bluuebunny/crossref_metadata_2025 huggingface dataset:
Purchases dominate the carbon footprint of research laboratories
Authors: De Paepe Marianne , Jeanneau Laurent , Mariette Jerôme , Aumont Olivier , Estevez-Torres Andŕe
Published: April 2023

Despite increasing interest for the carbon footprint of higher education institutions, little is known about the carbon footprint associated to research activities. Air travel and attendance to conferences concentrate recent data and debates but purchases have attracted little attention. Here we develop a hybrid method to estimate the greenhouse gas emissions (GHG) associated to research purchases. To do so, we combine macroe-conomic databases, research-centered companies footprints and life-cycle assesments to construct a public database of monetary emission factors (EF) for research purchases. We apply it to estimate the purchases emissions of a hundred of research laboratories in France, belonging to the Labos 1point5 network and gathering more than 20000 staff, from all disciplines. We find that purchases dominate laboratory emissions, accounting for more than 50% of emissions, with a median of 2.7 t CO2e/pers, which is 3 to 4-fold the separate contribution from travel, commutes and heating. Median electricity emissions are 5-fold lower in our dataset of laboratories using low carbon electricity but they become preponderant for high carbon electricity mixes (3.5 t CO2e/pers). Purchases emissions are very heterogeneous among laboratories and are linearly correlated with budget, with an average carbon intensity of 0.31±0.07 kg CO2e/€ and differences between research domains. Finally, we quantify the effect of a series of demand-driven mitigation strategies obtaining up to−20 % in total emissions (−40 % in purchases emissions), suggesting that effectively reducing the carbon footprint of research activities calls for systemic changes.

Significance statement

Research activities are recently interrogating their contribution to global warming, mainly through the impact of air travel but neglecting the emissions embodied in scientific purchases. However, goods and services used in a research laboratory emit greenhouse gases when they are produced. Here we construct a public and robust database of emission factors to quantify purchases emissions in a laboratory and we use it to assess emissions from a hundred of laboratories in France, from all disciplines. We find that purchases emissions represent half of the of the 6.3 t CO2e/pers per year emitted on average per laboratory. Emissions, however, vary greatly between laboratories and disciplines and an analysis of mitigation strategies shows that decreasing demand may significantly reduce purchases emissions.
Pathogenesis ofAchromobacter xylosoxidansrespiratory infections: colonization and persistence of airway epithelia and differential gene expression in synthetic cystic fibrosis sputum medium
Authors: Billiot Caitlin E. , McDaniel Melissa S. , Swords W. Edward , Lindgren Natalie R.
Published: April 2023

Cystic fibrosis (CF) is a genetic disease affecting epithelial ion transport, resulting in thickened mucus and impaired mucociliary clearance. Persons with CF (pwCF) experience life- long respiratory mucosal infections caused by a diverse array of opportunists, and these infections are a leading cause of morbidity and mortality for pwCF. In recent years, there has been increased appreciation for the range and diversity of microbes in CF-related respiratory infections. Introduction of new therapeutics and improved detection methodology has revealed CF related opportunists such asAchromobacter xylosoxidans(Ax).Axis a Gram-negative bacterial species that is widely distributed in the environment and has been increasingly observed in sputa and other samples from pwCF; typicallyAxinfections occur in patients in later stages of CF disease. In this study, we characterized CF clinical isolates ofAxand tested colonization and persistence ofAxin respiratory infection using immortalized human CF respiratory epithelial cells and BALB/c mice. Genomic analyses of clinicalAxisolates showed homologs for factors involved in flagellar synthesis, antibiotic resistance, and toxin secretion systems.Axisolates adhered to polarized CFBE14o- human immortalized CF bronchial epithelial cells and caused significant cytotoxicity and depolarization.Axcolonized and persisted in mouse lung for up to 72 hours post infection, with inflammatory consequences that include increased neutrophilia, lung damage, cytokine production, and mortality. Transcript profiling reveled differential expression ofAxgenes during growth in SCFM2 synthetic CF sputum media. Based on these results, we conclude thatAxis an opportunistic pathogen of significance in CF.
White matter integrity is associated with cognition and amyloid burden in older adult Koreans along the Alzheimer’s disease continuum
Authors: Hirschfeld Lauren Rose , Deardorff Rachael , Chumin Evgeny J. , Wu Yu-Chien , McDonald Brenna C. , Cao Sha , Risacher Shannon L. , Yi Dahyun , Byun Min Soo , Lee Jun-Young , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul-Ho , Nho Kwangsik , Saykin Andrew J. , Lee Dong Young ,   the KBASE Research Group
Published: April 2023

BACKGROUND

White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer’s disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations.

METHODS

We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥55 years, including 276 cognitively normal older adults (CN), 142 mild cognitive impairment (MCI), and 87 AD, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) at Seoul National University.

RESULTS

Compared to CN, AD and MCI subjects showed decreased WM integrity in the bilateral CBH. Cognition, mood, and higher amyloid burden were also associated with poorer WM integrity in the CBH.

CONCLUSION

These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies.
Vagina reconstruction by decellularization of healthy human vaginal tissue
Authors: Sueters J. , Xiao F. , Roovers J.P.R.W. , Bouman M.B. , Groenman F.A. , Maas H. , Huirne J.A.F. , Smit T.H.
Published: April 2023

When a healthy, full-size vagina is absent due to a disorder, various neovagina creation methods are available. Sometimes dilation or stretching of the vagina cavity is sufficient, but generally intestinal or dermal graft tissue is required. However, different inherent tissue properties cause complications. Therefore, when a body part is lost, it should be replaced by a similar material. The use of organ-specific acellular vaginal tissue carries great potential, as the similar architecture and matrix composition make it fit for vagina regeneration. We developed an optimized decellularization protocol for human vaginal tissue and determined suitability as tissue-mimicking scaffold for vagina reconstruction. Histological examination confirmed the preservation of structural features and minimal cellular residue was seen during fluorescence microscopy, DNA and RNA quantification and fragment-length examination. Biomechanical testing showed decreased (P<0,05) strain at rupture (23%), tensile stress (55%) and elastic modulus (68%) after decellularization. Fluorescence microscopy revealed preserved Fibronectin-I/II/III and Laminin-I/II, while Collagen-I and Ficolin-2B were decreased but mostly retained. The absence of cellular residue, minimally altered biomechanical ECM properties and mostly preserved structural proteins, appear to make our decellularized human vaginal matrix a suitable tissue-mimicking scaffold for vagina transplantation when tissue survival through vascularization and innervation are accomplished in the future.
Drivers of Early Childhood Vaccination Success in Nepal, Senegal, and Zambia: A Multiple Case Study Analysis Using the Consolidated Framework of Implementation Research
Authors: Escoffery Cam , Ogutu Emily , Sakas Zoe , Hester Kyra A. , Ellis Anna , Rodriguez Katie , Jaishwal Chandni , Yang Chenmua , Dixit Sameer , Bose Anindya , Sarr Moussa , Kilembe William , Bednarczyk Robert A. , Freeman Matthew C.
Published: April 2023

IntroductionThe fundamental components of a vaccine delivery system are well-documented, but robust evidence is needed onhowthe related processes and implementation strategies - including the facilitators and barriers-contribute to improvements in childhood vaccination coverage. The purpose of this study was to identify critical facilitators and barriers to the implementation of common interventions across three countries that have dramatically increased coverage of early childhood vaccination over the past 20 years, and to qualify common or divergent themes in their success.

MethodsWe conducted 277 key informant interviews and focus group discussions with public health leaders at the regional, district, and local levels and community members in Nepal, Senegal, and Zambia to identify intervention activities and the facilitators and barriers to implementation. We used thematic analysis grounded in the Consolidated Framework for Implementation Research (CFIR) to identify immunization program key facilitators and barriers.

ResultsWe found that the common facilitators to program implementation across the countries were the CFIR inner setting constructs of 1) networks and communications, 2) goals and feedback, 3) relative priority, and 4) readiness for implementation; and outer setting constructs of 4) cosmopolitanism and 5) external policies and mandates. The common barriers were incentives and rewards, available resources, access to knowledge and information, and patients needs and resources. Critical to the success of these national immunization programs were prioritization and codification of health as a human right, clear chain of command and shared ownership of immunization, communication of program goals and feedback, offering of incentives at multiple levels, training of staff central to vaccination education, the provision of resources to support the program, key partnerships and guidance on implementation and adoption of vaccination policies.

ConclusionAdequate organizational commitment, resources, communication, training, and partnerships were the most critical facilitators for these countries to improve childhood vaccination.
Blood biomarkers in Takotsubo syndrome point to an emerging role for inflammaging in disease pathophysiology
Authors: Nagai M. , Shityakov S. , Smetak M , Hunkler H.J. , Bär C. , Schlegel N. , Thum T. , Förster C. Y.
Published: April 2023

Takotsubo syndrome (TTS), an acute cardiac condition characterized by transient wall motion abnormalities mostly of the left ventricle, results in difficulties in diagnosing patients. We set out to present a detailed blood analysis of TTS patients analyzing novel markers to understand the development of TTS. Significant differences in pro-inflammatory cytokine expression patterns, sex steroid and glucocorticoid receptor (GR) expression levels were observed in the TTS patient collective. Remarkably, the measured catecholamine serum concentrations determined from TTS patient blood could be shown to be two orders of magnitude lower than the levels determined from experimentally induced TTS in laboratory animals. Consequently, exposure of endothelial cells and cardiomyocytes in vitro to such catecholamine concentrations did not damage the cellular integrity or function of neither endothelial cells forming the blood brain barrier, endothelial cells derived from myocardium nor cardiomyocytes in vitro. Computational analysis was able to link the identified blood markers, specifically, the pro-inflammatory cytokines and glucocorticoid receptor GR to microRNA (miR) relevant in the ontogeny of TTS (miR-15), and inflammation (miR-21, miR-146a), respectively. Amongst the well-described risk factors of TTS (older age, female gender), inflammaging-related pathways were identified to add to these relevant risk factors or prediagnostic markers of TTS.
MRI-Guided Focused Ultrasound Blood-Brain Barrier Opening Increases Drug Delivery and Efficacy in a Diffuse Midline Glioma Mouse Model
Authors: Martinez Payton , Nault Genna , Steiner Jenna , Wempe Michael F. , Pierce Angela , Brunt Breaunna , Slade Mathew , Mongin Andrew , Song Jane , Song Kang-Ho , Ellens Nicholas , Serkova Natalie , Green Adam , Borden Mark
Published: April 2023

Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB disruption (BBBD), allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promisingin vitroagent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-derived DMG cell line, BT-245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa PNP, 1 Hz PRF, 10 ms PL, 3 min treatment time) / (25 µL/kg, IV) targeting to the tumor location. In animals receiving panobinostat (10 mg/kg, IP) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, with only insignificant increase of the drug in the forebrain. In mice receiving three weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes by MRI (p= 0.01). Furthermore, FUS/MB improved the mean survival from 21 to 31 days (p< 0.0001). Our study demonstrates that FUS-mediated BBBD can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

One Sentence Summary

FUS and microbubbles can increase the delivery of panobinostat to a patient-derived xenograft (PDX) orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.
Therapeutic immunization with a whole cell vaccine reduces pneumococcal nasopharyngeal density, shedding, and middle ear infection in mice
Authors: Manning Jayne , Manna Sam , Dunne Eileen M , Bongcaron Viktoria , Pell Casey L , Patterson Natalie L , Kuil Sacha D , Dhar Poshmaal , Goldblatt David , Mulholland E Kim , Licciardi Paul V , Robins-Browne Roy M , Malley Richard , Wijburg Odilia , Satzke Catherine
Published: April 2023

Pneumococcal Conjugate Vaccines (PCVs) have substantially reduced the burden of disease caused byStreptococcus pneumoniae(the pneumococcus). However, protection is limited to vaccine serotypes, and when administered to children who are colonized with pneumococci at the time of vaccination, immune responses to the vaccine are blunted. Here, we investigate the potential of a killed whole cell pneumococcal vaccine (WCV) to reduce existing pneumococcal carriage and mucosal disease when given therapeutically to infant mice colonized with pneumococci. We show that a single dose of WCV reduced pneumococcal carriage density in an antibody-dependent manner. Therapeutic vaccination induced robust immune responses to pneumococcal surface antigens CbpA, PspA (family 1) and PiaA. In a co-infection model of otitis media, a single dose of WCV reduced pneumococcal middle ear infection. Lastly, in a two-dose model, therapeutic administration of WCV reduced nasal shedding of pneumococci. Taken together, our data demonstrate that WCV administered in colonized mice reduced pneumococcal density in the nasopharynx and the middle ear, and decreased shedding. A vaccine with similar properties in children would be beneficial in low and middle-income settings where pneumococcal carriage is high.

Importance

Although typically asymptomatic, pneumococcal carriage plays an essential role in transmission and the development of disease. Pneumococcal Conjugate Vaccines (PCVs) have reduced the burden of pneumococcal disease worldwide. However, their use has increased carriage and disease caused by non-vaccine serotypes, prompting investigations into serotype-independent pneumococcal vaccines. An additional limitation of PCVs is immune hypo-responsiveness to vaccines in children carrying pneumococci at the time of vaccination. Therefore, there is great interest in next generation vaccines such as whole cell vaccines. In this study we investigate a pneumococcal whole cell vaccine (WCV) for it effect on carriage in mice that are already colonized at the time of vaccination. We show that this ‘therapeutic’ vaccination of mice can reduce pneumococcal carriage density, shedding and infection of the middle ear. Our study suggests that WCV could be beneficial in high burden settings where carriage at the time of vaccination is more common.
Multiplicative Joint Coding in Preparatory Activity for Reaching Sequence in Macaque Motor Cortex
Authors: Wang Tianwei , Chen Yun , Zhang Yiheng , Cui He
Published: April 2023

Although motor cortex has been found to be modulated by sensory or cognitive sequences, the linkage between multiple movement elements and sequence-related responses is not yet understood. Here, we recorded neuronal activity from the motor cortex with implanted micro-electrode arrays and single electrodes while monkeys performed a double-reach task that was instructed by simultaneously presented memorized cues. We found that there existed a substantial multiplicative component jointly tuned to impending and subsequent reaches during preparation, then the coding mechanism transferred to an additive manner during execution. Multiplicative joint coding, which also spontaneously emerged in a recurrent neural network trained for double-reach, enriches neural patterns for sequential movement, and might explain the linear readout of elemental movements.
An emerging view of neural geometry in motor cortex supports high-performance decoding
Authors: Perkins Sean M. , Amematsro Elom A. , Cunningham John P. , Wang Qi , Churchland Mark M.
Published: April 2023

Decoders for brain-computer interfaces (BCIs) assume constraints on neural activity, chosen to reflect scientific beliefs while yielding tractable computations. Recent scientific advances suggest that the true constraints on neural activity, especially its geometry, may be quite different from those assumed by most decoders. We designed a decoder, MINT, to embrace statistical constraints that are potentially more appropriate. If those constraints are accurate, MINT should outperform standard methods that explicitly make different assumptions. Additionally, MINT should be competitive with expressive machine learning methods that can implicitly learn constraints from data. MINT performed well across tasks, suggesting its assumptions are well-matched to the data. MINT outperformed other interpretable methods in every comparison we made. MINT outperformed expressive machine learning methods in 37 of 42 comparisons. MINT’s computations are simple, scale favorably with increasing neuron counts, and yield interpretable quantities such as data likelihoods. MINT’s performance and simplicity suggest it may be a strong candidate for many BCI applications.
Vocal complexity in the long calls of Bornean orangutans
Authors: Erb Wendy M. , Ross Whitney , Kazanecki Haley , Setia Tatang Mitra , Madhusudhana Shyam , Clink Dena J.
Published: April 2023

Vocal complexity is central to many evolutionary hypotheses about animal communication. Yet, quantifying and comparing complexity remains a challenge, particularly when vocal types are highly graded. Male Bornean orangutans (Pongo pygmaeus wurmbii) produce complex and variable “long call” vocalizations comprising multiple sound types that vary within and among individuals. Previous studies described six distinct call (or pulse) types within these complex vocalizations, but none quantified their discreteness or the ability of human observers to reliably classify them. We studied the long calls of 13 individuals to: 1) evaluate and quantify the reliability of audio-visual classification by three well-trained observers, 2) distinguish among call types using supervised classification and unsupervised clustering, and 3) compare the performance of different feature sets. Using 46 acoustic features, we applied machine learning (i.e., support vector machines, affinity propagation, and fuzzy c-means) to identify call types and assess their discreteness. We additionally used Uniform Manifold Approximation and Projection (UMAP) to visualize the separation of pulses using both extracted features and spectrogram representations. Supervised approaches showed low inter-observer reliability and poor classification accuracy, indicating that pulse types were not discrete. We propose an updated pulse classification approach that is highly reproducible across observers and exhibits strong classification accuracy using support vector machines. Although the low number of call types suggests long calls are fairly simple, the continuous gradation of sounds seems to greatly boost the complexity of this system. This work responds to calls for more quantitative research to define call types and quantify gradedness in animal vocal systems and highlights the need for a more comprehensive framework for studying vocal complexity vis-à-vis graded repertoires.
Functional characterization of five triterpene synthases through De-novo assembly and transcriptome analysis ofEuphorbia grantiiandEuphorbia tirucalli
Authors: Kumar Ashish , Mulge Dhanashri S. , Thakar Kalyani J. , Pandreka Avinash , Warhekar Amruta D. , Ramkumar Sudha , Sharma Poojadevi , Upadrasta Sindhuri , Shanmugam Dhanasekaran , Thulasiram Hirekodathakallu V.
Published: April 2023

Euphorbia grantiiandEuphorbia tirucalliknown to synthesize diverse triterpenes including euphol and tirucallol. These two triterpenes known to possess potent anti-cancer, anti-bacterial, and anti-fungal properties along with various other biological activities. In this study, De-novo assembly and comparative transcriptome analysis of leaf and stem tissues ofE. tirucalliandE. grantiiwere carried out to identify thirteen triterpene synthases from 1,40,227 in correlation with the metabolic profiling. Comparative transcriptome analysis indicated that EutTTS4 and EutTTS5 genes which encodes for euphol/tirucallol and tirucallol synthase were highly expressed in leaf and stem tissue. The genes which encodes α-amyrin synthase (EutTTS1) and lupeol synthase (EutTTS2) were characterized by overexpressing them in YPH499 yeast strain. We have developed using hem1 and erg7 knock yeast strain of lanosterol deficient yeast (TMBL17) and used for over expression of friedelin synthase (EutTTS3), and two novel triterpenes synthases such as euphol/tirucallol synthase (EutTTS4) and tirucallol synthase (EutTTS5). These results are very useful in large scale production of triterpenes by genomic integration of respective triterpene synthases in TMBL yeast strain developed in this study.

Significance Statement

We have functionally characterized triterpene synthases fromE. tirucalliandE. grantiiand developed a hem1 and erg7 knock out of lanosterol deficient yeast (TMBL17) for the large-scale production of triterpene and triterpene related products.
Extensive diversity inEscherichia coliGroup 3 capsules is driven by recombination and plasmid transfer from multiple species
Authors: Hong Yaoqin , Qin Jilong , Forga Xavier Bertran , Totsika Makrina
Published: April 2023

Bacterial capsules provide protection against environmental challenges and host immunity. Historically,Escherichia coliK serotyping scheme, which relies on the hypervariable capsules, has identified around 80 K forms that fall into four distinct groups. Based on recent work by us and others, we predicted thatE. colicapsular diversity is grossly underestimated. We exploited Group 3 capsule gene clusters, the best genetically defined capsule group inE. coli, to analyse publicly availableE. colisequences for overlooked capsular diversity within the species. We report the discovery of seven novel Group 3 clusters that fall into two distinct subgroups (3A and 3B). The majority of the 3B capsule clusters were found on plasmids, contrary to the defining feature of Group 3 capsule genes localising at theserAlocus on theE. colichromosome. Other new Group 3 capsule clusters were derived from ancestral sequences through recombination events between shared genes found within the serotype variable central region 2. Intriguingly, flanking regions 1 and 3, known to be conserved areas among capsule clusters, showed considerable intra-subgroup variation in clusters from the 3B subgroup, containing genes of shared ancestry with other Enterobacteriaceae species. Variation of Group 3kpsclusters within dominantE. colilineages, including multi-drug-resistant pathogenic lineages, further supports thatE. colicapsules are undergoing rigorous change. Given the pivotal role of capsular polysaccharides in phage predation, our findings raise attention to the need of monitoringkpsevolutionary dynamics in pathogenicE. coliin supporting phage therapy.

IMPORTANCE

Capsular polysaccharides protect pathogenic bacteria against environmental challenges, host immunity, and phage predations. The historicalEscherichia coliK typing scheme, which relies on the hypervariable capsular polysaccharide, has identified around 80 different K forms that fall into four distinct groups. Taking advantage of the supposedly compact and genetically well-defined Group 3 gene clusters, we analysed publishedE. colisequences to identify seven new gene clusters and revealed an unexpected capsular diversity. Genetic analysis revealed that Group 3 gene clusters shared closely related serotype-specific region 2 and were diversified through recombination events and plasmid transfer between multiple Enterobacteriaceae species. Overall, capsular polysaccharides inE. coliare undergoing rigorous change. Given the pivotal role capsules play in phage interactions, this work highlighted the need to monitor the evolutionary dynamics of capsules in pathogenicE. colifor effective phage therapy.
End-to-end deep learning approach to mouse behavior classification from cortex-wide calcium imaging
Authors: Ajioka Takehiro , Nakai Nobuhiro , Yamashita Okito , Takumi Toru
Published: April 2023

Deep learning is a powerful tool for neural decoding, broadly applied to systems neuroscience and clinical studies. Interpretable and transparent models which can explain neural decoding for intended behaviors are crucial to identify essential features of deep learning decoders in brain activity. In this study, we examine the performance of deep learning to classify mouse behavioral states from mesoscopic cortex-wide calcium imaging data. Our convolutional neural network (CNN)-based end-to-end decoder combined with recurrent neural network (RNN) classifies the behavioral states with high accuracy and robustness to individual differences on temporal scales of sub-seconds. Using the CNN-RNN decoder, we identify that the forelimb and hindlimb areas in the somatosensory cortex significantly contribute to behavioral classification. Our findings imply that the end-to-end approach has the potential to be an interpretable deep learning method with unbiased visualization of critical brain regions.

Author Summary

Deep learning is used in neuroscience, and it has become possible to classify and predict behavior from massive data of neural signals from animals, including humans. However, little is known about how deep learning discriminates the features of neural signals. In this study, we perform behavioral classification from calcium imaging data of the mouse cortex and investigate brain regions important for the classification. By the end-to-end approach, an unbiased method without data pre-processing, we clarify that information on the somatosensory areas in the cortex is important for distinguishing between resting and moving states in mice. This study will contribute to the development of interpretable deep-learning technology.
Typical neural adaptation for familiar images in autistic adolescents
Authors: Westner Britta U. , Bosch Ella , Utzerath Christian , Buitelaar Jan , de Lange Floris P.
Published: April 2023

It has been proposed that autistic perception may be marked by a reduced influence of temporal context. Under this hypothesis, prior exposure to a stimulus should lead to a weaker or absent alteration of the behavioral and neural response to the stimulus in autism, compared to a typical population. To examine this hypothesis, we recruited two samples of human volunteers: a student sample (N=26), which we used to establish our analysis pipeline, and an adolescent sample (N=36), which consisted of a group of autistic (N=18) and a group of non-autistic (N=18) participants. All participants were presented with visual stimulus streams consisting of novel and familiar image pairs, while they attentively monitored each stream. We recorded task performance and used magnetoencephalography (MEG) to measure neural responses, and to compare the responses to familiar and novel images. We found behavioral facilitation as well as a reduction of event-related field (ERF) amplitude for familiar, compared to novel, images in both samples. Crucially, we found statistical evidence against between-group effects of familiarity on both behavioral and neural responses in the adolescent sample, suggesting that the influence of familiarity is comparable between autistic and non-autistic adolescents. These findings challenge the notion that perception in autism is marked by a reduced influence of prior exposure.
Naïve Huntington’s disease microglia mount a normal response to inflammatory stimuli but display impaired development of innate immune tolerance that can be counteracted by ganglioside GM1
Authors: Steinberg Noam , Galleguillos Danny , Zaidi Asifa , Sipione Simonetta
Published: April 2023

Chronic activation and dysfunction of microglia have been implicated in the pathogenesis and progression of many neurodegenerative disorders, including Huntington’s Disease (HD). HD is a genetic condition caused by a mutation that affects the folding and function of huntingtin (HTT). Signs of microglia activation have been observed in HD patients even before the onset of symptoms. It is unclear, however, whether pro-inflammatory microglia activation in HD results from cell-autonomous expression of mutant HTT or is the response of microglia to a diseased brain environment, or both. In this study, we used primary microglia isolated from HD knock-in mice (Q140) and wild-type (Q7) mice to investigate their response to inflammatory conditionsin vitroin the absence of confounding effects arising from brain pathology. We show that naïve Q140 microglia do not undergo spontaneous pro-inflammatory activation and respond to inflammatory triggers, including stimulation of TLR4 and TLR2 and exposure to necrotic cells, with similar kinetics of pro-inflammatory gene expression as wild-type microglia. Upon termination of the inflammatory insult, the transcription of pro-inflammatory cytokines is tapered off in Q140 and wild-type microglia with similar kinetics. However, the ability of Q140 microglia to develop tolerance in response to repeated inflammatory stimulations is partially impaired, potentially contributing to the establishment of chronic neuroinflammation in HD. We further show that ganglioside GM1, a glycosphingolipid with anti-inflammatory effects in wild-type microglia, not only decreases the production of pro-inflammatory cytokines and nitric oxide in activated Q140 microglia, but also dramatically dampen microglia response to re-stimulation with LPS in an experimental model of tolerance. These effects are independent from the expression of interleukin 1 receptor associated kinase 3 (Irak-3), a strong modulator of LPS signaling involved in the development of innate immune tolerance and previously shown to be upregulated by immune cell treatment with gangliosides. Altogether, our data suggest that external triggers are required for HD microglia activation, but a cell-autonomous dysfunction that affects the ability of HD microglia to acquire tolerance might contribute to the establishment of neuroinflammation in HD. Administration of GM1 might be beneficial to attenuate chronic microglia activation and neuroinflammation.
Aromatic and arginine content drives multiphasic condensation of protein–RNA mixtures
Authors: Chew Pin Yu , Joseph Jerelle A. , Collepardo-Guevara Rosana , Reinhardt Aleks
Published: April 2023

Multiphasic architectures are found ubiquitously in biomolecular condensates and are thought to have important implications for the organisation of multiple chemical reactions within the same compartment. Many of these multiphasic condensates contain RNA in addition to proteins. Here, we investigate the importance of different interactions in multiphasic condensates comprising two different proteins and RNA using computer simulations with a residue-resolution coarse-grained model of proteins and RNA. We find that in multilayered condensates containing RNA in both phases, protein–RNA interactions dominate, with aromatic residues and arginine forming the key stabilising interactions. The total aromatic and arginine content of the two proteins must be appreciably different for distinct phases to form, and we show that this difference increases as the system is driven towards greater multiphasicity. Using the trends observed in the different interaction energies of this system, we demonstrate that we can also construct multilayered condensates with RNA preferentially concentrated in one phase. The ‘rules’ identified can thus enable the design of synthetic multiphasic condensates to facilitate further study of their organisation and function.
Reproductive individuality of clonal fish raised in near-identical environments and its link to early-life behavioral individuality
Authors: Scherer Ulrike , Ehlman Sean M. , Bierbach David , Krause Jens , Wolf Max
Published: April 2023

Recent studies have documented among-individual variation that is unexplained by genetic or apparent environmental differences, but it remains an open question whether such seemingly stochastic variation has fitness consequences. We perform a life-history experiment with naturally clonal fish (Poecilia formosa), separated directly after birth into near-identical (i.e., highly standardized) environments, quantifying 2522 offspring from 152 broods over 280 days. We find that (i) individuals differ consistently in the size of offspring and broods produced over consecutive broods, (ii) these differences are observed even when controlling for trade-offs between brood size, offspring size and reproductive onset, indicating individual differences in life-history productivity and (iii) early-life behavioral individuality in activity and feeding patterns, with among-individual differences in feeding being predictive of growth, and consequently offspring size. In this work, we provide experimental evidence that processes unexplained by genetic and apparent environmental differences translate into predictable differences in life-history measures and ultimately fitness.
How Interactions During Viral-Viral Coinfection Can Shape Infection Kinetics
Authors: Pinky Lubna , DeAguero Joseph R , Remien Christopher H , Smith Amber M.
Published: April 2023

Respiratory virus infections are a leading cause of disease worldwide with multiple viruses detected in 20-30% of cases and several viruses simultaneously circulating. Some infections with viral copathogens have been shown to result in reduced pathogenicity while other virus pairings can worsen disease. The mechanisms driving these dichotomous outcomes are likely variable and have only begun to be examined in the laboratory and clinic. To better understand viral-viral coinfections and predict potential mechanisms that result in distinct disease outcomes, we first systematically fit mathematical models to viral load data from ferrets infected with respiratory syncytial virus (RSV) followed by influenza A virus (IAV) after 3 days. The results suggested that IAV reduced the rate of RSV production while RSV reduced the rate of IAV infected cell clearance. We then explored the realm of possible dynamics for scenarios not examined experimentally, including different infection order, coinfection timing, interaction mechanisms, and viral pairings. IAV coinfection with rhinovirus (RV) or SARS-CoV-2 (CoV2) was examined by using human viral load data from single infections together with murine weight loss data from IAV-RV, RV-IAV, and IAV-CoV2 coinfections to guide the interpretation of the model results. Similar to the results with RSV-IAV coinfection, this analysis showed that the increased disease severity observed during murine IAV-RV or IAV-CoV2 coinfection was likely due to slower clearance of IAV infected cells by the other viruses. On the contrary, the improved outcome when IAV followed RV could be replicated when the rate of RV infected cell clearance was reduced by IAV. Simulating viral-viral coinfections in this way provides new insights about how viral-viral interactions can regulate disease severity during coinfection and yields testable hypotheses ripe for experimental evaluation.
Genetic diversity and demographic history of the leopard seal: a Southern Ocean top predator
Authors: Bender Arona N. , Krause Douglas J. , Goebel Michael E. , Hoffman Joseph I. , Lewallen Eric A. , Carolina A. Bonin
Published: April 2023

Leopard seals (Hydrurga leptonyx) are top predators that can exert substantial top-down control of their Antarctic prey species. However, population trends and genetic diversity of leopard seals remain understudied, limiting our understanding of their ecological role. We investigated the genetic diversity, effective population size and demographic history of leopard seals to provide fundamental data that contextualizes their predatory influence on Antarctic ecosystems. Ninety leopard seals were sampled in the northern Antarctic Peninsula, during the austral summers of 2008–2019 and a 405bp region of the mitochondrial control region was sequenced for each individual. We uncovered moderate levels of nucleotide (π = 0.013) and haplotype (Hd = 0.96) diversity, and the effective population size was estimated at around 24,000 individuals (NE= 24,376; range 16,876 – 33,126). Consistent with findings from other ice-breeding pinnipeds, Bayesian skyline analysis also revealed evidence for population expansion during the last glacial maximum, suggesting that historical population growth may have been boosted by an increase in the abundance of sea ice. Although leopard seals can be found in warmer, sub-Antarctic locations, the species’ core habitat is centered around the Antarctic, making it inherently vulnerable to the loss of sea ice habitat due to climate change. Therefore, detailed assessments of past and present leopard seal population trends are needed to inform policies for Antarctic ecosystems.
Decoding the Cure-all Effects of Ginseng
Authors: Loo Shining , Kam Antony , Dutta Bamaprasad , Zhang Xiaohong , Feng Nan , Sze Siu Kwan , Liu Chuan-Fa , Wang Xiaoliang , Tam James P.
Published: April 2023

Ginseng has been known as a “cure-all” traditional medicine to treat various illnesses and as an adaptogen to relieve stress. However, the known active compounds of ginseng are small-molecule metabolites. Here we report ginsentides, which are disulfide-dense, super-stable and cell-penetrating peptides with 31–33 amino acids, as active compounds and adaptogens that restore homeostasis in response to stress. Using mass spectrometry-based target identification and functional studies, we show that ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via the PI3K/Akt signaling pathway. Ginsentides were also found to alleviate α1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of the aorta, decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40, inhibit P2Y12 receptors, reduce platelet aggregation, and thrombus formation in the lung. Orally administered ginsentides were effective in anti-stress behavior using animal models of tail suspension and forced swimming tests. Together, these results suggest that ginsentides interact with multiple systems to restore homeostasis by reversing stress-induced physiological changes and provide new insights into the panacea medicinal effects of ginseng.
CARE: a novel wearable-derived feature linking circadian amplitude to human cognitive functions
Authors: Cui Shuya , Lin Qingmin , Gui Yuanyuan , Zhang Yunting , Lu Hui , Zhao Hongyu , Wang Xiaolei , Li Xinyue , Jiang Fan
Published: April 2023

Circadian rhythms play a critical role in regulating physiological and behavioral processes, with amplitude being a key parameter for their characterization. However, accurately quantifying circadian amplitude in natural settings remains a challenge, as traditional melatonin methods require lab settings and are often costly and time-consuming. Wearable devices are a promising alternative as they can collect consecutive 24-h data for multiple days. The most commonly used measure of circadian amplitude from wearable device data, relative amplitude, is subject to the masking effect of behaviors and fails to leverage the rich information in high-dimensional data, as it only uses the sum of activity counts in time windows of pre-specified lengths. Therefore, in this study, we firstly proposed a pipeline to derive a novel feature to characterize circadian amplitude, namedcircadianactivityrhythmenergy (CARE), which can well address the above-mentioned challenges by decomposing raw accelerometer time series data, and then we validated the new feature CARE by assessing its correlation with melatonin amplitude (Pearson’sr= 0.46,P =0.007) in a dataset of 33 healthy participants. Secondly, we investigated its association with cognitive functions in two datasets: an adolescent dataset (Chinese SCHEDULE-A, n = 1,703) and an adult dataset (the UK Biobank dataset, n = 92,202), and we found that the CARE was significantly associated with the Global Executive Composite (β= 28.02,P= 0.016) in adolescents, and reasoning ability (OR = 0.01,P <0.001), short-term memory (OR = 3.42,P <0.001), and prospective memory (OR = 11.47,P <0.001) in adults. And finally, we explored the causal relationship using Mendelian randomization analysis in the adult dataset. We identified one genetic locus with 126 SNPs associated with CARE using genome-wide association study (GWAS), of which 109 variants were used as instrumental variables to conduct causal analysis. The results suggested that CARE had a significant causal effect on reasoning ability (β= -59.91,P< 0.0001), short-term memory (β= 7.94,P< 0.0001), and prospective memory (β= 16.85,P< 0.0001). The findings suggested that CARE is an effective wearable-based metric of circadian amplitude with a strong genetic basis and clinical significance, and its adoption can facilitate future circadian studies and potential interventions to improve circadian rhythms and cognitive functions.
Self-help digital psychosocial intervention for older adults with subthreshold depressive symptoms in primary care in Brazil (PRODIGITAL): Protocol for an individually randomised controlled trial
Authors: Didone Thiago Vinicius Nadaleto , Nakamura Carina Akemi , Seward Nadine , Moretti Felipe Azevedo , Souza dos Santos Monica , Mendes de Sá Martins Mariana , Pereira Luara Aragoni , da Silva Bitencourt Evelyn , Oliveira da Costa Marcelo , Queiroz de Souza Caio Hudson , Macias de Oliveira Gabriel , Machado Marcelo , Murdoch Jamie , Van de Ven Pepijn , Hollingworth William , Peters Tim J. , Araya Ricardo , Scazufca Marcia
Published: April 2023

Subthreshold depression is a substantial risk factor for the development of major depression. It is associated with poorer health, functional disabilities, and reduced quality of life in older adults. There is a paucity of cost-effective psychosocial interventions for this population in primary care worldwide, particularly in low- and middle-income countries. We present a protocol for evaluating the effectiveness and cost-effectiveness of the Viva Vida programme, a 6-week self-help digital psychosocial intervention for treating older adults with subthreshold depressive symptoms in primary care with a two-arm, individually randomised controlled trial with a 1:1 allocation ratio with integrated economic and process evaluations. We will include 450 individuals 60 years and older with subthreshold depressive symptoms (score between five and below 10 on the 9-item Patient Health Questionnaire (PHQ-9)), registered with one of the 46 primary care clinics in Guarulhos, Brazil. The Viva Vida programme will be delivered via automated audio and visual WhatsApp messages, with psychoeducation and behavioural activation content. It involves 48 messages, delivered twice daily, four days a week. Participants in the control arm will receive a single message with general information about depression. The primary outcome is the depressive symptoms at the three-month follow-up as measured by PHQ-9, which will be compared between study arms. The cost-effectiveness of the intervention will be assessed at five months. A detailed process evaluation will explore context and implementation outcomes. The Viva Vida programme is an innovative digital psychosocial intervention delivered via WhatsApp messaging without the participation of health professionals. The evaluation of the Viva Vida programme will contribute to the development of simple and cost-effective models of remote self-help interventions for reducing depressive symptoms among older adults with subthreshold depression in primary care. The protocol is registered with Registro Brasileiro de Ensaios Clinicos (ReBEC) (RBR-6c7ghfd).
Anticoagulation and associated complications in Veno-Arterial Extracorporeal Membrane Oxygenation in Adult Patients: A Protocol for a Systematic Review and Meta-Analysis
Authors: Vlok Ruan , Buscher Hergen , Delaney Anthony , Garside Tessa , Myburgh John , Nair Priya
Published: April 2023

Background

Veno-arterial Extracorporeal Membrane Oxygenation (VA-ECMO) is a rapidly expanding therapy with a relatively limited evidence base. Due to both quantitative and qualitative acquired coagulopathies in VA-ECMO, bleeding remains a major complication and with potentially catastrophic outcomes. Simultaneously, coagulation activation occurs via blood contact with the extracorporeal circuit, which risks not only vital organ emboli, but also the circuit viability. This carries the risk of equally catastrophic complications. As such, VA-ECMO patients are routinely anticoagulated. A large variation in practice exists surrounding anticoagulation in VA-ECMO. Despite an increasing uptake in the therapy, the evidence base is limited and current guidelines surrounding anticoagulation practice are based on expert opinion. We will perform a study level systematic review and meta-analysis of VA-ECMO patients comparing anticoagulation strategies, including the agent of anticoagulation, the method of monitoring and the targeted degree of anticoagulation to assess the association between described anticoagulation strategies and bleeding and thrombotic complications.

Methods

We will perform a study level meta-analysis of randomised controlled trials (RCTs) and cohort studies that report on bleeding and thrombotic complications in VA-ECMO. Our primary objective is to describe the incidence of bleeding and thrombotic complications associated with individual anticoagulation strategies. In order to be included, a study must report the anticoagulant drug used, the method of monitoring used, or the anticoagulation target used, and at least one outcome of interest. Four databases will be systematically reviewed by two authors. Two authors will extract and assess for risk of bias using the Cochrane Risk of Bias tool for RCTs and the ROBINS-I tool for observational studies. Data will be analysed via incidence rates of bleeding and thrombotic complications, with a subgroup analysis of each anticoagulation strategy where able. The study will be reported in line with PRISMA guidelines.