bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of six exercise-based interventions for individuals undergoing hemodialysis: a network meta-analysis of randomized clinical trials
Authors: Ferrari Filipe , Andrade Francini P , Teixeira Marcelo S , Ziegelmann Patrícia K , Carvalho Gabriel , Bittencourt Eduarda S S , Barcellos Franklin C , Stein Ricardo
Published: April 2023

Background

Evidence comparing different exercise modalities in individuals undergoing hemodialysis remains incipient. Our aim was to conduct a systematic review and network meta-analysis of randomized clinical trials to compare and synthesize the efficacy of five different intradialytic exercise modalities and home-based training in this population.

Design, setting, participants, and measurements

Studies were searched in PubMed/MEDLINE, Cochrane Library, Embase, Cinahl, and Scopus from their inception to 19 September 2022. We used traditional random-effects models and Bayesian network meta-analysis models. The risk of bias was assessed using the RoB v.2.0 tool, and the assessment of confidence in the results through the Confidence in Network Meta-Analysis (CINeMA) tool.

Results

Seventy-eight studies involving 3326 participants were included. Our network meta-analysis showed that combined training was the intervention with the best performance to increase VO2 peak [mean difference (MD) = 3.94 ml/kg/min; 95% credible interval (CrI), 2.38 to 5.76] and to reduce diastolic blood pressure (MD = −5.19 mmHg; 95%CrI, −9.35 to −0.96) compared to the usual care group. Inspiratory muscle training was the intervention that most improved the 6-minute walk test distance (MD = 70.97 m; 95%CrI, 18.09 to 129.87). C-reactive protein decreased in resistance training (MD = −2.6 mg/l; 95%CrI, −4.97 to −0.33) and aerobic training (MD = −1.4 mg/l; 95%CrI, −3.15 to −0.06). Kt/V improved in aerobic training (MD = 0.11; 95%CrI, 0.02 to 0.18), and SF-36 physical functioning outcomes improved in resistance training (MD = 10.66 points; 95%Crl, 1.91 to 20.22). No intradialytic exercise modality was superior to others or comparable with home-based training in improving the evaluated outcomes. Subgroup analysis revealed that exercise interventions >12 weeks improved functional capacity more than interventions ≤12 weeks, and that combined training reduces diastolic blood pressure only after 12 weeks of follow-up. Furthermore, our results suggest that moderate or moderate-to-vigorous intensity training leads to more pronounced improvements in functional capacity, whereas mild or mild-to-moderate intensity training does not have the same effect. In this review, most of the included studies were assessed as having some concern, which resulted in a low to very low level of confidence in the overall findings.

Conclusions

Both intradialytic training and home-based training can promote benefits for individuals undergoing hemodialysis, with no evidence of the superiority of either training modality over the other.
Towards Non-essentialism – Tracking Rival Views of Legitimacy as a Right to Rule
Authors: Brinkmann Matthias , Vorland Wibye Johan
Published: April 2023

Abstract—

It is common in the literature to claim that legitimacy is the right to rule and that, accordingly, Hohfeldian rights analysis can be used to understand the concept. However, we argue that authors in the legitimacy literature have not generally realised the full potential of Hohfeldian analysis. We discuss extant approaches in the literature that conceptually identify legitimacy with one particular Hohfeldian incident, or, more rarely, a determinate set of incidents. Against these views, and building on parallel debates in property theory, we suggest that Hohfeldian analysis pushes one towards the claim that legitimacy possesses no determinate essence. We provide a rationale for this novel view and disarm a series of objections.
Improving health outcomes for patients and families with preferred language other than English or French (PLOEF)
Authors: Do Victor , Asim Ashna , Coffey Maitreya , Mahant Sanjay
Published: April 2023

Equitable care considers the unique needs of an individual—including social determinants of health such as language, race, and gender. Health equity and providing equitable care are considered fundamental to medicine, however, in practice there continues to be significant gaps to providing equitable care. There is a growing body of research on health care disparities, such as research on patients and families who have a preferred language other than English or French (PLOEF), who have worse health outcomes. Language barriers have been associated with increased risk of hospital admission, increased risks of misdiagnosis, poorer patient understanding of and adherence to prescribed treatment, lower patient satisfaction, and increased risk of experiencing adverse events. This commentary aims to examine issues faced by patients and families with PLOEF, particularly among hospitalized children and youth, and propose how the paediatric community can work to improve their care and health outcomes.
Phytochromes enhance SOS2-mediated PIF1 and PIF3 phosphorylation and degradation to promote Arabidopsis salt tolerance
Authors: Ma Liang , Han Run , Yang Yongqing , Liu Xiangning , Li Hong , Zhao Xiaoyun , Li Jianfang , Fu Haiqi , Huo Yandan , Sun Liping , Yan Yan , Zhang Hongyan , Li Zhen , Tian Feng , Li Jigang , Guo Yan
Published: April 2023

Soil salinity is one of the most detrimental abiotic stresses affecting plant survival, and light is a core environmental signal regulating plant growth and responses to abiotic stress. However, how light modulates the plant's response to salt stress remains largely obscure. Here, we show that Arabidopsis (Arabidopsis thaliana) seedlings are more tolerant to salt stress in the light than in the dark, and that the photoreceptors phytochrome A (phyA) and phyB are involved in this tolerance mechanism. We further show that phyA and phyB physically interact with the salt tolerance regulator SALT OVERLY SENSITIVE2 (SOS2) in the cytosol and nucleus, and enhance salt-activated SOS2 kinase activity in the light. Moreover, SOS2 directly interacts with and phosphorylates PHYTOCHROME-INTERACTING FACTORS PIF1 and PIF3 in the nucleus. Accordingly, PIFs act as negative regulators of plant salt tolerance, and SOS2 phosphorylation of PIF1 and PIF3 decreases their stability and relieves their repressive effect on plant salt tolerance in both light and dark conditions. Together, our study demonstrates that photoactivated phyA and phyB promote plant salt tolerance by increasing SOS2-mediated phosphorylation and degradation of PIF1 and PIF3, thus broadening our understanding of how plants adapt to salt stress according to their dynamic light environment.
Multiomics analysis reveals the molecular mechanisms underlying virulence in Rhizoctonia and jasmonic acid–mediated resistance in Tartary buckwheat (Fagopyrum tataricum)
Authors: He Yuqi , Zhang Kaixuan , Li Shijuan , Lu Xiang , Zhao Hui , Guan Chaonan , Huang Xu , Shi Yaliang , Kang Zhen , Fan Yu , Li Wei , Chen Cheng , Li Guangsheng , Long Ou , Chen Yuanyuan , Hu Mang , Cheng Jianping , Xu Bingliang , Chapman Mark A , Georgiev Milen I , Fernie Alisdair R , Zhou Meiliang
Published: April 2023

Rhizoctonia solani is a devastating soil-borne pathogen that seriously threatens the cultivation of economically important crops. Multiple strains with a very broad host range have been identified, but only 1 (AG1-IA, which causes rice sheath blight disease) has been examined in detail. Here, we analyzed AG4-HGI 3 originally isolated from Tartary buckwheat (Fagopyrum tataricum), but with a host range comparable to AG1-IA. Genome comparison reveals abundant pathogenicity genes in this strain. We used multiomic approaches to improve the efficiency of screening for disease resistance genes. Transcriptomes of the plant–fungi interaction identified differentially expressed genes associated with virulence in Rhizoctonia and resistance in Tartary buckwheat. Integration with jasmonate-mediated transcriptome and metabolome changes revealed a negative regulator of jasmonate signaling, cytochrome P450 (FtCYP94C1), as increasing disease resistance probably via accumulation of resistance-related flavonoids. The integration of resistance data for 320 Tartary buckwheat accessions identified a gene homolog to aspartic proteinase (FtASP), with peak expression following R. solani inoculation. FtASP exhibits no proteinase activity but functions as an antibacterial peptide that slows fungal growth. This work reveals a potential mechanism behind pathogen virulence and host resistance, which should accelerate the molecular breeding of resistant varieties in economically essential crops.
SALT OVERLY SENSITIVE2 stabilizes phytochrome-interacting factors PIF4 and PIF5 to promoteArabidopsisshade avoidance
Authors: Han Run , Ma Liang , Lv Yang , Qi Lijuan , Peng Jing , Li Hong , Zhou Yangyang , Song Pengyu , Duan Jie , Li Jianfang , Li Zhen , Terzaghi William , Guo Yan , Li Jigang
Published: April 2023

Sun-loving plants trigger the shade avoidance syndrome (SAS) to compete against their neighbors for sunlight. Phytochromes are plant red (R) and far-red (FR) light photoreceptors that play a major role in perceiving the shading signals and triggering SAS. Shade induces a reduction in the level of active phytochrome B (phyB), thus increasing the abundance of PHYTOCHROME-INTERACTING FACTORS (PIFs), a group of growth-promoting transcription factors. However, whether other factors are involved in modulating PIF activity in the shade remains largely obscure. Here, we show that SALT OVERLY SENSITIVE2 (SOS2), a protein kinase essential for salt tolerance, positively regulates SAS in Arabidopsis thaliana. SOS2 directly phosphorylates PIF4 and PIF5 at a serine residue close to their conserved motif for binding to active phyB. This phosphorylation thus decreases their interaction with phyB and posttranslationally promotes PIF4 and PIF5 protein accumulation. Notably, the role of SOS2 in regulating PIF4 and PIF5 protein abundance and SAS is more prominent under salt stress. Moreover, phyA and phyB physically interact with SOS2 and promote SOS2 kinase activity in the light. Collectively, our study uncovers an unexpected role of salt-activated SOS2 in promoting SAS by modulating the phyB-PIF module, providing insight into the coordinated response of plants to salt stress and shade.
Policing the world’s oldest democracy during the pandemic
Authors: Petropoulos Nikolaos (Nick)
Published: April 2023

The present study examines the role of the Hellenic Police during the COVID-19 Pandemic. In particular, based on data available through various sources, it will attempt to describe how the Hellenic Police dealt with what was unanimously described as an “unprecedented crisis” at a global level. In order to so, it will endorse a bi-fold approach. Firstly, we will seek to identify the policies and strategies implemented by the Hellenic Police during the COVID-19 crisis; Secondly, we will attempt to assess the effectiveness of these strategies and identify whether this affected the relationship between the Police and the public. Although our analysis indicated that the Hellenic Police played an important role in protecting the public from the effects of the pandemic, there is a lack of consistent and comprehensive data regarding citizens’ views of police legitimacy during the COVID-19 pandemic. Our study concludes that more studies should focus on the effect of COVID-19 on the citizens’ trust in the police as a government institution that during the COVID-19 era was in charge of enforcing a number of policies and strategies that were far from pleasant.
Television, Authoritarianism, and Support for Trump: A Replication
Authors: Hermann Erik , Morgan Michael , Shanahan James , Yan Harry Yaojun
Published: April 2023

Many factors contributed to support for Donald Trump in the 2016 US presidential election, among them media influences. Morgan and Shanahan (2017) found that television viewing was associated with support for Trump, mediated through authoritarianism. In light of the changes in the political and media environments during Trump’s presidency, our study examined whether Morgan and Shanahan’s (2017) findings still held in the 2020 US presidential election. Replicating their findings, we found that authoritarianism still mediates the relationship between television viewing and Trump support. As in the original study, the indirect effect is moderated by political ideology and gender, with stronger indirect effects among liberals and females.
Multiomics Analyses Reveal Microbiome–Gut–Brain Crosstalk Centered on Aberrant Gamma-Aminobutyric Acid and Tryptophan Metabolism in Drug-Naïve Patients with First-Episode Schizophrenia
Authors: Wang Zhuo , Yuan Xiuxia , Zhu Zijia , Pang Lijuan , Ding Shizhi , Li Xue , Kang Yulin , Hei Gangrui , Zhang Liyuan , Zhang Xiaoyun , Wang Shuying , Jian Xuemin , Li Zhiqiang , Zheng Chenxiang , Fan Xiaoduo , Hu Shaohua , Shi Yongyong , Song Xueqin
Published: April 2023

Background and Hypothesis

Schizophrenia (SCZ) is associated with complex crosstalk between the gut microbiota and host metabolism, but the underlying mechanism remains elusive. Investigating the aberrant neurotransmitter processes reflected by alterations identified using multiomics analysis is valuable to fully explain the pathogenesis of SCZ.

Study Design

We conducted an integrative analysis of multiomics data, including the serum metabolome, fecal metagenome, single nucleotide polymorphism data, and neuroimaging data obtained from a cohort of 127 drug-naïve, first-episode SCZ patients and 92 healthy controls to characterize the microbiome–gut–brain axis in SCZ patients. We used pathway-based polygenic risk score (PRS) analyses to determine the biological pathways contributing to genetic risk and mediation effect analyses to determine the important neuroimaging features. Additionally, a random forest model was generated for effective SCZ diagnosis.

Study Results

We found that the altered metabolome and dysregulated microbiome were associated with neuroactive metabolites, including gamma-aminobutyric acid (GABA), tryptophan, and short-chain fatty acids. Further structural and functional magnetic resonance imaging analyses highlighted that gray matter volume and functional connectivity disturbances mediate the relationships between Ruminococcus_torgues and Collinsella_aerofaciens and symptom severity and the relationships between species Lactobacillus_ruminis and differential metabolites l-2,4-diaminobutyric acid and N-acetylserotonin and cognitive function. Moreover, analyses of the Polygenic Risk Score (PRS) support that alterations in GABA and tryptophan neurotransmitter pathways are associated with SCZ risk, and GABA might be a more dominant contributor.

Conclusions

This study provides new insights into systematic relationships among genes, metabolism, and the gut microbiota that affect brain functional connectivity, thereby affecting SCZ pathogenesis.
Explaining the training disadvantage of less-educated workers: the role of labor market allocation in international comparison
Authors: Hornberg Carla , Heisig Jan Paul , Solga Heike
Published: April 2023

Less-educated workers have the lowest participation rates in job-related further training across the industrialized world, but the extent of their disadvantage varies. Using data on 28 high- and middle-income countries, we assess different explanations for less-educated workers’ training disadvantage relative to intermediate-educated workers, with a focus on the role of labor market allocation (i.e. job tasks, other job features and firm characteristics). Shapley decompositions reveal a broadly similar pattern for all countries: differences in labor market allocation between less- and intermediate-educated workers are more important for explaining the training gap than differences in individual learning disposition (i.e. cognitive skills and motivation to learn). Our analysis further suggests that the training gap is related to educational and labor market institutions and that labor market allocation processes play a key role in mediating any institutional ‘effects’. Strong conclusions regarding the role of institutions are hampered by the small country-level sample, however.
Reducing Delay in Payments in Welfare Programs: Experimental Evidence from an Information Dissemination Intervention
Authors: Das Upasak , Paul Amartya , Sharma Mohit
Published: April 2023

This paper assesses the impact of an information dissemination intervention on the local-level implementation of the rural public works program in India. One key feature of the intervention is to provide information to workers once their wages get credited into their accounts. Using administrative and survey data, its impact on delays in wage payments and days of work along with the awareness levels of the entitlements is evaluated. The findings indicate a substantial reduction in payment delays and in trips made for wage withdrawal, in addition to improvements in awareness. The decrease in the payment delays in the treated villages persists even beyond the intervention period. While a limited impact on work days is observed during the intervention, a significant increase in the post-intervention period is found. The findings substantiated through qualitative evidence provide a platform for an innovative and cost-effective intervention to improve the implementation of social protection programs.
Duration of type 2 diabetes and liver-related events in nonalcoholic fatty liver disease: A landmark analysis
Authors: Zhang Xinrong , Yip Terry Cheuk-Fung , Tse Yee-Kit , Hui Vicki Wing-Ki , Li Guanlin , Lin Huapeng , Liang Lilian Yan , Lai Jimmy Che-To , Chan Henry Lik-Yuen , Chan Stephen Lam , Kong Alice Pik-Shan , Wong Grace Lai-Hung , Wong Vincent Wai-Sun
Published: April 2023

Background and Aims:

We aimed to determine the impact of the duration of type 2 diabetes (T2D) on the risk of liver-related events and all-cause mortality in patients with NAFLD.

Approach and Results:

We conducted a territory-wide cohort study of adult patients with NAFLD diagnosed between January 1, 2000, and July 31, 2021, in Hong Kong. T2D was defined by the use of any antidiabetic agents, laboratory tests, and/or diagnosis codes. The primary endpoint was liver-related events, defined as a composite endpoint of HCC and cirrhotic complications. To conduct a more granular assessment of the duration of T2D, we employed landmark analysis in four different ages of interest (biological age of 40, 50, 60, and 70 years). By multivariable analysis with adjustment of non–liver-related deaths, compared with patients without diabetes at age 60 (incidence rate of liver-related events: 0.70 per 1,000 person-years), the adjusted subdistribution HR (SHR) of liver-related events was 2.51 (95% CI: 1.32–4.77; incidence rate: 2.26 per 1,000 person-years) in patients with T2D duration < 5 years, 3.16 (95% CI: 1.59–6.31; incidence rate: 2.54 per 1,000 person-years) in those with T2D duration of 6–10 years, and 6.20 (95% CI: 2.62–14.65; incidence rate: 4.17 per 1000 person-years) in those with T2D duration more than 10 years. A similar association between the duration of T2D and all-cause mortality was also observed.

Conclusions:

Longer duration of T2D is significantly associated with a higher risk of liver-related events and all-cause mortality in patients with NAFLD.
A Socioecological Model of Transition to Nursing Practice
Authors: Gilroy Heidi , Douglas Laura , Short Yashamika , Jarrard Victoria
Published: April 2023

A newly licensed nurse’s (NLN) transition to practice (TTP) is affected by interactions inside and outside the hospital. The aim of this Delphi study was to create a socioecological model of TTP. Included in the socioecological model are personal characteristics and interactions at the relationship, community, and societal levels that the NLNs feel affects their TTP. This socioecological model can be used to plan TTP programs that address the holistic needs of the NLNs.
Beyond Onboarding
Authors: Kennedy Maureen Shawn
Published: April 2023

Onboarding new nurses is but one role of nurse professional development practitioners during this nursing shortage; those in staff development need to develop strategies that will help retain experienced nurses. This article reviews recent reports on acute care staffing and focuses on nurse involvement in quality improvement initiatives and reporting as a means for engaging experienced staff.
Supervised biological network alignment with graph neural networks
Authors: Ding Kerr , Wang Sheng , Luo Yunan
Published: April 2023

Motivation

Despite the advances in sequencing technology, massive proteins with known sequences remain functionally unannotated. Biological network alignment (NA), which aims to find the node correspondence between species’ protein-protein interaction (PPI) networks, has been a popular strategy to uncover missing annotations by transferring functional knowledge across species. Traditional NA methods assumed that topologically similar proteins in PPIs are functionally similar. However, it was recently reported that functionally unrelated proteins can be as topologically similar as functionally related pairs, and a new data-driven or supervised NA paradigm has been proposed, which uses protein function data to discern which topological features correspond to functional relatedness.

Results

Here, we proposeGraNA, a deep learning framework for the supervised NA paradigm for the pairwise network alignment problem. Employing graph neural networks, GraNA utilizes within-network interactions and across-network anchor links for learning protein representations and predicting functional correspondence between across-species proteins. A major strength of GraNA is its flexibility to integrate multi-faceted non-functional relationship data, such as sequence similarity and ortholog relationships, as anchor links to guide the mapping of functionally related proteins across species. Evaluating GraNA on a benchmark dataset composed of several NA tasks between different pairs of species, we observed that GraNA accurately predicted the functional relatedness of proteins and robustly transferred functional annotations across species, outperforming a number of existing NA methods. When applied to a case study on a humanized yeast network, GraNA also successfully discovered functionally replaceable human-yeast protein pairs that were documented in previous studies.

Availability

The code of GraNA is available athttps://github.com/luo-group/GraNA.

Contact

yunan@gatech.edu
Large scale eDNA database reveals latitudinal diversity gradients with seasonal variations
Authors: Kasada Minoru , Shinohara Naoto , Fukasawa Riku , Tanabe Akifumi S. , Kondoh Michio
Published: April 2023

Withdrawal Statement

The authors have withdrawn their manuscript owing to conflicts regarding the use of data. Therefore, the authors do not wish this work to be cited as reference for the project. The revised version will be updated once this issue has been resolved. If you have any questions, please contact the corresponding author.
Targeting Transferrin Receptor to Transport Antisense Oligonucleotides Across the Blood-Brain Barrier
Authors: Barker Scarlett J , Thayer Mai B , Kim Chaeyoung , Tatarakis David , Simon Matthew , Dial Rebekah L , Nilewski Lizanne , Wells Robert C , Zhou Yinhan , Afetian Megan , Chappell Alfred , Chew Kylie S , Chow Johann , Clemens Allisa , Discenza Claire B , Dugas Jason , Dwyer Chrissa , Earr Timothy , Ha Connie , Huynh David , Jayaraman Srini , Kwan Wanda , Mahon Cathal , Pizzo Michelle , Roche Elysia , Sanders Laura , Stergioulis Alexander , Tong Raymond , Tran Hai , Zuchero Joy , Estrada Anthony A , Gadkar Kapil , Koth Christopher MM , Sanchez Pascal E , Thorne Robert G , Watts Ryan J , Sandmann Thomas , Kane Lesley , Rigo Frank , Dennis Mark S , Lewcock Joseph W , DeVos Sarah L
Published: April 2023

Antisense oligonucleotides (ASO) are promising therapies for neurological disorders, though they are unable to cross the blood-brain barrier (BBB) and must be delivered directly to the central nervous system (CNS). Here, we use a human transferrin receptor (TfR)-binding molecule to transport ASO across the BBB in mice and non-human primates, termed oligonucleotide transport vehicle (OTV). Systemically delivered OTV drives significant, cumulative, and sustained knockdown of the ASO target across multiple CNS regions and all major cell types. Further, systemic OTV delivery enables more uniform ASO biodistribution and knockdown compared to two other clinically relevant ASO delivery routes: a standard, high affinity TfR antibody, or direct ASO delivery to the CSF. Together, our data support systemically delivered OTV as a potential therapeutic platform for neurological disorders.

One-Sentence Summary

Systemically dosed OTV delivered via TfR1 targeting shows widespread and cumulative target knockdown in the mouse and NHP CNS.
Using sentinel nodes to evaluate changing connectivity in a protected areas network
Authors: O’Brien Paul , Carr Natasha , Bowman Jeff
Published: April 2023

It has been recognized that well-connected networks of protected areas are needed to halt the continued loss of global biodiversity. The recently signed Kunming-Montreal biodiversity agreement commits countries to protecting 30% of terrestrial lands in well-connected networks of protected areas by 2030. To meet these ambitious targets, land-use planners and conservation practitioners will require tools to identify areas important for connectivity and track future changes. In this study we present methods using circuit theoretic models with a subset of sentinel park nodes to evaluate connectivity for a protected areas network. We assigned a lower cost to natural areas within protected areas, under the assumption that animal movement within parks should be less costly given the regulation of activities. We found that by using mean pairwise effective resistance (MPER) as an indicator of overall network connectivity, we were able to detect changes in a parks network in response to simulated land-use changes. As expected, MPER increased with the addition of high-cost developments and decreased with the addition of new, low-cost protected areas. We tested our sentinel node method by evaluating connectivity for the protected areas network in the province of Ontario, Canada. Our method can help provide protected areas ecologists and planners with baseline estimates of connectivity for a given protected areas network and an indicator that can be used to track changes in connectivity in the future.
Phase-specific stimulation reveals consistent sinusoidal modulation of human corticospinal excitability along the oscillatory beta cycle
Authors: Keute Marius , Gebühr Julian-Samuel , Guggenberger Robert , Trunk Bettina Hanna , Gharabaghi Alireza
Published: April 2023

The responsiveness of neuronal populations to incoming information fluctuates. Retrospective analyses of randomly applied stimuli reveal a neural input-output relationship along the intrinsic oscillatory cycle. Prospectively harnessing this biological mechanism would necessitate frequency- and phase-specificity, intra- and inter-individual consistency, and instantaneous access to the oscillatory cycle.

We used a novel real-time approach to electroencephalography-triggered transcranial magnetic stimulation to precisely target 8 equidistant phases of the oscillatory cycle in the human motor cortex of male and female healthy participants. The phase-dependency of corticospinal excitability was investigated in ten different intrinsic frequencies (4, 8, 12, 16, 20, 24, 28, 32, 36, and 40Hz) and indexed by motor-evoked potentials (MEP) in the corresponding forearm muscle.

On both the individual and group level, we detected a consistent sinusoidal MEP modulation along the oscillatory cycle at 24Hz (χ22=9.2, p=.01), but not at any other target frequency (all χ22<5, all p>.08). Moreover, cross-validations showed also at 24Hz the highest consistency of the optimal phase between prospective (real-time) and retrospective (out-of-sample) testing (r=.605, p<.001), and across experimental sessions on three different days (r≥.45). The optimal corticospinal signal transmission was at the transition from the trough to the rising flank of the oscillatory 24Hz cycle.

Integrating real-time measurement and brain stimulation revealed that the sinusoidal input-output relationship of corticospinal signal transmission is frequency- and phase specific, and consistent within and across individuals and sessions. In future, this approach allows to selectively and repetitively target windows of increased responsiveness, and to thereby investigate potential cumulative effects on plasticity induction.
STAPLER: Efficient learning of TCR-peptide specificity prediction from full-length TCR-peptide data
Authors: Kwee Bjørn P. Y. , Messemaker Marius , Marcus Eric , Oliveira Giacomo , Scheper Wouter , Wu Catherine J. , Teuwen Jonas , Schumacher Ton N.
Published: April 2023

The prediction of peptide-MHC (pMHC) recognition by αβ T-cell receptors (TCRs) remains a major biomedical challenge. Here, we develop STAPLER (Shared TCR And Peptide Language bidirectional Encoder Representations from transformers), a transformer language model that uses a joint TCRαβ- peptide input to allow the learning of patterns within and between TCRαβ and peptide sequences that encode recognition. First, we demonstrate how data leakage during negative data generation can confound performance estimates of neural network-based models in predicting TCR – pMHC specificity. We then demonstrate that, because of its pre-training and fine-tuning masked language modeling tasks, STAPLER outperforms both neural network-based and distance-based ML models in predicting the recognition of known antigens in an independent dataset, in particular for antigens for which little related data is available. Based on this ability to efficiently learn from limited labeled TCR- peptide data, STAPLER is well-suited to utilize growing TCR – pMHC datasets to achieve accurate prediction of TCR – pMHC specificity.
Propulsive cell entry diverts pathogens from immune degradation by remodeling the phagocytic synapse
Authors: Zhang Zihan , Gaetjens Thomas K. , Yu Yanqi , Mallory D. Paul , Abel Steven M. , Yu Yan
Published: April 2023

Phagocytosis is a critical immune function for infection control and tissue homeostasis. This process is typically described as non-moving pathogens being internalized and degraded in phagolysosomes. For pathogens that evade immune degradation, the prevailing view is that virulence factors that biochemically disrupt the biogenesis of phagoslysosomes are required. In contrast, here we report that physical forces exerted by pathogens during cell entry divert them away from the canonical phagolysosomal degradation pathway, and this altered intracellular fate is determined at the time of phagocytic synapse formation. We used the eukaryotic parasiteToxoplasma gondiias a model because liveToxoplasmauses gliding motility to actively invade into host cells. To differentiate the effect of physical forces from that of virulence factors in phagocytosis, we developed a strategy that used magnetic forces to induce propulsive entry of inactivatedToxoplasmainto macrophage cells. Experiments and computer simulations collectively reveal that large propulsive forces suppress productive activation of receptors by hindering their spatial segregation from phosphatases at the phagocytic synapse. Consequently, the inactivated parasites, instead of being degraded in phagolysosomes, are engulfed into vacuoles that fail to mature into degradative units, following an intracellular pathway strikingly similar to that of the live motile parasite. Using opsonized beads, we further confirmed that this mechanism is general, not specific to the parasite used. These results reveal previously unknown aspects of immune evasion by demonstrating how physical forces exerted during active cell entry, independent of virulence factors, can help pathogens circumvent phagolysosomal degradation.
Dozer: Debiased personalized gene co-expression networks for population-scale scRNA-seq data
Authors: Lu Shan , Keleş Sündüz
Published: April 2023

Population-scale single cell RNA-seq (scRNA-seq) datasets create unique opportunities for quantifying expression variation across individuals at the gene co-expression network level. Estimation of co-expression networks is well-established for bulk RNA-seq; however, single-cell measurements pose novel challenges due to technical limitations and noise levels of this technology. Gene-gene correlation estimates from scRNA-seq tend to be severely biased towards zero for genes with low and sparse expression. Here, we present Dozer to debias gene-gene correlation estimates from scRNA-seq datasets and accurately quantify network level variation across individuals. Dozer corrects correlation estimates in the general Poisson measurement model and provides a metric to quantify genes measured with high noise. Computational experiments establish that Dozer estimates are robust to mean expression levels of the genes and the sequencing depths of the datasets. Compared to alternatives, Dozer results in fewer false positive edges in the co-expression networks, yields more accurate estimates of network centrality measures and modules, and improves the faithfulness of networks estimated from separate batches of the datasets. We showcase unique analyses enabled by Dozer in two population-scale scRNA-seq applications. Co-expression network-based centrality analysis of multiple differentiating human induced pluripotent stem cell (iPSC) lines yields biologically coherent gene groups that are associated with iPSC differentiation efficiency. Application with population-scale scRNA-seq of oligodendrocytes from postmortem human tissues of Alzheimer disease and controls uniquely reveals co-expression modules of innate immune response with markedly different co-expression levels between the diagnoses. Dozer represents an important advance in estimating personalized co-expression networks from scRNA-seq data.
Organization of orbitofrontal-auditory pathways in the Mongolian gerbil
Authors: Ying Rose , Hamlette Lashaka , Nikoobakht Laudan , Balaji Rakshita , Miko Nicole , Caras Melissa L.
Published: April 2023

Sound perception is highly malleable, rapidly adjusting to the acoustic environment and behavioral demands. This flexibility is the result of ongoing changes in auditory cortical activity driven by fluctuations in attention, arousal, or prior expectations. Recent work suggests that the orbitofrontal cortex (OFC) may mediate some of these rapid changes, but the anatomical connections between the OFC and the auditory system are not well-characterized. Here, we used virally-mediated fluorescent tracers to map the projection from OFC to the auditory midbrain, thalamus, and cortex in a classic animal model for auditory research, the Mongolian gerbil (Meriones unguiculatus). We observed no connectivity between the OFC and the auditory midbrain, and an extremely sparse connection between the dorsolateral OFC and higher-order auditory thalamic regions. In contrast, we observed a robust connection between the ventral and medial subdivisions of the OFC and the auditory cortex, with a clear bias for secondary auditory cortical regions. OFC axon terminals were found in all auditory cortical lamina but were significantly more concentrated in the infragranular layers. Tissue-clearing and lightsheet microscopy further revealed that auditory cortical-projecting OFC neurons send extensive axon collaterals throughout the brain, targeting both sensory and non-sensory regions involved in learning, decision-making, and memory. These findings provide a more detailed map of orbitofrontal-auditory connections and shed light on the possible role of the OFC in supporting auditory cognition.
SeqImprove: Machine Learning Assisted Creation of Machine Readable Sequence Information
Authors: Mante Jeanet , Sents Zach , Myers Chris J.
Published: April 2023

The progress and utility of synthetic biology is currently hindered by the lengthy process of studying literature and replicating poorly documented work. Reconstruction of crucial design information through post-hoc curation is highly noisy and error-prone. To combat this, author participation during the curation process is crucial. To encour-age author participation without overburdening them, an ML-assisted curation tool called SeqImprove has been developed. Using named entity recognition, named entity normalization, and sequence matching, SeqImprove creates machine-readable sequence data and metadata annotations, which authors can then review and edit before sub-mitting a final sequence file. SeqImprove makes it easier for authors to submit FAIR sequence data that is findable, accessible, interoperable, and reusable.
Connectome embedding in multidimensional graph-invariant spaces
Authors: Mach Mathieu , Amico Enrico , Liégeois Raphaël , Preti Maria Giulia , Griffa Alessandra , Van De Ville Dimitri , Pedersen Mangor
Published: April 2023

The topological organization of brain networks, or connectomes, can be quantified using graph theory. Here, we investigated brain networks in higher dimensional spaces defined by up to ten node-level graph theoretical invariants. Nodal invariants are intrinsic nodal properties which reflect the topological characteristics of the nodes with respect to the whole network, including segregation (e.g., clustering coefficient) and centrality (e.g., betweenness centrality) measures. Using 100 healthy unrelated subjects from the Human Connectome Project, we generated multiple types of connectomes (structural/functional networks and binary/weighted networks) and embedded the corresponding network nodes (brain regions) into multidimensional graph spaces defined by the invariants. First, we observed that nodal invariants are correlated between them (i.e., they carry similar network information) at a whole-brain and subnetwork level. Second, we conducted a machine learning analysis to test whether brain regions embedded in multidimensional graph spaces can be accurately classified into higher order (association, subcortical and cerebellar) and lower order (visual, somatomotor, attention) areas. Brain regions of higher order and lower order brain circuits were classified with an 80-87% accuracy in a 10-dimensional (10D) space. 10D graph metrics performed better than 2D and 3D graph metrics, and non-linear Gaussian kernels performed better than linear kernels. This suggests a non-linear brain network information gain in a high-dimensional graph space. Finally, we quantified the inter-subject Euclidean distance of each brain region embedded in the multidimensional graph space. The inter-individual distance was largest for regions of the default mode and frontoparietal networks, providing a new avenue for subject-specific network coordinates in a multidimensional space. To conclude, we propose a new framework for quantifying connectome features in multidimensional spaces defined by graph invariants, providing a new avenue for subject-specific network coordinates and inter-individual distance analyses.
Statistical learning in epilepsy: Behavioral, anatomical, and causal mechanisms in the human brain
Authors: Aljishi Ayman , Sherman Brynn E. , Huberdeau David M. , Obaid Sami , Sivaraju Adithya , Turk-Browne Nicholas B. , Damisah Eyiyemisi C.
Published: April 2023

Statistical learning, the fundamental cognitive ability of humans to extract regularities across experiences over time, engages the medial temporal lobe in the healthy brain. This leads to the hypothesis that statistical learning may be impaired in epilepsy patients, and that this impairment could contribute to their varied memory deficits. In turn, epilepsy patients provide a platform to advance basic understanding of statistical learning by helping to evaluate the necessity of medial temporal lobe circuitry through disease and causal perturbations. We implemented behavioral testing, volumetric analysis of the medial temporal lobe substructures, and direct electrical brain stimulation to examine statistical learning across a cohort of 61 epilepsy patients and 28 healthy controls. Behavioral performance in a statistical learning task was negatively associated with seizure frequency, irrespective of where seizures originated in the brain. The volume of hippocampal subfields CA1 and CA2/3 correlated with statistical learning performance, suggesting a more specific role of the hippocampus. Indeed, transient direct electrical stimulation of the hippocampus disrupted statistical learning. Furthermore, the relationship between statistical learning and seizure frequency was selective: behavioral performance in an episodic memory task was impacted by structural lesions in the medial temporal lobe and by antiseizure medications, but not by seizure frequency. Overall, these results suggest that statistical learning may be hippocampally dependent and that this task could serve as a clinically useful behavioral assay of seizure frequency distinct from existing neuropsychological tests. Simple and short statistical learning tasks may thus provide patient-centered endpoints for evaluating the efficacy of novel treatments in epilepsy.
Improving the solubility of pseudo-hydrophobic Alzheimer’s Disease medicinal chemicals through co-crystal formulation
Authors: A Tse , I Janilkarn-Urena , Lin J , Chang X , Efthymiou C , Idrissova A , Zhang M , CK Williams , Magaki S , HV Vinters , DL Davies , Gonen T , HJ Gukasyan , PM Seidler
Published: April 2023

Natural products are ligands and potential inhibitors of Alzheimer’s disease (AD) tau. Dihydromyricetin (DHM) is a CNS active natural product. Despite having signature polyphenolic character, DHM is ostensibly hydrophobic owing to intermolecular hydrogen bonds that shield hydrophilic phenols. Our research shows DHM becomes ionized at near-neutral pH allowing formulation of salts with transformed solubility. The MicroED co-crystal structure with trolamine reveals DHM salts as metastable solids with unlocked hydrogen bonding and a thermodynamic bent to solubilize in water. All salt formulations show better inhibitory activity against AD tau than the non-salt form, with efficacies correlating to enhanced solubilities. These results underscore the role of structural chemistry in guiding selection of solubilizing agents for chemical formulation. We propose DHM salts are appropriate formulations for research as dietary supplements to promote healthy aging by combating protein misfolding. Additionally, DHM is a suitable lead for medicinal chemistry and possible development of CNS pharmaceuticals.
A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer
Authors: Zeng Jianhao , Singh Shambhavi , Jiang Ying , Casarez Eli , Atkins Kristen A. , Janes Kevin A. , Zong Hui
Published: April 2023

Basal-like breast cancer is an aggressive breast cancer subtype, often characterized by a deficiency inBRCA1function and concomitant loss ofp53. While conventional mouse models enable the investigation of its malignant stages, one that reveals its initiation and pre-malignant progression is lacking. Here, we leveraged a mouse genetic system known asMosaicAnalysis withDoubleMarkers (MADM) to generate rare GFP-labeledBrca1,p53-deficient cells alongside RFP+ wildtype sibling cells in the mammary gland. The mosaicism resembles the sporadic initiation of human cancer and enables spatially resolved analysis of mutant cells in comparison to paired wildtype sibling cells. Mammary tumors arising in the model show transcriptomic and genomic characteristics similar to human basal-like breast cancer. Analysis of GFP+ mutant cells at interval time points before malignancy revealed a stepwise progression of lesions from focal expansion to hyper-alveolarization and then to micro-invasion. These stereotyped morphologies indicate the pre-malignant stage irrespective of the time point at which it is observed. Paired analysis of GFP-RFP siblings during focal expansion suggested that hyper-alveolarized structures originate from ductal rather than alveolar cells, despite their morphological similarities to alveoli. Evidence for luminal-to-basal transition at the pre-malignant stages was restricted to cells that had escaped hyper-alveoli and progressed to micro-invasive lesions. Our MADM-based mouse model presents a useful tool for studying the pre-malignancy of basal-like breast cancer.

Summary statement

A mouse model recapitulates the process of human basal-like breast tumorigenesis initiated from sporadicBrca1, p53-deficient cells, empowering spatially-resolved analysis of mutant cells during pre-malignant progression.
Motor unit tracking using blind source separation filters and waveform cross-correlations: reliability under physiological and pharmacological conditions
Authors: Goodlich Benjamin I. , Vecchio Alessandro Del , Kavanagh Justin J.
Published: April 2023

Recent advancements in the analysis of high-density surface electromyography (HDsEMG) have enabled the identification, and tracking, of motor units (MUs) to study muscle activation. This study aimed to evaluate the reliability of MU tracking using two common methods: blind source separation filters and two-dimensional waveform cross-correlation. An experiment design was developed to assess physiological reliability, and reliability for a drug intervention known to reduce the firing rate of motoneurones (cyproheptadine). HDsEMG signals were recorded from tibialis anterior during isometric dorsiflexions to 10%, 30%, 50% and 70% of maximal voluntary contraction. MUs were matched within session (2 hr) using the filter method, and between sessions (7 days) via the waveform method. Both tracking methods demonstrated similar reliability during physiological conditions (e.g., MU discharge: filter ICC 10% of MVC = 0.76, to 70% of MVC = 0.86; waveform ICC: 10% of MVC = 0.78, to 70% of MVC = 0.91). Although reliability slightly reduced after the pharmacological intervention, there were no discernible differences in tracking performance (e.g., MU disc filter ICC: 10% of MVC = 0.73, to 70% of MVC = 0.75; DR waveform ICC: 10% of MVC = 0.84, to 70% of MVC = 0.85). The poorest reliability typically occurred at higher contraction intensities, which aligned with the greatest variability in MU characteristics. This study confirms that tracking method may not impact the interpretation of MU data, provided that an appropriate experiment design is employed. However, caution should be used when tracking MUs during higher intensity isometric contractions.

NEW AND NOTEWORTHY

The most direct way to validate longitudinal tracking of motor unit data extracted from high-density surface electromyography is to contrast findings with intramuscular electromyography. We use pharmacology to changes motor unit discharge properties as a non-invasive alternative to validate the reliability tracking motor units. This study confirmed that the specific tracking method may not impact interpretation of motor unit data at lower contraction intensities, however caution should be used when tracking units during higher intensities.