bluuebunny/crossref_metadata_2025 huggingface dataset:
Awake Hippocampal-Cortical Co-reactivation Is Associated with Forgetting
Authors: Tanrıverdi Büşra , Cowan Emily T , Metoki Athanasia , Jobson Katie R. , Murty Vishnu P. , Chein Jason , Olson Ingrid R.
Published: December 2022

Systems consolidation theories posit that consolidation occurs primarily through a coordinated communication between hippocampus and neocortex (McClelland and O’Reilly 1995; Kumaran et al., 2016; Moscovitch and Gilboa, 2022). Recent sleep studies in rodents have shown that hippocampus and visual cortex replay the same information at temporal proximity (“co-replay”) (Ji & Wilson, 2007; Lansink et al., 2009; Wierzynski et al., 2009; Peyrache et al., 2009). We developed a novel TR-based co-reactivation (TRCR) analysis method to study hippocampal-cortical co-replays in humans using functional MRI. Thirty-six young adults completed an image (face or scene)-location paired associate encoding task in the scanner, which were preceded and followed by resting state scans. We identified post-encoding rest TRs (+/− 1) that showed neural reactivation of each image-location trials in both hippocampus (HPC) and category-selective cortex (fusiform face area, FFA). This allowed us to characterize temporally proximal coordinated reactivations (“co-reactivations”) between HPC and FFA. Moreover, we found that increased HPC-FFA co-reactivations were associated with incorrectly recognized trials after a 1-week delay (p= 0.004). Finally, we found that these HPC-FFA co-reactivations were also associated with trials that were initially correctly recognized immediately after encoding but were later forgotten in 1-day (p= 0.043) and 1-week delay period (p= 0.031). We discuss these results from a trace transformation perspective (Winocur and Moscovitch, 2011; Sekeres et al., 2018) and speculate that HPC-FFA co-reactivations may be integrating related events, at the expense of disrupting event-specific details, hence leading to forgetting.
Clinical performance validation of the STANDARD G6PD Test: A multi-country pooled analysis
Authors: Adissu Wondimagegn , Brito Marcelo , Garbin Eduardo , Macedo Marcela , Monteiro Wuelton , Mukherjee Sandip , Myburg Jane , Alam Mohammad Shafiul , Bancone Germana , Bansil Pooja , Pal Sampa , Sharma Abhijit , Zobrist Stephanie , Bryan Andrew , Chu Cindy S , Das Santasabuj , Domingo Gonzalo J , Hann Amanda , Kublin James , Lacerda Marcus VG , Layton Mark , Ley Benedikt , Murphy Sean C , Nosten Francois , Pereira Dhélio , Price Ric N , Talukdar Arunansu , Yilma Daniel , Gerth-Guyette Emily
Published: December 2022

Introduction

Screening for G6PD deficiency can inform disease management including malaria. Treatment with the antimalarial drugs primaquine and tafenoquine can be guided by point-of-care testing for G6PD deficiency.

Methods and Findings

Data from similar clinical studies evaluating the performance of the STANDARD™G6PD Test (SD Biosensor, South Korea) conducted in Bangladesh, Brazil, Ethiopia, India, Thailand, the United Kingdom, and the United States were pooled. Test performance was assessed in a retrospective analysis on capillary and venous specimens. All study sites used spectrophotometry for reference G6PD testing, and either the HemoCue or complete blood count for reference hemoglobin measurement.

The sensitivity of the STANDARD™G6PD Test using the manufacturer thresholds for G6PD deficient and intermediate cases in capillary specimens from 4212 study participants was 100% (95% Confidence Interval (CI): 97.5%–100%) for G6PD deficient cases with <30% activity and 77% (95% CI 66.8%– 85.4%) for females with intermediate activity between 30%–70%. Specificity was 98.1% (95% CI 97.6%–98.5%) and 92.8% (95% CI 91.6%–93.9%) for G6PD deficient individuals and intermediate females, respectively. The majority (12/20) of G6PD intermediate females with false normal results had activity levels >60% on the reference assay. Negative predictive values for females with G6PD activity >60% was 99.6% (95% CI 99.1%–99.8%) on capillary specimens. Test sensitivity among 396P. vivaxmalaria cases was 100% (69.2%–100.0%) for both deficient and intermediate cases. In the study population, a high proportion of those classified as G6PD deficient or intermediate resulted from true normal cases. Despite this, the majority cases would receive the correct medication and no true G6PD deficient cases would be treated inappropriately.

Conclusions

The STANDARD G6PD Test enables safe access to drugs which are contraindicated for individuals with G6PD deficiency. Operational considerations will inform test uptake in specific settings.
Artificial light at night advances reproductive phenology and reduces reproductive capacity of a wild plant
Authors: Wang Shuo , Wang Zhihui , Xiao Lu , Zhang Hongxiang , Liu Yanjie
Published: December 2022

With the rapid increase in artificial light at night (ALAN) during the last century, a growing proportion of the world’s ecosystems have been exposed to ALAN. While the effects of low-intensity ALAN on morphology and phenology are well known in laboratory and greenhouse studies, little is known about these effects of ALAN on wild plants. Moreover, how these morphological and phenological responses affect the fitness of wild plants is unclear.

Using the annual herbaceous plant,Elsholtzia densa, as a model species, we performed a field manipulation experiment and tested the responses of plant morphology, reproductive phenology, and reproductive capacity to ALAN.

We found that ALAN significantly increased the specific leaf area but decreased the number of secondary branches. It also advanced the onset of budding, blooming, fruiting, and seed maturity from 3.4 to 6.2 d. In addition, ALAN significantly increased the length of the top inflorescences of the species but decreased the percentage of the individuals with undeveloped top inflorescences. Consequently, ALAN reduced the number of fruity inflorescences.

Our results demonstrated that low-intensity ALAN, even with a relatively short period of exposure (i.e., one growing season), could cause passive responses in morphological traits of the wild plant, resulting in a decline in its reproductive capacity. In addition, the advanced reproductive phenology (e.g., flowering and blooming) induced by ALAN may cause plant-pollinator mismatches and threaten species coexistence at the community level.
Modeling and Predicting Cancer Clonal Evolution with Reinforcement Learning
Authors: Ivanovic Stefan , El-Kebir Mohammed
Published: December 2022

Cancer results from an evolutionary process that typically yields multiple clones with varying sets of mutations within the same tumor. Accurately modeling this process is key to understanding and predicting cancer evolution. Here, we introduce CloMu (Clone ToMutation), a flexible and low-parameter tree-generative model of cancer evolution. CloMu uses a two-layer neural network trained via reinforcement learning to determine the probability of new mutations based on the existing mutations on a clone. CloMu supports several prediction tasks, including the determination of evolutionary trajectories, tree selection, causality and interchangeability between mutations, and mutation fitness. Importantly, previous methods support only some of these tasks, and many suffer from overfitting on datasets with a large number of mutations. Using simulations, we demonstrate that CloMu either matches or outperforms current methods on a wide variety of prediction tasks. In particular, for simulated data with interchangeable mutations, current methods are unable to uncover causal relationships as effectively as CloMu. On breast cancer and leukemia cohorts, we show that CloMu determines similarities and causal relationships between mutations as well as the fitness of mutations. We validate CloMu’s inferred mutation fitness values for the leukemia cohort by comparing them to clonal proportion data not used during training, showing high concordance. In summary, CloMu’s low-parameter model facilitates a wide range of prediction tasks regarding cancer evolution on increasingly available cohort-level datasets.
Drivers of the negative diversity-invasibility relationship: nutrient availablity, allelopathy, soil biota and soil legacy effects
Authors: Oduor Ayub M. O. , van Kleunen Mark , Liu Yanjie
Published: December 2022

Elton’s diversity-invasibility hypothesis predicts that high-diversity native communities should be less easily invaded than low-diversity communities. Although various mechanisms have been proposed to explain it, it remains unclear which of those mechanisms is more important and whether they operate simultaneously. Using one pool of native plant species and one pool of invasive alien plant species that naturally co-occur in China, we here tested in four separate experiments whether nutrient availability, allelopathy, soil microbiota and soil-legacy effects can all mediate the diversity-invasibility relationship. While soil-nutrient availability, allelopathy, soil biota and soil-legacy effects separately influenced biomass production of alien plant species and native plant communities, our results suggest that only soil biota and allelopathy influenced diversity-invasibility relationship in our study system. Importantly, by excluding the potential effects of allelopathy and soil biota in the nutrient-competition experiment, nutrient competition alone is not necessarily related to the negative diversity-invasibility relationship.
Causal network inference based on cross-validation predictability
Authors: Zhang Yuelei , Li Qingcui , Chang Xiao , Chen Luonan , Liu Xiaoping
Published: December 2022

Identifying causal relations or causal networks among molecules/genes, rather than just their correlations, is of great importance but challenging in biology and medical field, which is essential for unravelling molecular mechanisms of disease progression and developing effective therapies for disease treatment. However, there is still a lack of high-quality causal inference algorithms for any observed data in contrast to time series data. In this study, we developed a new causal concept for any observed data and its causal inference algorithm built on cross-validated predictability (CVP) can quantify the causal effects among molecules/genes in the whole system. The causality was extensively validated by combining a large variety of statistical simulation experiments and available benchmark data (simulated data and various real data). Combining the predicted causal network and the real benchmark network, the CVP algorithm demonstrates high accuracy and strong robustness in comparison with the mainstream algorithms. In particular, the CVP algorithm is robust in identifying reliable driver genes and network biomarkers from the perspective of network biology, with the prediction results outperforming the mainstream conventional methods for predicting driver genes. CRISPR-Cas9 knockdown experiments in the liver cancer have validated that the functional driver genes identified by the CVP algorithm effectively inhibit the growth and colony formation of liver cancer cells. By knockdown experiments, we demonstrated the accuracy and significance of the causality predicted by CVP and identified the novel regulatory targets of functional driver genes SNRNP200 and RALGAPB in the liver cancer. These inferred causal networks explain regulatory patterns in different biological contexts in a clear sense and provide biological insights into molecular mechanisms of disease progression from a causality perspective.
Transcriptomic landscape and potential therapeutic targets for human testicular aging revealed by single-cell RNA sequencing
Authors: Xia Kai , He Siyuan , Luo Peng , Dong Lin , Gao Feng , Chen Xuren , Ye Yunlin , Gao Yong , Ma Yuanchen , Zhang Yadong , Yang Qiyun , Han Dayu , Feng Xin , Wan Zi , Cai Hongcai , Ke Qiong , Wang Tao , Li Weiqiang , Tu Xiang’an , Sun Xiangzhou , Deng Chunhua , Xiang Andy Peng
Published: December 2022

Background:

Testicular aging is known to cause male age-related fertility decline and hypogonadism, but the underlying molecular mechanisms remain unclear.

Methods:

We survey the single-cell transcriptomic landscape of testes from young and old men and examine age-related changes in germline and somatic niche cells.

Results:

In-depth evaluation of the gene expression dynamics of germline cells reveals that disturbance of base-excision repair pathway is a major feature of aging spermatogonial stem cells (SSCs), suggesting that defective DNA repair of SSCs may serve as a potential driver for increased de novo germline mutations with age. Further analysis of aging-associated transcriptional changes shows that stress-related changes and apoptotic signaling pathway accumulate in aged somatic cells. We identify age-related impairment of redox homeostasis in aged Leydig cells and find that pharmacological treatment with antioxidants alleviate this cellular dysfunction of Leydig cells and promote testosterone production. Lastly, our results reveal that decreased pleiotrophin (PTN) signaling is a contributing factor for testicular aging.

Conclusions:

These findings provide a comprehensive understanding of the cell-type-specific mechanisms underlying human testicular aging at a single-cell resolution, and suggest potential therapeutic targets that may be leveraged to address age-related male fertility decline and hypogonadism.

Funding:

This work was supported by the National Key Research and Development Program of China (2018YFA0107200, 2018YFA0801404), the National Natural Science Foundation of China (32130046, 82171564, 82101669, 81871110, 81971759), the Key Research and Development Program of Guangdong Province (2019B020234001), the Natural Science Foundation of Guangdong Province, China (2022A1515010371), the Major Project of Medical Science and Technology Development Research Center of National Health Planning Commission, China (HDSL202001000), the Open Project of NHC Key Laboratory of Male Reproduction and Genetics (Family Planning Research Institute of Guangdong Province) (KF202001), the Guangdong Province Regional Joint Fund-Youth Fund Project (2021A1515110921), the China Postdoctoral Science Foundation (2021M703736).
Absence of the bile acid enzyme CYP8B1 increases brain chenodeoxycholic acid and reduces neuronal excitotoxicity in mice
Authors: Monteiro-Cardoso Vera F. , Yeo Xin Yi , Bae Han-Gyu , Mayan David Castano , Wehbe Mariam , Lee Sejin , Krishna-K Kumar , Baek Seung Hyun , Palomera Leon F. , Shanmugam Sangeetha , Sem Kai Ping , Parsons Matthew P. , Hayden Michael R. , Liehn Elisa A. , Sajikumar Sreedharan , Davanger Svend , Jo Dong-Gyu , Jung Sangyong , Singaraja Roshni R.
Published: December 2022

Background

Bile acids (BAs), which act in the liver-brain axis, are liver-derived signaling molecules found in the brain. However, how they modulate neurological function remains largely unknown.

Methods

To assess the role of BAs in the brain, we generated mice with absent 12α-hydroxylase (Cyp8b1), a BA synthesis enzyme, and determined if brain BA levels were altered in these mice, and if and how this may modulate neuronal function.

Results

The absence of CYP8B1 increased brain levels of the primary BA chenodeoxycholic acid (CDCA), and decreased ischemic stroke infarct area. Furthermore, CDCA administration reduced ischemic stroke lesion area inwild-typemice. Excitotoxicity due to elevated extra-cellular glutamate contributes to neuronal death in ischemic stroke. Neurons fromCyp8b1-/-mice showed reduced susceptibility to glutamate-induced toxicity, and exogenous CDCA reduced glutamate-induced toxicity in neurons fromwild-typemice. These data suggest that CDCA-mediated decreases in excitotoxic neuronal death contributes to the reduced stroke lesion area inCyp8b1-/-mice. Aberrant N-methyl-D-aspartate receptor (NMDAR) over-activation contributes to excitotoxicity. CDCA decreased NMDAR-mediated excitatory post-synaptic currents (EPSCs) inwild-typebrain slices, by reducing over-activation of the NMDAR subunit GluN2B. In line with this, synaptic NMDAR activity was also decreased inCyp8b1-/-brain slices. Expression level and synaptic distribution of GluN2B were unaltered inCyp8b1-/-mice, suggesting that CDCA may directly antagonize GluN2B-containing NMDARs.

Conclusions

Our data suggests that CDCA acts in the liver-brain axis and decreases the aberrant over-activation of neuronal GluN2B-containing NMDARs, contributing to neuroprotection.
Severe Acute Respiratory Syndrome Coronavirus 2 detection in induced sputum of asthmatic patients using saliva sampling device
Authors: Moermans Catherine , Gerday Sara , Bricmont Noémie , Bonhiver Romane , Schleich Florence , Guiot Julien , Njock Makon Sébasien , Henket Monique , Guissard Françoise , Paulus Virginie , Di Valentin Emmanuel , Minner Frédéric , Gillet Laurent , Bureau Fabrice , Louis Renaud
Published: December 2022

Since the beginning of the severe acute respiratory syndrome coronavirus 2 pandemic, the potential contamination of the induced sputum obtained from asthmatic patients in routine is a question of concern. The goal of this study was to assess this contamination using a saliva sample collection device. One hundred seventy-five sputum samples of asthmatic patients without fever were tested. We did not identify any positive PCR on sputum samples from asthmatic patients reporting chronic/episodic respiratory symptoms similar to what is seen in case of COVID-19. This technique was useful to evaluate the contamination of sputum samples generated during the pandemic.
Proteome-wide structure-based accessibility analysis of ligandable and detectable cysteines in chemoproteomic datasets
Authors: White Matthew E. H. , Gil Jesús , Tate Edward W.
Published: December 2022

Covalent drug discovery, in particular targeting reactive cysteines, has undergone a resurgence over the past two decades, demonstrated by recent clinical successes of covalent inhibitors for high-priority cancer targets. Reactive cysteine profiling, first pioneered by the Cravatt lab, has emerged in parallel as a powerful approach for proteome-wide on- and off-target profiling. Thus far however, structural analysis of liganded cysteines has been restricted to experimentally determined protein structures. We combined AlphaFold-predicted amino acid side chain accessibilities for >95% of the human proteome with a meta-analysis of thirteen public cysteine profiling datasets, totalling 40,070 unique cysteine residues, revealing accessibility biases in sampled cysteines primarily dictated by warhead chemistry. Analysis of >3.5 million cysteine-fragment interactions further suggests that exposed cysteine residues are preferentially targeted by elaborated fragments and drug-like compounds. We finally propose a framework for benchmarking coverage of ligandable cysteines in future cysteine profiling approaches, considering both selectivity for high-priority residues and quantitative depth. All analysis and produced resources (freely available atwww.github.com/TateLab) are readily extendable to reactive amino acids beyond cysteine, and related questions in chemical biology.
PTPRC, KDM5C, GABBR1 and HDAC1 are the major targets of valproic acid in regulation of its anticonvulsant pharmacological effects
Authors: Kumar Arun HS
Published: December 2022

Background

Valproic acid (VPA) is a small molecule which is the 3rdmost prescribed drug among anticonvulsant therapeutics. Understanding of the pharmacology of VPA targets will help optimally rationalise the therapeutic effects and also minimise the undesired outcomes. Hence this study analysed the human specific targets of VPA and assessed the affinity of VPA to these targets to interpret potential safe therapeutic range for VPA.

Materials and Methods

The targets of VPA were identified from the SwissTargetPrediction server and STITCH database and analysed for their affinity with VPA using Autodock vina 1.2.0. The volume of distribution (Vd, L) and the dose of VPA reported in the DrugBank database was used for estimation of the plasma and CSF concentration. The plasma and CSF Concentration Affinity (CA) ratio of VPA against each of the high affinity targets was assessed at variable Vd (0.1 to 0.4 L/kg) to identify the therapeutic safety window of VPA.

Results

The plasma/CSF concentration of VPA range from 170 to 7000 µM and 17 to 700 µM respectively. The plasma concentration achieved was within the safety limits (170 to 700 µM) at higher Vd (>10 L), while at lower Vd (<10L), the plasma or CSF concentration achieved was of concern at VPA dose of >1000 mg/day. The plasma concentration at very low Vd (< 2L) was of concern even at dose of 500 mg/day. The affinity of VPA against all its human specific targets ranged from 2.9 to 52.1 mM. The CA ratio of VPA against its high affinity target was observed to be greater than 0.8, indicating potentially significant modulation of these targets. The following four targets showed CA ratio of over 1: PTPRC, KDM5C, GABBR1 and HDAC1, indicating their preferential targeting by VPA. CES1 and SLC22A12 are high affinity targets of VPA which can contribute to its undesired pharmacological effects (CNS oedema and hepatotoxicity).

Conclusion

This study offers a novel insight into the anticonvulsant and undesired pharmacology of VPA by specifically identifying the targets involved and recommends an evidence based approach to personalise dose titration of VPA to achieve optimal therapeutic benefits.
Structural and Mechanistic Basis of Substrate Transport by the Multidrug Transporter MRP4
Authors: Bloch Magnus , Raj Isha , Pape Tillmann , Taylor Nicholas M.I.
Published: December 2022

Multidrug resistance-associated protein 4 (MRP4) is an ATP-binding cassette (ABC) transporter expressed at multiple tissue barriers where it actively extrudes a wide variety of drug compounds. Overexpression of MRP4 provides resistance to clinically used antineoplastic and antiviral agents, making it a highly attractive therapeutic target for countering multidrug resistance.

Here we report the cryo-EM structures of multiple physiologically relevant states of membrane-embedded human MRP4, including complexes between MRP4 and two widely used chemotherapeutic agents and a complex between MRP4 and its native substrate. The structures display clear similarities and distinct differences in the coordination of these chemically diverse substrates and, in combination with functional and mutational analysis, reveal molecular details of the transport mechanism. Our study provides key insights regarding the basis of the unusually broad substrate specificity of MRP4 and constitutes an important contribution towards a general understanding of the versatile ensemble of multidrug transporters.
Activity-based proteomics uncovers suppressed hydrolases and aneo-functionalised antibacterial enzyme at the plant-pathogen interface
Authors: Sueldo Daniela J. , Godson Alice , Kaschani Farnusch , Krahn Daniel , Kessenbrock Till , Buscaill Pierre , Schofield Christopher J. , Kaiser Markus , van der Hoorn Renier A. L.
Published: December 2022

The extracellular space of plant tissues contains hundreds of hydrolases that might harm colonizing microbes. Successful pathogens may suppress these hydrolases to enable disease. Here, we report the dynamics of extracellular hydrolases in leaves upon infection withPseudomonas syringae.

Using activity-based proteomics with a cocktail of biotinylated probes we simultaneously monitored 171 active hydrolases, including 109 serine hydrolases (SHs), 49 glycosidases (GHs) and 13 cysteine proteases (CPs). The activity of 82 of these hydrolases (mostly SHs) increases during infection, whilst the activity of 60 hydrolases (mostly GHs and CPs) is suppressed during infection. Active β-galactosidase-1 (BGAL1) is amongst the suppressed hydrolases, consistent with production of the BGAL1 inhibitor byP. syringae. One of the other suppressed hydrolases, the pathogenesis-relatedNbPR3, decreases bacterial growth when transiently overexpressed. This is dependent on its active site, revealing a role forNbPR3 activity in antibacterial immunity. Despite being annotated as a chitinase,NbPR3 does not possess chitinase activity, and contains a E112Q active site substitution that is essential for antibacterial activity and is conserved only inNicotianaspecies.

This study introduces a powerful approach to reveal novel components of extracellular immunity, exemplified by the discovery of the suppression of neo-functionalisedNicotiana-specificantibacterialNbPR3.
Distinct Subsets of Multi-Lymphoid Progenitors Support Ontogeny-Related Changes in Human Lymphopoiesis
Authors: Keita Seydou , Diop Samuel , Lekiashvili Shalva , Chabaane Emna , Nelson Elisabeth , Strullu Marion , Arfeuille Chloé , Guimiot Fabien , Domet Thomas , Duchez Sophie , Evrard Bertrand , Darde Thomas , Larghero Jerome , Verhoeyen Els , Cumano Ana , Macintyre Elizabeth A. , Jouen François , Goodhardt Michele , Garrick David , Chalmel Frederic , Hussen Kutaiba Alhaj , Canque Bruno
Published: December 2022

Changes in lymphocyte production patterns occurring across human ontogeny remain poorly defined. In this study, we demonstrate that human lymphopoiesis is supported by three waves of embryonic, fetal, and postnatal multi-lymphoid progenitors (MLPs) differing in CD7 and CD10 expression and their output of CD127-/+early lymphoid progenitors (ELP). Our results reveal that, like the fetal-to-adult switch in erythropoiesis, transition to postnatal life coincides with a shift from multilineage to B lineage-biased lymphopoiesis and an increase in production of CD127+ELPs which persists until puberty. A further developmental transition is observed in elderly individuals where B-cell differentiation bypasses the CD127+compartment and branches directly from CD10+MLPs. Functional analyses indicate that these changes are determined at the level of the hematopoietic stem cell. Besides reconciling controversies about the identity and function of human MLPs, these results may shed light on the causes of age-related differences in the incidence of lymphoblastic leukemia.
Class background reverses the effect of a polygenic index of cognitive performance on economic ideology
Authors: Ahlskog Rafael
Published: December 2022

Variation in political preferences is increasingly understood to stem from both environmental influences and genetics. Research has argued that a possible pathway for genetic effects on ideology is via cognitive performance, showing a genetic overlap between the traits. Yet, an unambiguous link between cognitive performance and economic policy preferences remains elusive, with results ranging from negative to positive effects on economic conservatism. In this study, I argue that this heterogeneity reflects an underlying gene-by-environment interaction. I depart from the assumption that cognitive performance, rather than being directly connected to a set of policy preferences, influences the capacity to correctly optimize those preferences. Combined with insights from standard models in political economics, this leads to the proposal that genetics associated with cognitive performance should cause more left-wing economic preferences if you grow up in relative poverty, but more right-wing preferences if you grow up in relative affluence. Utilizing variation in a polygenic index of cognitive performance within dizygotic twin pairs, coupled with unique register data on economic conditions for both the twins, their parents, and their childhood neighborhood, I show that the effect of the PGI on a finegrained measure of economic conservatism is zero on average, but indeed sizable and sign-discordant by class background. To my knowledge, this represents the first sign-discordant GxE finding for a socially relevant outcome, which has implications for future social science research using PGIs.
Long COVID: G Protein-Coupled Receptors (GPCRs) responsible for persistent post-COVID symptoms
Authors: Das Sanisha , Kumar Suresh
Published: December 2022

As of early December 2022, COVID-19 had a significant impact on the lives of people all around the world, with over 630 million documented cases and over 6 million deaths. A recent clinical analysis revealed that under certain conditions, a patient’s disease symptoms are more likely to persist. Long COVID is characterised by many symptoms that continue long after the SARS-CoV-2 infection has resolved. This work utilised computational methods to analyse the persistence of COVID symptoms after recovery and to identify the relevant genes. Based on functional similarity, differentially expressed genes (DEGs) of SARS-CoV-2 infection and 255 symptoms of long covid were examined, and potential genes were identified based on the rank of functional similarity. Then, hub genes were identified by analysing the interactions between proteins. Using the identified key genes and the drug-gene interaction score, FDA drugs with potential for possible alternatives were identified. Also discovered were the gene ontology and pathways for 255 distinct symptoms. A website (https://longcovid.omicstutorials.com/) with a list of significant genes identified as biomarkers and potential treatments for each symptom was created. All of the hub genes associated with the symptoms, GNGT1, GNG12, GNB3, GNB4, GNG13, GNG8, GNG3, GNG7, GNG10, and GNAI1, were discovered to be associated with G-protein coupled receptors. This demonstrates that persistent COVID infection affects various organ systems and promotes chronic inflammation following infection. CTLA4, PTPN22, KIT, KRAS, NF1, RET, and CTNNB1 were identified as the common genes that regulate T-cell immunity via GPCR and cause a variety of symptoms, including autoimmunity, cardiovascular, dermatological, general symptoms, gastrointestinal, pulmonary, reproductive, genitourinary, and endocrine symptoms (RGEM). Among other functions, they were found to be involved in the positive regulation of protein localization to the cell cortex, the regulation of triglyceride metabolism, the binding of G protein-coupled receptors, the binding of G protein-coupled serotonin receptors, the heterotrimeric G-protein complex, and the cell cortex region. These biomarker data, together with the gene ontology and pathway information that accompanies them, are intended to aid in determining the cause and improving the efficacy of treatment.
GENERALIST: An efficient generative model for protein sequence families
Authors: Akl Hoda , Emison Brooke , Zhao Xiaochuan , Mondal Arup , Perez Alberto , Dixit Purushottam D.
Published: December 2022

Generative models of protein sequence families are an important tool in the repertoire of protein scientists and engineers alike. However, state-of-the-art generative approaches face inference, accuracy, and overfitting-related obstacles when modeling moderately sized to large proteins and/or protein families with low sequence coverage. To that end, we present a simple to learn, tunable, and accurate generative model, GENERALIST:GENERAtive nonLInear tenSor-factorizaTionfor protein sequences. Compared to state-of-the-art methods, GENERALIST accurately captures several high order summary statistics of amino acid covariation. GENERALIST also predicts conservative local optimal sequences which are likely to fold in stable 3D structure. Importantly, unlike other methods, the density of sequences in GENERALIST-modeled sequence ensembles closely resembles the corresponding natural ensembles. GENERALIST will be an important tool to study protein sequence variability.
Mycorrhizal status impacts the genetic architecture of mineral accumulation in field grown maize (Zea maysssp.maysL.)
Authors: Li Meng , Perez-Limón Sergio , Ramírez-Flores M. Rosario , Barrales-Gamez Benjamín , Meraz-Mercado Marco Antonio , Ziegler Gregory , Baxter Ivan , Olalde-Portugal Víctor , Sawers Ruairidh J. H.
Published: December 2022

Arbuscular mycorrhizal fungi (AMF) establish symbioses with major crop species, providing their hosts with greater access to mineral nutrients and promoting tolerance to heavy metal toxicity. There is considerable interest in AMF as biofertilizers and for their potential in breeding for greater nutrient efficiency and stress tolerance. However, it remains a challenge to estimate the nutritional benefits of AMF in the field, in part due to a lack of suitable AMF-free controls. Here we evaluated the impact of AMF on the concentration of 20 elements in the leaves and grain of field grown maize using a custom genetic mapping population in which half of the families carry the AMF-incompatibility mutationcastor. By comparing AMF-compatible and AMF-incompatible families, we confirmed the benefits of AMF in increasing the concentration of essential mineral nutrients (e.g., P, Zn, and Cu) and reducing the concentration of toxic elements (e.g., Cd and As) in a medium-input subtropical field. We characterised the genetic architecture of element concentration using quantitative trait mapping and identified loci that were specific to AMF-compatible or AMF-incompatible families, consistent with their respective involvement in mycorrhizal or direct nutrient uptake. Patterns of element covariance changed depending on AMF status and could be used to predict variation in mycorrhizal colonisation. We comment on the potential of AMF to drive genotype-specific differences in the host ionome across fields and to impact the alignment of biofortification breeding targets. Our results highlight the benefits of AMF in improving plant access to micronutrients while protecting from heavy metals, and indicate the potential benefits of considering AMF in biofortification programs.
Breeding the phenylketonuria mouse: novel dietary regimen enables breeding of female C57BL/6J mice homozygous for thePahenu2mutation without fostering
Authors: Durrer Katherine E. , Mancilla Viviana J. , Allen Michael S.
Published: December 2022

ThePahenu2mutation in C57BL/6J mice is a well characterized model for studying phenylketonuria (PKU), withPahenu2homozygotes displaying heightened blood phenylalanine and other characteristics of PKU.Pahenu2homozygous females do not successfully rear young on any conventional diet due to their disease status. The most commonly used successful breeding strategy is crossingPahenu2heterozygous females with homozygous mutant males; producing litters of 50% homozygous and 50% heterozygous animals. In many treatment studies the heterozygous pups produced are not useable, but add to experimental costs and total animals used. To this end our lab created a dietary regimen with reduced phenylalanine and increased large neutral amino acid content, enabling homozygous mating. Phenylalanine levels in homozygous females and males on the new diet are significantly lower than that of homozygous females and males on traditional diets (p= 1.35×10-4andp= 1.5×10-5respectively). Litters born toPahenu2homozygous mothers on this diet demonstrate no significant difference in litter size compared to litters born to heterozygous mothers (p> 0.75). No observable defects were noted in litters born from homozygous crosses. This dietary regimen enables litter production of 100%Pahenu2homozygous animals for investigators who wish to rapidly expand theirPahenu2mouse colony size or do not require heterozygous littermate controls in their PKU studies.
Interactive auditory task reveals complex sensory-action integration in mouse primary auditory cortex
Authors: Liu Ji , Kanold Patrick O.
Published: December 2022

Predictive coding theory postulates that the brain achieves perception by actively making predictions about the incoming sensory information and correcting them if errors signals arise. These signals are likely the most relevant when the individual is actively interacting with the environment and where the sensory outcome determines the ongoing action. In addition, the cerebral cortex is thought to play a key role in generating these signals. Thus, to study the representation of error signals in the primary sensory cortex, we trained mice to perform an interactive auditory task that coupled their actions to the generated sound and perturbed this coupling to evoke putative error responses. We imaged Layer 2/3 (L2/3) and Layer 4 (L4) neurons in the mouse primary auditory cortex, and we identified not only neurons that mainly encoded action related information but also neurons encoding the mismatch between the action and the sound. These results show that a subset of A1 neurons encode the nonlinear interactions between the sound and the action. Furthermore, more L2/3 neurons encoded action related information than L4, indicating that action-sound integration emerges hierarchically in A1 circuits. Together, our results show that complex interactions between action and sound happen in A1 and that some A1 neurons responses reflect the violation of the learnt relationship between the action and sound feedback. Thus, primary sensory cortices not only encode sensory driven activity but also represent the complex interplay between sensory inputs, expectations, and errors.
Composition of minor ampullate silk makes its properties different from those of major ampullate silk
Authors: Nakamura Hiroyuki , Kono Nobuaki , Mori Masaru , Masunaga Hiroyasu , Numata Keiji , Arakawa Kazuharu
Published: December 2022

Spider’s minor ampullate silk, or MI-silk, exhibits distinct mechanical properties and water resistance compared to its major ampullate counterpart (MA-silk). The principal protein constituent of MI-silk is known as minor ampullate spidroin, or MiSp, and while its sequence has been deciphered and is thought to underlie the differences in properties with MA-silk, the composition of MI-silk and the relationship between its composition and properties remain elusive. In this study, we set out to investigate the mechanical properties, water resistance, and proteome of MA-silk and MI-silk fromAraneus ventricosusandTrichonephila clavata. We also synthesized artificial fibers from major ampullate spidroin, MaSp1 and 2, and MiSp to compare their properties. Our proteomic analysis reveals that the MI-silk of both araneids is composed of MiSp, MaSp1, and spidroin constituting elements (SpiCEs). The absence of MaSp2 in the MI-silk proteome and the comparison of the water resistance of artificial fibers suggest that the presence of MaSp2 is the reason for the disparity in water resistance between MI-silk and MA-silk.
Intention to breastfeed and association with subsequent breastfeeding duration, a linked population level routine data study - The Born in Wales cohort 2018-2021
Authors: Jones H , Seaborne M , Mhereeg M , James M , Kennedy N , Bandyopadhyay A , Brophy S
Published: December 2022

Objective

The World Health Organisation recommends exclusive breastfeeding for the first six months of life. This study aimed to examine 1) If intention to breastfeed is associated with higher levels of breastfeeding, and 2) If the pandemic impacted the intention to breastfeed and the breastfeeding rates in Wales.

Methods

This was a cohort study utilising routinely collected, linked healthcare data from the Secure Anonymised Information Linkage databank (SAIL). SAIL combines data from the National Community Child Health (NCCH) and Maternal Indicators (MIDS) datasets. All women that gave birth between 2018 and 2021 recorded in the NCCH dataset and MIDS dataset were included.

Results

Intention to breastfeed was associated with being 27.5 times more likely to continue to breastfeed for six months compared to those who did not intend to breastfeed (OR 27.5, 95% CI: 24.8-30.5). 57.8% of expectant mothers intended to breastfeed pre-pandemic and 58.7% intended to breastfeed in 2020. Exclusive breastfeeding rates to six months were 16.6% pre-pandemic, 20.5% in 2020 and 19.7% in 2021. Those aged 30-39 were 3.91 times more likely to breastfeed.

Conclusion

The biggest predictor of exclusive breastfeeding at six months was intention to breastfeed. During the pandemic those who intended to breastfeed were more likely to breastfeed exclusively for six months compared to before and after the pandemic, suggesting time at home may facilitate breastfeeding. Therefore, targeted interventions during pregnancy planning and early pregnancy to promote and encourage intention to start breastfeeding and promoting home working could improve breastfeeding rates and duration.
Internal limiting membrane disruption facilitates engraftment of transplanted human stem cell derived retinal ganglion cells
Authors: Aguzzi Erika A , Zhang Kevin Y , Nagalingam Arumugam , Quillen Sarah , Hariharakumar Shreya , Chetla Nitin , Madhoun Salaheddine , Edwards Malia M , Quigley Harry A , Zack Donald J , Johnson Thomas V
Published: December 2022

Retinal ganglion cell (RGC) death causes irreversible vision loss in patients with glaucoma and other forms of optic neuropathy because the mammalian retina and optic nerve lack endogenous regenerative capacity. RGC transplantation and optic nerve regeneration represent a potential translational approach to vision restoration in glaucoma secondary to RGC loss. Functional RGC replacement requires that 1) donor RGCs integrate into the recipient retina and receive synaptic input from afferent bipolar and amacrine cells and that 2) donor RGCs extend their axons and establish synaptic connections to appropriate neurons in the brain. Here, in an effort to address retinal integration, we demonstrate that the internal limiting membrane (ILM) acts as a physical barrier to the integration of transplanted human stem cell-derived RGCs (hRGCs) into the recipient retina following intravitreal transplantationin vivo. To circumvent the ILM barrier, we intravitreally injected the nonspecific protease pronase-E in immunosuppressed adult C57BL/6J mice prior to transplantation of hRGCs. Separately, we also transplanted hRGCs into adultLama1nmf223mice, which harbor a point mutation in theirLama-α1gene that causes developmental ILM dysgenesis. We assessed donor hRGC survival and engraftment using 3D reconstructions of confocal z-stacks in retinal flatmounts. Migration of surviving donor RGC somas into the recipient RGC layer significantly increased after proteolytic or developmental ILM disruption. Moreover, lamination of dendritic arbors into the recipient inner plexiform layer was observed exclusively following ILM disruption. To assess the clinical translatability of this finding, we transplanted hRGCs onto postmortem organotypic human retinal explant cultures and observed significantly increased engraftment following proteolytic ILM digestion. These findings enhance our understanding of the barriers faced by transplanted hRGCs in the adult murine and human retina and provide an avenue for clinically translatable regenerative medicine approaches to vision restoration in optic neuropathy.
Tunneling nanotubes between neuronal and microglial cells allow bi-directional transfer ofα-Synuclein and mitochondria
Authors: Chakraborty Ranabir , Zurzolo Chiara
Published: December 2022

Tunneling Nanotubes (TNTs) facilitate contact-mediated intercellular communication over long distances. Material transfer via TNTs can range from ions and intracellular organelles to protein aggregates and pathogens. Prion-like toxic protein aggregates accumulating in several disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases have been shown to spread via TNTs not only between neurons, but also between neurons-astrocytes, and neurons-pericytes, indicating the importance of TNTs in mediating neuron-glia interactions. TNT-like structures were also reported between microglia, however their roles in neuron-microglia interaction remain elusive. In this work, we quantitatively characterise microglial TNTs and their cytoskeletal composition, and demonstrate that TNTs form between human neuronal and microglial cells. We show thatα-Synuclein (α-Syn) aggregates increase the global TNT-mediated connectivity between cells, along with the number of TNT connections per cell pair. Homotypic TNTs formed between microglial cells, and heterotypic TNTs between neuronal and microglial cells are furthermore shown to be functional, allowing movement of bothα-Syn and mitochondria. Quantitative analysis shows thatα-Syn aggregates are transferred predominantly from neuronal to microglial cells, possibly as a mechanism to relieve the burden of accumulated aggregates. By contrast, microglia transfer mitochondria preferably toα-Syn burdened neuronal cells over the healthy ones, likely as a potential rescue mechanism. Besides describing novel TNT-mediated communication between neurons and microglia, this work allows us to better understand the cellular mechanisms of spreading of neurodegenerative diseases, shedding light on the role of microglia.
Speaker-induced suppression in EEG during a naturalistic reading and listening task
Authors: Kurteff Garret L. , Lester-Smith Rosemary A. ,   CCC-SLP, Martinez Amanda , Currens Nicole , Holder Jade , Villarreal Cassandra , Mercado Valerie R. , Truong Christopher , Huber Claire , Pokharel Paranjaya , Hamilton Liberty S.
Published: December 2022

Speaking elicits a suppressed neural response when compared to listening to others’ speech, a phenomenon known as speaker-induced suppression (SIS). Previous research has focused on investigating SIS at constrained levels of linguistic representation, such as the individual phoneme and word level. Here we present scalp EEG data from a dual speech perception and production task where participants read sentences aloud then listened to playback of themselves reading those sentences. Playback was separated into predictable repetition of the previous trial and unpredictable, randomized repetition of a former trial to investigate the role predictive processing plays in SIS. Concurrent EMG was recorded to control for movement artifact during speech production. In line with previous research, event-related potential analyses at the sentence level demonstrated suppression of early auditory components of the EEG for production compared to perception. To evaluate whether specific neural representations contribute to SIS (in contrast with a global gain change), we fit linear encoding models that predicted scalp EEG based on phonological features, EMG activity, and task condition. We found that phonological features were encoded similarly between production and perception. However, this similarity was only observed when controlling for movement by using the EMG response as an additional regressor. Our results suggest SIS is at the representational level a global gain change between perception and production, not the suppression of specific characteristics of the neural response. We also detail some important considerations when analyzing EEG during continuous speech production.
Predictive coding during action observation revealed by human electrocorticographic activity
Authors: Qin Chaoyi , Michon Frederic , Onuki Yoshiyuki , Ishishita Yohei , Otani Keisuke , Kawai Kensuke , Fries Pascal , Gazzola Valeria , Keysers Christian
Published: December 2022

Predictive coding is a theoretical framework that has received much attention for its ability to generate testable hypotheses on how multiple brain regions integrate information during cognitive functions. Given relatively large sensorimotor delays, during social interactions, predicting the behavior of others is crucial to enable joint actions or provide competitive advantages. The action observation network (AON) has been extensively studied, but how information is integrated across its main nodes remains poorly understood. Here we leverage the high spatial and temporal resolution of intracranial Electrocorticography (ECoG), to characterize how the key nodes of the AON - including precentral, supramarginal and visual areas - exchange information. We found more top-down beta oscillation from precentral to supramarginal contacts during the observation of predictable actions while more bottom-up gamma oscillation from visual to supramarginal contacts were measured for unpredictable actions. These results, in line with predictive coding, provide critical evidence towards an understanding of how nodes of the AON integrate information to process the actions of others.