introduce a random walk model with stochastic resetting to depict the movements of searching ants. Stochastic resetting refers to spatially resetting at random times the position of agents to a given location, here the nest of searching ants. We investigate the effect of a range of resetting mechanisms and compare the macroscopic predictions of our model to laboratory and field data. We find that all returning mechanisms very robustly ensure that scouts exploring the surroundings of a nest will be exponentially distributed with distance from the nest. We also find that a decreasing probability for searching ants to return to their nest is compatible with empirical data, resulting in scouts going further away from the nest as the number of foraging trips increases. Our findings highlight the importance of resetting random walk models for depicting the movements of central place foragers and nurture novel questions regarding the searching behaviour of ants.
Culture and effectiveness of distance restriction policies: evidence from the COVID-19 pandemic
Authors: Xu Yang , Dong Chen , Shao Wenjing
Published: July 2024

Natural disasters bring indelible negative impacts to human beings, and people usually adopt somepost hocstrategies to alleviate such impacts. However, the same strategies may have different effects in different countries (or regions), which is rarely paid attention by the academic community. In the context of COVID-19, we examine the effect of distance restriction policies (DRP) on reducing human mobility and thus inhibiting the spread of the virus. By establishing a multi-period difference-in-differences model to analyse the unique panel dataset constructed by 44 countries, we show that DRP does significantly reduce mobility, but the effectiveness varies from country to country. We built a moderating effect model to explain the differences from the cultural perspective and found that DRP can be more effective in reducing human mobility in countries with a lower indulgence index. The results remain robust when different sensitivity analyses are performed. Our conclusions call for governments to adapt their policies to the impact of disasters rather than copy each other.
Brain asymmetry as minimization of free energy: a theoretical model
Authors: Vallortigara Giorgio , Vitiello Giuseppe
Published: July 2024

The asymmetry between the left and right sides seems to be a general principle of organization of the nervous systems in Bilateria, providing the foundations for a plethora of leftward and rightward biases in behaviour as documented in species ranging fromCaenorhabditis elegansnematodes to humans. Several theories have been put forward to account for the existence and maintenance in the evolution of the asymmetric organization of the brain at both individual and population levels. However, what is missing in theorizing about the evolution of brain asymmetry is an overarching general hypothesis that may subsume all different aspects of current models. Here, we tried to provide an overarching general framework based on the energy and free-energy minimization principle, which proved so valuable in other areas of neuroscience. We found that at the individual level the antisymmetric singlet configuration realizes the lowest energy state of the system, whereas at the group level, the spontaneous emergence of directional asymmetry arises as a consequence of the minimization of the free energy of the system, which guarantees its stability and equilibrium. We thus argue that the various phenomenological aspects of brain asymmetry that have been captured in biology—e.g. sparing of neural tissue, control of unitary motor responses and, at the population level, evolutionarily stable strategies described by mathematical games theory—may be thought of as the manifestation of a more general principle of energy minimization generating, among others, asymmetry of the brains.
Sex tweaks eye color
Authors: Bressan Paola
Published: July 2024

Here I challenge the conventional view of eye-color inheritance by showing that eye color depends (doubly) on sex: the sex of the parent and the sex of the child. I rely on the eye color records of over 30,000 Italians—a single-ethnicity population that features the largest genetic and eye-color diversity in Europe. First, more men than women express eye colors at the two extremes of the melanin range (blue and dark-brown) and more women than men express colors in the middle (green, hazel, brown, and mixed). Second, dark-brown-eyed mothers produce moresonswith dark-brown eyes and fewer with very-light-brown ones than do dark-brown-eyed fathers. Symmetrically, dark-brown-eyed fathers produce moredaughterswith dark-brown eyes and fewer with very-light-brown ones than do dark-brown-eyed mothers. All of this suggests that human eye pigmentation is controlled by a gene sitting on chromosome X—a chromosome which fathers pass on only to daughters, and sons inherit only from mothers. Such knowledge can improve forensic tools’ ability to predict eye color from DNA found at crime scenes and help in the identification of a known individual’s unknown birth parents. On a grander scale, these findings cast a new light on the origin of other, more fateful sex differences.
A detailed protocol for generating spike trans-complemented SARS-CoV-2 replicons
Authors: Yang Qi , Manicassamy Balaji , Neelamegham Sriram
Published: July 2024

Multiple approaches have been implemented for basic science studies that attempt to investigate SARS-CoV-2 biology or virology in biosafety level-2 setting. These include pseudotyped-virus based on lentivirus and vesicular stomatitis virus, virus-like particles that only contain the SARS-CoV-2 structural proteins, and single-cycle replicons. Among these, the single-cycle replicons most closely resemble the authentic virus as they essentially include the full viral genome, except for essential elements required for active virus multiplication. In this regard, we previously developed a SARS-CoV-2 replicon system where a Gaussia Dura luciferase-P2A-mNeonGreen reporter cassette replaced viral spike. In this short paper, we present an optimized protocol for the use of this reagent that overcomes previous technical limitations. We demonstrate that co-transfection of this bacmid along with spike plasmid, using the improved protocol, yields high-quality spike bearing SARS-CoV-2 virus particles with single-cycle infectivity. Due to the nature of bacmid construction, this approach is particularly useful for studying the impact of spike mutagenesis on virus evolution in BSL-2 setting.
Factors Associated with Acute Kidney Injury in COVID-19 Hospitalized Patients in Central Java, Indonesia
Authors: Partiningrum Dwi Lestari , Chionardes Melissa Angela , Yusri Nurul Hasanah , Aji Indra Adhim Karunia , Subagya Jonathan Christianto , Liemarto Aldrich Kurniawan
Published: July 2024

Backgroud and Objective

Acute kidney injury (AKI) is a significant complication of COVID-19 infection, with varied incidence rates globally. COVID-19 has exacerbated AKI cases, with a significant portion of patients experiencing kidney damage. This study investigates the prevalence and risk factors associated with AKI among COVID-19 patients in Semarang, Central Java, Indonesia.

Methods

Data from 364 hospitalized COVID-19 patients in a hospital in Semarang between March 2020 and September 2021 were analyzed. Statistical analysis using chi-square and logistic regression examined the relationship between AKI and its determinants, with p≤0.05 considered significant.

Results

The majority of patients were male, most had no prior medical conditions. Analysis indicated links between AKI and various factors like several physical and supportive examination results. Few comorbidities were found to increase the risk of AKI, followed also by abnormal vital signs except blood pressure, several elevated level of laboratory results, and radiologic pneumonia finding.

Conclusion

COVID-19 may harm the kidneys causing AKI. This study highlights the importance of history taking, examination, and laboratory monitoring to detect AKI in COVID-19 patients.
A Machine Learning-enabled SIR Model for Adaptive and Dynamic Forecasting of COVID-19
Authors: Mortensen Peter , Lauer Katharina , Rautenbach Stefan Petrus , Gallotta Marco , Sharapova Natasha , Takkides Ioannis , Wright Michael , Linley Mathew
Published: July 2024

The COVID-19 pandemic has posed significant challenges to public health systems worldwide, necessitating accurate and adaptable forecasting models to manage and mitigate its impacts. This study presents a novel forecasting framework based on a Machine Learning-enabled Susceptible-Infected-Recovered (ML-SIR) model with time-varying parameters to predict COVID-19 dynamics across multiple geographies. The model incorporates emergent patterns from reported time-series data to estimate new hospitalisations, hospitalised patients, and new deaths. Our framework adapts to the evolving nature of the pandemic by dynamically adjusting the infection rate parameter over time and using a Fourier series to capture oscillating patterns in the data. This approach improves upon traditional SIR and forecasting models, which often fail to account for the complex and shifting dynamics of COVID-19 due to new variants, changing public health interventions, and varying levels of immunity. Validation of the model was conducted using historical data from the United States, Italy, the United Kingdom, Canada, and Japan. The model’s performance was evaluated based on the Mean Absolute Percentage Error (MAPE) and Absolute Percentage Error of Cumulative values (CAPE) for three-month forecast horizons. Results indicated that the model achieved an average MAPE of 32.5% for new hospitalisations, 34.4% for patients, and 34.8% for new deaths, for three-month forecasts. Notably, the model demonstrated superior accuracy compared to existing forecasting models with like-for-like disease metrics, countries and forecast horizons. The proposed ML-SIR model offers a robust and adaptable tool for forecasting COVID-19 dynamics, capable of adjusting to new time-series data and varying geographical contexts. This adaptability makes it suitable for localised hospital capacity planning, scenario modelling, and for application to other respiratory infectious diseases with similar transmission dynamics, such as influenza and RSV. By providing reliable forecasts, the model supports informed public health decision-making and resource allocation, enhancing preparedness and response efforts.
Validation and reproducibility of mapping positron emission tomography uptake in the aortic wall and thrombus
Authors: Bragulat-Arévalo Mireia , Ferrer-Cornet Marta , Dux-Santoy Lydia , Oliveró-Soldevila Ruper , Garcia-Reyes Marvin , Teixido-Tura Gisela , Garrido-Oliver Juan , Galian-Gay Laura , Lopez-Gutierrez Pere , Morales-Galán Alberto , Catalá-Santarrufina Alba , García Garzón Jose Ramon , Martinez Esquerda Noemi , Solsona Javier , Ferreira-González Ignacio , Bellmunt-Montoya Sergi , Rodriguez-Palomares Jose , Guala Andrea
Published: July 2024

INTRODUCTION

Aortic aneurysms are prevalent diseases of the aorta, with limited knowledge about their aetiology, progression, and risk, and no effective pharmacological treatment. 18F-fluorodesoxyglucose Positron Emission Tomography (18F-FDG PET) provides molecular level information of glucose activity, serving as potential analogue of vascular inflammation, which may be relevant to improve knowledge and clinical management of aortic aneurysms. Nonetheless, current clinical assessment of 18F-FDG uptake presents several limitations.

PURPOSE

The aim of this study was to develop, test and validate an innovative aortic wall uptake mapping.

METHODS

PET/magnetic resonance (MR) data from 72 patients were acquired. The aortic lumen was segmented, and 9 anatomical landmarks were identified to create a standardised aortic lumen discretization including up to 80 patches. Black-blood MR images were used to guide thrombus segmentation if present, which was merged with lumen segmentation to generate a thoraco-abdominal aortic wall mask. This mask was then expanded by 1 to 5 mm in the inward and outward directions, resulting in an aortic wall volume of interest. Median and percentile 95th standard uptake value (SUV) was calculated on each aortic patch. A second observer performed the same analysis on 23 randomly selected patients for inter-observer reproducibility assessment. Validation was performed by comparisons with regional SUV measured by a nuclear medicine expert.

RESULTS

The technique was highly feasible, permitting the analysis of all 72 patients and in the 99.6% of aortic wall patches. The image analysis workflow was highly reproducible, resulting in Dice scores of 0.90 [0.57, 0.91] and 0.85 [0.78, 0.88] for aortic and thrombus segmentations, respectively, and in excellent co-localization for anatomical references (5.74 [3.62, 8.73] mm).

The inter-observer reproducibility of aortic wall SUV mapping was excellent (ICC between 0.924 and 0.945), with limited differences with respect to aortic wall thickness and similar performances for SUV quantification in the thrombus. The validation of regional SUV values showed good agreement, with limited impact of aortic wall thickness values. A balance between reproducibility and accuracy was obtained with a volume of interest of 6 mm thickness.

CONCLUSIONS

An image analysis implementation based on multi-modality PET/MR data provides reproducible and accurate quantitative aortic wall 18F-FDG uptake maps. This approach may enable exploring local factors related to an inflammatory vascular state, with possible repercussions in clinical practice.
Opioid-Induced Inter-regional Dysconnectivity Correlates with Analgesia in Awake Mouse Brains
Authors: Mariani Jean-Charles , Diebolt Samual , Beynac Laurianne , Santos Renata , Schulz Stefan , Deffieux Thomas , Tanter Mickael , LENKEI Zsolt , Kliewer Andrea
Published: July 2024

The mu-opioid receptor (MOP) is crucial for both the therapeutic and addictive effects of opioids. Using a multimodal experimental approach, here we combined awake functional ultrasound (fUS) imaging with behavioral and molecular assessments, to examine opioid-induced changes in brain activation and functional connectivity (FC). Morphine, fentanyl, and methadone induce significant dose- and time-dependent reorganization of brain perfusion, oscillations and FC in awake mice. Notably, opioids induce a transient, region-specific hyperperfusion, followed by a consistent MOP-specific dysconnectivity marked by decreased FC of the somatosensory cortex to hippocampal and thalamic regions, alongside increased subcortical and intra-cortical FC. These FC changes temporally correlate with generalized brain MOP activation and analgesia, but not with hypermobility and respiratory depression, suggesting a reorganization of inter-regional FC as a key opioid effect.
Interactive effects of temperature acclimation and dietary fatty acids on metabolic rate and body composition of zebra finches (Taeniopygia guttata)
Authors: Campbell Michael J. , Mastromonaco Gabriela F. , Burness Gary
Published: July 2024

Climate change is contributing to geographic range shifts in many bird species, with possible exposure to novel diets. How individuals respond physiologically across chronic time frames to the interacting effects of diet and environmental temperature has been little explored. We acclimated zebra finches to either cool (20-24°C) or thermoneutral (35°C) temperatures over 6-months and provided them with diets enriched in either unsaturated or saturated fatty acids. We measured body mass throughout the study, and basal metabolic rate (BMR) and body composition at 3- and 6-months, respectively. Individuals held in cool conditions and fed a diet enriched with unsaturated fatty acids lost mass initially relative to the other groups, however, effects were reversible, and all individuals had a similar mass at 6- months. Chronic exposure to cool conditions increased BMR and the mass of the pectoral muscle and visceral organs. However, we could detect no long-term effect of diet on any physiological parameter. Our results contrast with those of birds studied over acute time frames, in which diet and temperature interact to determine energy expenditure. Over chronic time frames individuals appear to reach a new steady-state, with long-term physiological responses driven primarily by thermoregulatory responses to environmental temperature.

Research Highlights:

With climate change, birds may encounter novel diets and temperatures

In zebra finches we show that chronic acclimation to cool temperatures increased energy expenditure and changed body composition.

Dietary fatty acid content had little long-term impact on the physiological parameters we measured.
Hypersynchronous iPSC-derivedSHANK2neuronal networks are rescued by mGluR5 agonism
Authors: McCready Fraser P. , Pradeepan Kartik S. , Khaki Milad , Wei Wei , Matusiak Nicole , Piekna Alina , Martinez-Trujillo Julio , Ellis James
Published: July 2024

Variants in the gene encoding the postsynaptic scaffolding protein SHANK2 are associated with several neurodevelopmental disorders, including autism spectrum disorder. Here, we usedin vitromultielectrode arrays and pharmacological manipulations to characterize how functional connectivity and network-level firing properties were altered in cultures of human iPSC-derivedSHANK2neurons. Using two isogenic pairs ofSHANK2cell lines, we showed that theSHANK2hyperconnectivity phenotype was recapitulated at the network level.SHANK2networks displayed significantly increased frequency and reduced duration of network burst events relative to controls.SHANK2network activity was hypersynchronous, with increased functional correlation strength between recording channels. Analysis of intra-network burst firing dynamics revealed that spikes withinSHANK2network bursts were organized into high-frequency trains, producing a distinctive network burst shape. Calcium-dependent events called reverberating super bursts (RSBs) were observed in control networks but rarely occurred inSHANK2networks.SHANK2network hypersynchrony and numbers of strong correlations were fully rescued by the group 1 mGluR agonist DHPG, that also restored detection of RSBs and significantly improved network burst frequency and duration metrics. Our results demonstrate thatSHANK2variants produce a functional hyperconnectivity phenotype that deviates from the developmental trajectory of isogenic control networks. Furthermore, the hypersynchronous phenotype was rescued by pharmacologically regulating glutamatergic neurotransmission.
A bioactive soluble recombinant mouse LIGHT promotes effective tumor immune cell infiltration delaying tumor growth
Authors: del Rio Maria-Luisa , Roncador Giovanna , Cubria Juan Carlos , Schneider Pascal , Rodriguez-Barbosa Jose-Ignacio
Published: July 2024

The TNF family member LIGHT (TNFSF14) binds to two receptors, HVEM (TNFSFR14) and LTβR (TNFSFR3). HVEM functions as a costimulatory molecule, whereas LTβR is involved in the development of lymph nodes and ectopic tertiary lymphoid structures at chronic inflammation sites. The classical approach of fusing soluble recombinant proteins to the Fc fragment of IgG resulted in a functionally inactive Ig.mouse (m) LIGHT protein. However, in line with the fact that TNF family members cluster receptors as trimers, addition of a small homotrimeric domain (foldon) N-terminal of mLIGHT produced an active Ig.Foldon-mLIGHT protein able to bind and engage HVEM and LTβR in a reporter cell-based bioassay.

In the tumor model of B16.F10 melanoma cells implanted into syngeneic recipients, cells transduced with membrane-bound mLIGHT grew as aggressively as mock-transduced cells, but growth of tumors of B16.F10 cells expressing Ig.Foldon-mLIGHT was delayed and characterized by significant immune cell infiltration.

This work unveils the potential of active soluble LIGHT, as a single agent, to recruit cytotoxic cells and dendritic cells at the tumor site to inhibit tumor growth. This effect may be further enhanced with immune checkpoint blockade therapies.
Distinct adaptation and epidemiological success of different genotypes withinSalmonella entericaserovar Dublin
Authors: Sia Cheryll M , Ambrose Rebecca L , Valcanis Mary , Andersson Patiyan , Ballard Susan A , Howden Benjamin P , Williamson Deborah A , Pearson Jaclyn S , Ingle Danielle J
Published: July 2024

SalmonellaDublin is a host-adapted, invasive non-typhoidalSalmonella(iNTS) serovar that causes bloodstream infections in humans and demonstrates increasing prevalence of antimicrobial resistance (AMR). Using a global dataset of 1,303 genomes, coupled within vitroassays, we examined the evolutionary, resistance, and virulence characteristics ofS. Dublin. Our analysis revealed strong geographic associations between AMR profiles and plasmid types, with highly resistant isolates confined predominantly to North America, linked to IncC plasmids co-encoding AMR and heavy metal resistance. By contrast, Australian isolates were largely antimicrobial-susceptible, reflecting differing AMR pressures. We identified two phylogenetically distinct Australian lineages, ST10 and ST74, with a small number of ST10 isolates harbouring a novel hybrid plasmid encoding both AMR and mercuric resistance. Whereas the ST10 lineage remains globally dominant, the ST74 lineage was less prevalent. ST74 exhibited unique genomic features including a larger pan genome compared to ST10 and the absence of key virulence loci including SPI-19 which encodes a type VI secretion system (T6SS). Despite these genomic differences, the ST74 lineage displayed enhanced intracellular replication in human macrophages and induced less pro-inflammatory responses compared with ST10, suggesting alternative virulence strategies that may support systemic dissemination of ST74. The Vi antigen was absent in all ST10 and ST74 genomes, highlighting challenges for serotyping and vaccine development, and has implications for current diagnostic and control strategies forS.Dublin infections. Collectively, this study represents the most comprehensive investigation ofS. Dublin to date and importantly, has revealed distinct adaptations of two genotypes within the same serovar, leading to different epidemiological success. The regional emergence and evolution of distinctS.Dublin lineages highlights the need to understand the divergence of intra-serovar virulence mechanisms which may impact the development of effective control measures against this important global pathogen.
Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation
Authors: Carter-Cusack Dylan , Huang Stephen , Keshvari Sahar , Patkar Omkar , Sehgal Anuj , Allavena Rachel , Byrne Robert , Morgan Paul , Bush Stephen J. , Summers Kim M. , Irvine Katharine M. , Hume David A.
Published: July 2024

Adaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in theCsf1rgene (Csf1rko) severely compromises pre-weaning somatic growth and maturation of organ function. Transfer of wild-type bone marrow cells (BMT) at weaning rescues tissue macrophage populations permitting normal development and long-term survival. To dissect the phenotype and function of macrophages in postnatal development, we generated transcriptomic profiles of all major organs of wild-type andCsf1rkorats at weaning and selected organs following rescue by BMT. The transcriptomic profiles revealed subtle effects of macrophage deficiency on development of all major organs. Network analysis revealed a common signature of CSF1R-dependent resident tissue macrophages that includes the components of complement C1Q (C1qa/b/cgenes). Circulating C1Q was almost undetectable inCsf1rkorats and rapidly restored to normal levels following BMT. Tissue-specific macrophage signatures were also identified, notably including sinus macrophage populations in the lymph nodes. Their loss inCsf1rkorats was confirmed by immunohistochemical localisation of CD209B (SIGNR1). By 6-12 weeks,Csf1rkorats succumb to emphysema-like pathology associated with the selective loss of interstitial macrophages and granulocytosis. This pathology was reversed by BMT. Along with physiological rescue, BMT precisely regenerated the abundance and expression profiles of resident macrophages. The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia. In addition, the transferred BM failed to restore blood monocyte or CSF1R-positive bone marrow progenitors. These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity.
Unraveling cysteine deficiency-associated rapid weight loss
Authors: Varghese Alan , Gusarov Ivan , Gamallo-Lana Begña , Dolgonos Daria , Mankan Yatin , Shamovsky Ilya , Phan Mydia , Jones Rebecca , Gomez-Jenkins Maria , White Eileen , Wang Rui , Jones Drew , Papagiannakopoulos Thales , Pacold Michael E. , Mar Adam C , Littman Dan R , Nudler Evgeny
Published: July 2024

Forty percent of the US population and 1 in 6 individuals worldwide are obese, and the incidence of this disease is surging globally1,2. Various dietary interventions, including carbohydrate and fat restriction, and more recently amino acid restriction, have been explored to combat this epidemic3–6. We sought to investigate the impact of removing individual amino acids on the weight profiles of mice. Compared to essential amino acid restriction, induction of conditional cysteine restriction resulted in the most dramatic weight loss, amounting to 20% within 3 days and 30% within one week, which was readily reversed. This weight loss occurred despite the presence of substantial cysteine reserves stored in glutathione (GSH) across various tissues7. Further analysis demonstrated that the weight reduction primarily stemmed from an increase in the utilization of fat mass, while locomotion, circadian rhythm and histological appearance of multiple other tissues remained largely unaffected. Cysteine deficiency activated the integrated stress response (ISR) and NRF2-mediated oxidative stress response (OSR), which amplify each other, leading to the induction of GDF15 and FGF21, hormones associated with increased lipolysis, energy homeostasis and food aversion8–10. We additionally observed rapid tissue coenzyme A (CoA) depletion, resulting in energetically inefficient anaerobic glycolysis and TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds and amino acids. In summary, our investigation highlights that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings may pave the way for innovative strategies for addressing a range of metabolic diseases and the growing obesity crisis.
Intraperitoneal programming of tailored CAR macrophages via mRNA-LNP to boost cancer immunotherapy
Authors: Gu Kedan , Liang Ting , Hu Luting , Zhao Yifan , Ying Weiyang , Zhang Mengke , Chen Yashuang , Liang Benmeng , Lin Xinrui , Zhang Yanqi , Wu Hongyu , Wang Meng , Zhu Yuping , Wang Wenxi , Zhang Yu , Zuo Chao , Du Zhen , Zhang Penghui , Song Jia , Liu Xiangsheng , Xie Sitao , Tan Weihong
Published: July 2024

Therapeutic strategies for peritoneal metastasis in solid tumors are urgently needed in the clinic. Programming chimeric antigen receptor macrophages (CAR-Ms)in situoffers opportunities for an unmet demand. However, potential intracellular domains (ICDs) for CAR design and their antitumor mechanisms for macrophage empowerment remain to be explored systematically. By developing a targeted mRNA-LNP delivery system for macrophages, we have investigated 36 CAR combinations to determine the impact of CAR-Ms on immune regulationin vitroandin vivo. In two solid tumor mouse models, intraperitoneal programming of CAR-Ms was shown to elicit robust adaptive immune activation and significantly synergize with PD-1/L1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis revealed that CAR-Ms could reshape the immunosuppressive tumor microenvironment (TME) and boost the TCF1+PD-1+progenitor- exhausted CD8+T cells (Tpex) population. Meanwhile, we found that tailored CAR-M with CD3ζ/TLR4 ICDs could favorably maintain proinflammatory phenotype and simultaneously upregulate MHC I and PD-L1 expression by perturbing NF-κB pathways. Moreover, the synergism between macrophage PD-L1 knockdown and CAR-M therapy highlighted the need to block the PD-1/L1 axis in antigen cross-presentation. In short, we developed an mRNA-LNP delivery system for intraperitoneal programming of tailored CAR-Msin vivoand broadened understanding of both regulatory and feedback mechanisms for CAR-M therapies against solid tumors.
Extending the capabilities of deconvolution to provide cell type specific pathway analysis of bulk RNA-seq data for idiopathic pulmonary fibrosis
Authors: Calvero Mifflin-Rae , Meghadri Sri Harsha , Carleo Alfonso , Prasse Antje , DeLuca David S.
Published: July 2024

Motivation

Transcriptome data are confounded by differences in cell type proportions. Differentiating between regulated changes in gene expression and changes due to differing cell type proportions remains a challenge. Therefore, we apply a deconvolution method to correct for changes in cell type proportions and provide a novel cell-type specific pathway analysis.

Results

We demonstrate the technique in the context of idiopathic pulmonary fibrosis. Inferred cell type proportions indicated a significant increase in fibroblasts, myofibroblasts, and a decrease in vascular endothelial capillary cells. Pathway analysis after adjustment for proportions indicated IPF-related changes in extracellular matrix organization and TGF-β regulation. Cell-type specific pathway analysis suggested the role of interferon signaling in ATII cells. These results demonstrate that deconvolution is not only useful for assessing cell type proportions, but also can provide cell type-specific pathway analysis, allowing for a much more nuanced interpretation of bulk RNA-seq data.
Regulatory T-cells in multiple sclerosis are activated by Epstein-Barr Virus and produce IL-10 in the central nervous system
Authors: Pulvirenti N. , Righetti C. , Clemente F. , Serafini B. , Pietroboni A. , Galeota E. , Rosicarelli B. , Cordiglieri C. , Iannone C. , de Riz M. , Vasco C. , Espadas de Arias A. , De Feo T. , Valenti L. , Prati D. , Abrignani S. , Gerosa M. , Caporali R. , Galimberti D. , Scarpini E. , Geginat J.
Published: July 2024

Regulatory T-cells (Tregs) maintain immune homeostasis, but antigens activating adaptive Tregs in human pathologies are ill-defined. EOMES+type-1 regulatory (EOMES+Tr1-like) T-cells had a dysregulated homeostasis in multiple sclerosis (MS), which was related to their activation in the central nervous system (CNS). EOMES+Tr1-like cells were strongly enriched in patient’s cerebrospinal fluid (CSF) and were the main IL-10-producing T-cells in the CSF. IL-10+EOMES+Tr1-like were present in MS brain lesions, and some were found close to Epstein-Barr Virus (EBV)-infected B-cells. EOMES+Tr1-like cells and FOXP3+Tregs produced IL-10 with EBV-derived antigens, but not with major myelin antigens. EOMES+Tr1-like cells responded selectively to the latency-associated antigen EBNA1, whereas FOXP3+Tregs responded also to lytic antigens. EBNA1-specific EOMES+Tr1-like cells were associated with anti-EBNA1 IgG, disappeared upon therapeutic B-cell depletion and were relatively abundant in patients with the HLA-DRB1*15 risk haplotype. The aberrant anti-viral specificities of Tregs in MS could undermine their protective functions and anti-EBV immune surveillance.
Structural Basis of βKNL2 Centromeric Targeting Mechanism and Its Role in Plant-Specific Kinetochore Assembly
Authors: Yadala Ramakrishna , Camara Amanda S , Yalagapati Surya P , Jaroschinsky Pascal , Meitzel Tobias , Ariyoshi Mariko , Fukagawa Tatsuo , Rutten Twan , Bui Thu-Giang T , Lermontova Inna
Published: July 2024

The kinetochore is an essential protein complex that ensures proper chromosome segregation during cell division. Kinetochore assembly is initiated by the incorporation of CENP-A/CENH3. This process depends on KNL2/M18BP1 and CENP-C proteins. In plants, two variants of KNL2, αKNL2 and βKNL2, are present. Both possess the conserved SANTA domain, while αKNL2 additionally has the centromere-targeting CENPC-k motif. Despite lacking the CENPC-like motif, the plant-specific βKNL2 localizes to centromeres and aids in CENP-A/CENH3 loading. We found that efficient centromeric targeting of βKNL2 requires the SANTA domain and the C-terminal part, while nuclear targeting depends on a conserved C-terminal motif-III. Structural predictions and experimental validations reveal that βKNL2 forms homodimers and interacts with centromeric DNA and αKNL2. We confirm that centromeric targeting of βKNL2 depends on αKNL2 in a tissue-dependent manner. Our findings provide crucial insights into the unique mechanisms of plant-specific kinetochore assembly, highlighting βKNL2’s essential role in this process.

Graphical abstract
The representational nature of spatio-temporal recurrent processing in visual object recognition
Authors: Xie Siying , Singer Johannes , Yilmaz Bati , Kaiser Daniel , Cichy Radoslaw M.
Published: July 2024

The human brain orchestrates object vision through an interplay of feedforward processing in concert with recurrent processing. However, where, when and how recurrent processing contributes to visual processing is incompletely understood due to the difficulties in teasing apart feedforward and recurrent processing. We combined a backward masking paradigm with multivariate analysis on EEG and fMRI data to isolate and characterize the nature of recurrent processing. We find that recurrent processing substantially shapes visual representations across the ventral visual stream, starting early on at around 100ms in early visual cortex (EVC) and in two later phases of around 175 and 300ms in lateral occipital cortex (LOC), adding persistent rather than transient neural dynamics to visual processing. Using deep neural network models for comparison with the brain, we show that recurrence changes the feature format in LOC from predominantly mid-level to more high-level features. Finally, we show that recurrence is mediated by four distinct spectro-temporal neural components in EVC and LOC, which span the theta to beta frequency range. Together, our results reveal the nature and mechanisms of the effects of recurrent processing on the visual representations in the human brain.
Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques
Authors: Bosinger Steven E. , Edwards Christopher T , Karunakaran Kirti A. , Garcia Elijah , Beutler Nathan , Gagne Matthew , Golden Nadia , Aoued Hadj , Pellegrini Kathryn , Burnett Matthew R. , Honeycutt Christopher Cole , Lapp Stacey A. , Ton Thang , Lin Mark C. , Metz Amanda , Bombin Andrei , Goff Kelly , Scheuermann Sarah E. , Wilkes Amelia , Wood Jennifer S. , Ehnert Stephanie , Weissman Stacey , Curran Elizabeth H. , Moore Ian N. , Roy Melissa , Dessasau Evan , Paiardini Mirko , Upadhyay Amit A. , Maness Nicholas J. , Douek Daniel C. , Piantadosi Anne , Andrabi Raiees , Rogers Thomas R , Burton Dennis R.
Published: July 2024

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (beta-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other beta-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n=6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-beta-CoV vaccines.
Second impact of an acute total body irradiation on thymic epithelial cells
Authors: Namiki Kano , Muramatsu Wataru , Miyao Takahisa , Ishii Hiroto , Endo Rin , Hagiwara Naho , Miyauchi Maki , Yoshida Masaki , Akiyama Nobuko , Akiyama Taishin
Published: July 2024

The thymus, a crucial organ for T cell development, undergoes transient involution following exposure to sublethal total body irradiation. The impact of sublethal irradiation on the thymus is reportedly bimodal: thymic involution recurs after the recovery of the thymus from the initial impact of acute sublethal irradiation. While the second impact of acute irradiation has been acknowledged for thymocytes, its influence on thymic epithelial cells (TECs), which are crucial for thymic T cell differentiation and selection, remains to be elucidated. In this study, we aim to elucidate this influence. Mice were subjected to acute sublethal total body irradiation, and TECs were evaluated at three distinct time points: during the initial impact, during the recovery phase post-initial impact, and during the second impact phase. Flow cytometry analysis revealed that during the second impact phase, mTECs were reduced, whereas cTECs remained unaffected. Among mTECs, the subset expressing high levels of the co-stimulatory molecule CD80 (mTEChi) experienced the most pronounced reduction. RNA sequencing analysis of mTEChicells at early differentiation stages revealed significant alterations in gene expression profiles during the second impact phase. Notably, gene signatures of tuft-like TECs and Aire-expressing TECs were preferentially influenced in these mTEChisubpopulations. These findings suggest that acute total body irradiation disrupts mTEC frequencies and gene expression in a bimodal manner, possibly compromising thymic functions over extended periods.
Derivation of aerial insect concentration with a 94GHz FMCW cloud radar
Authors: Lochmann Moritz , Kalesse-Los Heike , Haest Birgen , Vogl Teresa , van Klink Roel , Addison Freya , Maahn Maximilian , Schimmel Willi , Wirth Christian , Quaas Johannes
Published: July 2024

Aerial insects are vital for nature and society. Though methods to observe flying insects have consistently improved in the last decades, insects remain difficult to monitor systematically and consistently over large spatial and temporal scales. Remote sensing with radars has proved to be one of the more effective tools for observation. However, as radars are most sensitive to targets similar in size to the radar wavelength, the detectable sub-group of aerial insects of a certain size range depends on the employed radar. Here, we present a novel method based on data of a zenith-pointing W-band (94 GHz,λ= 0.32 cm) Doppler cloud radar to estimate insect concentration in a vertical profile. Multiple meteorological state-of-the-art algorithms are combined to extract insect signals from the radar data and quantify their abundance from 50 m to 1000 m above the ground. For evaluation, this method is applied to Doppler cloud radar data from a summertime 30 day observation period in central Germany. Results are compared to data from an X-band (9.4 GHz,λ= 3.2 cm) radar in the same region. Aerial insect concentration derived from the W-band radar, which is sensitive to insects in the mm size range, is substantially higher than from the X-band radar, detecting insects in the cm size range. In addition, diel flight timings vary between the different sub-groups of aerial insects observed by the two radar instruments. With its superior sensitivity to smaller insects like aphids, the proposed methodology complements existing entomological radar techniques and contributes to achieving a more complete description of aerial insect activity.
Aging and Germination of Long-term Stored Seeds: Can MicroRNAs Unlock the Secrets?
Authors: Puchta-Jasińska Marta , Bolc Paulina , Groszyk Jolanta , Boczkowska Maja
Published: July 2024

Background

Small non-coding RNAs appear to be one of the key components of the germination process. To investigate how small non-coding RNAs correlate with germination of seeds with different levels of viability, miRNA-Seq analyses were performed.

Results

Our analysis sequencing identified 62 known miRNAs from 11 families and 234 new miRNAs after imbibition process. Among the miRNAs with the highest expression levels, we can mention: miR159, miR168 and miR166. The study placed particular emphasis on miRNAs with significant differences in expression levels at different stages of imbibition and among seeds with different viability. DEG analysis identified 28 miRNAs with significant differences in expression levels, their function was assessed byin silicoanalyses and confirmed by degradome-seq analysis. The expression of miRNAs was verified by qRT-PCR.

Conclusion

Our data provides a useful source of information on miRNA during germination long term storage seeds with different viability. The studies suggest that miRNAs are involved in the germination process by their regulation DNA and RNA binding, regulation of developmental process and ribosome.
Sequence and structural analysis of adaptors of Toll-like receptor 4 sheds light on the evolutionary trajectory and functional emergence
Authors: Verma Shailya , Sowdhamini Ramanathan
Published: July 2024

1.

Type 4 Toll-like receptors 4 (TLR4) recognise lipopolysaccharides (LPS) from bacteria as their conventional ligands and undergo downstream signalling to produce cytokines. They mediate the signalling either by the TIRAP-MyD88 complex or by the TRAM-TRIF complex. The MyD88 pathway is common to all other TLRs, whereas the TRAM-TRIF complex is largely exclusive to TLR4. We studied the TIR domain of TRAM and TRIF homologue proteins, that are crucial for downstream signalling. From our previous work on pan-genome-wide survey, we findCallorhincus millito be the ancestral organism with both TRAM and TRIF proteins. To gain a deeper insight about the functioning of these proteins and comparison with the adaptor proteins inHomo sapiens, we performed TRAM and TRIF dimer docking to model the TRAM-TRIF complex of representative organisms across various taxa. These provide us insights to ascertain a possible interaction surface, calculate the energetics, electrostatic potential, and then employ Normal Mode Analysis (NMA) to examine fluctuating, interacting and specific residue clusters which can be important for the protein functioning in both organisms. We also performed molecular dynamics simulations of these complexes and cross validated the functionally important residues using network parameters. While the critical residues of TIRAP, TRIF, and MyD88 were preserved, we found that the important residues of TRAM signalling were not conserved inCallorhincus milli. This suggests the presence of functional TIRAP-MyD88 mediated TLR4 signalling and TRIF mediated TLR3 signalling in the ancestral species. The overall biological function of this signalling domain appears to be gradually acquired through the orchestration of several motifs through evolutionary scale.