bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifiability in Functional Connectivity May Unintentionally Inflate Prediction Results
Authors: Orlichenko Anton , Qu Gang , Su Kuan-Jui , Liu Anqi , Shen Hui , Deng Hong-Wen , Wang Yu-Ping
Published: August 2023

Functional magnetic resonance (fMRI) is an invaluable tool in studying cognitive processes in vivo. Many recent studies use functional connectivity (FC), partial correlation connectivity (PC), or fMRI-derived brain networks to predict phenotypes with results that sometimes cannot be replicated. At the same time, FC can be used to identify the same subject from different scans with great accuracy. In this paper, we show a method by which one can unknowingly inflate classification results from 61% accuracy to 86% accuracy by treating longitudinal or contemporaneous scans of the same subject as independent data points. Using the UK Biobank dataset, we find one can achieve the same level of variance explained with 50 training subjects by exploiting identifiability as with 10,000 training subjects without double-dipping. We replicate this effect in four different datasets: the UK Biobank (UKB), the Philadelphia Neurodevelopmental Cohort (PNC), the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP), and an OpenNeuro Fibromyalgia dataset (Fibro). The unintentional improvement ranges between 7% and 25% in the four datasets. Additionally, we find that by using dynamic functional connectivity (dFC), one can apply this method even when one is limited to a single scan per subject. One major problem is that features such as ROIs or connectivities that are reported alongside inflated results may confuse future work. This article hopes to shed light on how even minor pipeline anomalies may lead to unexpectedly superb results.
Examining a Preclinical Alzheimer’s Cognitive Composite for Telehealth Administration, the tPACC, for Reliability between In-Person and Remote Cognitive Testing with Neuroimaging Biomarkers
Authors: Duran Tugce , Gaussoin Sarah A. , Latham Lauren A. , Rundle Melissa M. , Espeland Mark A. , Williams Benjamin J. , Hughes Timothy M. , Craft Suzanne , Sachs Bonnie C. , Bateman James R. , Lockhart Samuel N.
Published: August 2023

INTRODUCTION

We defined a telehealth preclinical Alzheimer’s cognitive composite (tPACC) derived from remotely administered cognitive assessments and examined its relationship with neuroimaging biomarkers.

METHODS

We examined neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core cohort and a pilot study to form a modified PACC (PACC5-RAVLT) and tPACC. We performed intraclass correlation coefficient (ICC) analysis for reliability of tPACC and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal (NC) and impaired participants.

RESULTS

There was a significant positive relationship between in-person tPACC and PACC5-RAVLT (ICC=0.88), in-person PACC5-RAVLT and remote tPACC (ICC=0.73), and in-person tPACC and remote tPACC (ICC=0.82). Overall, tPACC showed significant associations with imaging biomarkers.

DISCUSSION

There is a good agreement between tPACC and PACC5-RAVLT for NC and impaired individuals. The tPACC is associated with common neuroimaging markers.

Research in Context

1. Systematic Review:We reviewed the literature to identify the reliability of remote cognitive testing, concordance of in-person and remote cognitive testing, and remote Preclinical Alzheimer’s Cognitive Composite (PACC) to differentiate cognitive functioning in older adults with or without cognitive impairment. We searched studies to examine relationships between remote PACC score and neuroimaging biomarkers related to early stages of Alzheimer’s Disease. We found no studies simultaneously examining a telehealth PACC (tPACC) score with neuroimaging biomarkers that provide crucial implications for detecting cognitive differences.

2. Interpretation:Our findings reveal that a tPACC score can serve as a harmonized composite measure for heterogeneous cognitive data to discriminate those with or without cognitive impairment and inform neuroimaging outcomes.

3. Future Directions:Future work is necessary to test tPACC performance in larger longitudinal studies and relationships with other neuroimaging (e.g., PET) or plasma biomarkers in older adults across the cognitive spectrum.
Subthalamic deep brain stimulation alleviates motor symptoms without restoring deficits in corticospinal suppression during movement preparation in Parkinson’s disease
Authors: Wilhelm Emmanuelle , Derosiere Gerard , Quoilin Caroline , Cakiroglu Inci , Paço Susana , Raftopoulos Christian , Nuttin Bart , Duque Julie
Published: August 2023

Background

Parkinson’s disease (PD) patients exhibit alterations in neurophysiological mechanisms underlying movement preparation, especially the suppression of corticospinal excitability – called “preparatory suppression” – considered to propel movement execution by increasing motor neural gain in healthy individuals.

Objective

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) being an attractive treatment for advanced PD, we aimed to investigate the potential contribution of this nucleus to PD-related changes in such corticospinal dynamics.

Methods

On two consecutive days, we applied single-pulse transcranial magnetic stimulation over both primary motor cortices in 20 PD patients treated with bilateral STN-DBS (ON vs. OFF), as well as 20 healthy control subjects. Motor-evoked potentials were elicited at rest or during a left- or right-hand response preparation in an instructed-delay choice reaction time task. Preparatory suppression was assessed by expressing amplitudes of motor potentials evoked during movement preparation relative to rest.

Results

Advanced PD patients exhibited a deficit in corticospinal suppression during movement preparation, limited to the responding hand (especially the most-affected), independently of STN-DBS. Significant links between preparatory suppression and clinical variables were found for least-affected hands only.

Conclusion

Our study provides evidence of altered corticospinal dynamics during movement preparation in advanced PD patients treated with STN-DBS. Consistent with results in earlier-stage patients, preparatory suppression deficits were limited to the responding hand and most pronounced on the most-affected side. STN-DBS did not restore this abnormality, which warrants further investigations into possible neuroanatomical sources of such corticospinal suppression, necessary to understand the consistent lack of this mechanism in PD patients.
A Co-Creation Process Toward Sustainable Adoption of Integrated Care for Prevention of Unplanned Hospitalizations
Authors: Herranz Carmen , Gómez Alba , Hernández Carme , González-Colom Rubèn , Contel Joan Carles , Cano Isaac , Piera-Jiménez Jordi , Roca Josep
Published: August 2023

Introduction

Complex chronic patients (CCP) are prone to unplanned hospitalizations leading to a high burden on healthcare systems. To date, interventions to prevent unplanned admissions show inconclusive results. We report a co-creation process performed into the EU initiative JADECARE (2020-2023) to elaborate an integrated care program aiming at preventing unplanned hospitalizations.

Methods

A two-phase process of structured interviews and design thinking (DT) sessions was conducted. Firstly, we assessed the management of CCP in Catalonia (ES) through twenty interviews (five patients and fifteen professionals), including the results of a cluster analysis of 761 hospitalizations, followed by two DT sessions (Oct 2021 to Feb 2022). Then, we examined the 30- and 90-day post-discharge periods of 49,604 hospitalizations as input for two DT sessions with seven professionals.

Discussion

The co-creation process identified poor personalization of the interventions, the need for organizational changes, immature digitalization, and suboptimal services evaluation as main explanatory factors of the observed efficacy-effectiveness gap. Additionally, a program for prevention of unplanned hospitalizations, to be evaluated during 2023-2025, was generated.

Conclusions

A digitally enabled adaptive case management approach to foster collaborative work, as well as organizational re-engineering, are endorsed for value-based prevention of unplanned hospitalizations.
Perspectives of professional experts in relation to the development of community-based exercise for young adults with schizophrenia – A qualitative study
Authors: Andersen MF , Roed K , Riis A , Rafn BS , Ebdrup BH , Midtgaard J
Published: August 2023

Background

Physical activity is a key modifiable factor in protecting physical and mental health in people with severe mental illness including schizophrenia. Therefore, early promotion of physical activity is recommended and programmes supporting long-term maintenance of physically active behaviour are warranted. This study aimed to explore the perspectives of professional experts in relation to the development of a sustainable community-based exercise programme tailored to young adults with schizophrenia and intended to promote change and adoption of physical activity.

Methods

We conducted nine semi-structured interviews with 11 clinical and professional experts. Qualitative content analysis, as described by Graneheim and Lundman, was applied to analyse data.

Results

We identified four categories: (1) living a physical active life with schizophrenia, (2) exercise as promotor of personal recovery, (3) prescribing safe and relevant exercise, and (4) instructors’ qualifications and formation.

Conclusions

When developing sustainable community-based exercise programmes tailored to young adults with schizophrenia, developers should ensure instructors’ qualifications and provide an exercise protocol. In addition, developers should consider providing an inclusive and recovery-oriented exercise environment.

Key messages

What is already known on this topic

Physical activity is a key modifiable factor in protecting physical and mental health in people with severe mental illness, including schizophrenia.

Sustainable community-based programmes to support adoption of physical activity for young adults with schizophrenia are warranted.

What this study adds

Developers of community-based exercise for young adults with schizophrenia must ensure a strategy for identifying and training exercise instructors and the provision of a protocol for delivering safe and clinically relevant exercise.

Community-based exercise may have the potential to promote personal recovery and thus considerations regarding the balance between overcoming potential barriers towards participation while promoting a non-clinical exercise environment are provided.

How this study might affect research, practice or policy

These findings could support and inform the development of community-based programmes promoting physical activity for people with schizophrenia and may be adaptable or inspirable to other psychiatric populations in other geographical settings.
PanCanAID – Pancreas Cancer Artificial Intelligence Driven Diagnosis in CT Scan Imaging: A Protocol for a Multicentric Ambispective Diagnostic Study
Authors: Safavi-Naini Seyed Amir Ahmad , Behnamnia Armin , Khorasanizadeh Faezeh , Soroush Ali , Zamani Farhad , Salahshour Faeze , Sadeghi Amir , Mirtajaddini Seyedmahdi , Zandi Ashkan , Shojaeian Fatemeh , Saeedi Maryam , Ehasni Azade , Chavoshi Khamneh Abdolhamid , Mohsenifar Zhaleh , Azmoudeh Ardalan Farid , Firouznia Kavous , Shahrokh Shabnam , Raoufi Masoomeh , Dehghan Pooneh , Ketabi Moghadam Pardis , Mansour-Ghanaei Alireza , Mellatdoust Parinaz , Malekpour Habib , Rasekhi Alireza , Mansour-Ghanaei Fariborz , Sohrabi Masoudreza , Zarei Fariba , Radmard Amir Reza , Ghanaati Hossein , Assadzadeh Aghdaei Hamid , Zali Mohammad Reza , Rabiee Hamid R.
Published: August 2023

Introduction

Pancreatic cancer is thought to have an extremely dismal prognosis. Most cancer-related deaths occur from metastasis rather than the primary tumor, although individuals with tumors smaller than 1 cm in diameter have more than 80% 5-year survival. Thus, the current protocol introduces PanCanAID project which intends to develop several computer-aided-diagnosis (CAD) systems to enhance pancreatic cancer diagnosis and management using CT scan imaging.

Methods and analysis

Patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) or pancreatic neuroendocrine tumor (PNET) will be included as pancreatic cancer cases. The controls will be patients without CT evidence of abdominal malignancy. A data bank of contrast-enhanced abdominopelvic CT scans, survival data, and demographics will be collected from ten medical centers in four provinces. Endosonography images and clinical data, if available, will be added to the data bank. Annotation and manual segmentation will be handled by radiologists and confirmed by a second expert radiologist in abdominal imaging. PanCanAID intelligent system is designed to (1) detect abdominopelvic CT scan phase, (2) segment pancreas organ, (3) diagnose pancreatic cancer and its subtype in arterial phase CT scan, (4) diagnose pancreatic cancer and its subtype in non-contrast CT scan, (5) carry out prognosis (TNM stage and survival) based on arterial phase CT scan, (6) and estimate tumor resectability. A domain adaptation step will be handled to use online data and provide pancreas organ segmentation to reduce the segmentation time. After data collection, a state-of-the-art deep learning algorithm will be developed for each task and benchmarked against rival models.

Conclusion

PanCanAID is a large-scale, multidisciplinary AI project to assist clinicians in diagnosing and managing pancreas cancer. Here, we present the PanCanAID protocol to assure the quality and replicability of our models. In our experience, the effort to prepare a detailed protocol facilitates a positive interdisciplinary culture and the preemptive identification of errors before they occur.
What should be included in an educational programme for non-health professional exercise instructors in charge of community-based exercise targeting young adults in antipsychotic treatment – A focus group study of stakeholder perspectives
Authors: Andersen MF , Roed K , Sørensen V , Riis A , Rafn BS , Ebdrup BH , Midtgaard J
Published: August 2023

Background

Exercise plays a crucial role in addressing the increased cardiometabolic morbidity and premature mortality in people with schizophrenia. When delivered in community-based settings, exercise may also reduce loneliness, while promoting overall physical active behaviours. Skilled instructors are essential to deliver effective community-based exercise; however, knowledge about their roles and required training is lacking. We investigated stakeholders’ perspectives on components needed for an educational programme for non-health professional exercise instructors delivering community-based exercise targeting young adults in antipsychotic treatment.

Methods

We conducted six focus groups comprising a total of 30 individuals representing five different stakeholder groups, namely clinical staff within mental health, physiotherapists, exercise instructors, young adults in antipsychotic treatment, and relatives to young adults in antipsychotic treatment. Data were analysed using qualitative content analysis, as described by Graneheim and Lundman.

Results

The analysis identified three categories: (i)acknowledging mental illness, (ii)applying a resource-oriented approach, and (iii)promoting exercise as a shared activity, and one overarching theme:instructors as guardians of an inclusive culture.

Conclusions

An educational programme for exercise instructors delivering community-based exercise to young adults in antipsychotic treatment should focus on securing an inclusive culture that embraces an anti-stigmatising approach. Results of the current study informed the development of an educational programme consisting of an instructor manual, a one-day educational programme for instructors, and a continuous exchange of experiences between instructors.
Influence of Prior SARS-CoV-2 Infection on COVID-19 Severity: Evidence from the National COVID Cohort Collaborative
Authors: Hendrix Nathaniel , Sidky Hythem , Sahner David K. ,   The N3C Consortium
Published: August 2023

Background

A large share of SARS-CoV-2 infections now occur among previously infected individuals. In this study, we sought to determine whether prior infection modifies disease severity relative to no prior infection.

Methods

We used data from first and second COVID-19 episodes in the National COVID Cohort Collaborative, a nationwide collection of de-identified electronic health records. We used nested logistic regressions of monthly cohorts weighted on the inverse probability of prior infection to assess risk of hospitalization, death, and increased severity in the first versus second infection cohorts.

Results

We included a total of 2,058,274 individuals in the analysis, 147,592 of whom had two recorded infections. The impact of prior infection differed meaningfully between months. Prior infection was largely protective prior to March 2022, with odds ratios (ORs) as low as 0.66 (95% confidence interval: 0.51 to 0.86) in November 2021 for hospitalization. and as low as 0.23 (0.06 to 0.86) in June 2021 for death. However, prior infection was associated with an increased risk of hospitalization and death, mostly after March 2022 when the ORs were as high as 1.87 (1.26 to 2.80) and 2.99 (1.65 to 5.41) in April 2022, respectively. The overall OR for more severe disease was 1.06 (1.03 to 1.10) among previously infected individuals.

Conclusion

In the pandemic’s first two years, previously infected patients generally had less severe disease than people without prior infection. During the Omicron era, however, previously infected patients had the same or worse severity of disease as patients without prior infection.
BAC Transgenic Expression of Human TREM2-R47H Remodels Amyloid Plaques but Unable to Reprogram Plaque-associated Microglial Reactivity in 5xFAD Mice
Authors: Lee C.Y. Daniel , De La Rocha Amberlene J. , Inouye Kellie , Langfelder Peter , Daggett Anthony , Gu Xiaofeng , Jiang Lu-Lin , Pamonag Zoe , Vaca Raymond G. , Richman Jeffrey , Kawaguchi Riki , Gao Fuying , Xu Huaxi , Yang X. William
Published: August 2023

Background

Genetic study of late-onset Alzheimer’s disease (AD) reveals that a rare Arginine-to-Histamine mutation at amino acid residue 47 (R47H) in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) results in increased disease risk. TREM2 plays critical roles in regulating microglial response to amyloid plaques in AD, leading to their clustering and activation surrounding the plaques. We previously showed that increasing humanTREM2gene dosage exerts neuroprotective effects against AD-related deficits in amyloid depositing mouse models of AD. However, thein vivoeffects of the R47H mutation on human TREM2-mediated microglial reprogramming and neuroprotection remains poorly understood.

Method

Here we created a BAC transgenic mouse model expressing human TREM2 with the R47H mutation in its cognate genomic context (BAC-TREM2-R47H). Importantly, the BAC used in this study was engineered to delete critical exons of other TREM-like genes on the BAC to prevent confounding effects of overexpressing multiple TREM-like genes. We crossed BAC-TREM2- R47H mice with 5xFAD [1], an amyloid depositing mouse model of AD, to evaluate amyloid pathologies and microglial phenotypes, transcriptomics andin situexpression of keyTREM2-dosage dependent genes. We also compared the key findings in 5xFAD/BAC-TREM2-R47H to those observed in 5xFAD/BAC-TREM2 mice.

Result

Both BAC-TREM2 and BAC-TREM2-R47H showed proper expression of three splicing isoforms ofTREM2that are normally found in human. In 5xFAD background, elevated TREM2-R47H gene dosages significantly reduced the plaque burden, especially the filamentous type. The results were consistent with enhanced phagocytosis and altered NLRP3 inflammasome activation in BAC- TREM2-R47H microglia in vitro. However, unlike TREM2 overexpression, elevated TREM2- R47H in 5xFAD failed to ameliorate cognitive and transcriptomic deficits.In situanalysis of keyTREM2-dosage dependent genes and microglial morphology uncovered that TREM2-R47H showed a loss-of-function phenotype in reprogramming of plaque-associated microglial reactivity and gene expression in 5xFAD.

Conclusion

Our study demonstrated that the AD-risk variant has a previously unknown, mixture of partial and full loss of TREM2 functions in modulating microglial response in AD mouse brains. Together, our new BAC-TREM2-R47H model and prior BAC-TREM2 mice are invaluable resource to facilitate the therapeutic discovery that target human TREM2 and its R47H variant to ameliorate AD and other neurodegenerative disorders.
A Multi-Centre, Tolerability Study of a Cannabidiol-enriched Cannabis Herbal Extract for Chronic Headaches in Adolescents: the CAN-CHA Protocol
Authors: Chhabra Manik , Lewis Evan C. , Balshaw Robert , Stewart Breanne , Zaslawski Zina , Lowthian Trinity , Alidina Zahra , Chesick-Gordis Melila , Xie Wenli , Drögemöller Britt I. , Wright Galen E.B. , Birnie Kathryn A , Boerner Katelynn E , Tsang Vivian W. L. , Irwin Samantha Lee , Pohl Daniela , Weil Alexander G , Sell Erick , Penz Erika , MacKay Amy Robson- , Mbabaali Sophia , Blackman Stephanie , Gordon Shanlea , Alcorn Jane , Huntsman Richard J. , Oberlander Tim F , Finley G Allen , Kelly Lauren E
Published: August 2023

Introduction

Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents.

Methods and analysis

Youth, parents and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies, will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2-0.4 mg/kg of CBD per day escalating monthly up to 0.8-1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE.

Discussion

This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials.

Trial registration:CAN-CHA trial is registered with ClinicalTrials.gov with a number of registerNCT05337033.
Detecting co-selection through excess linkage disequilibrium in bacterial genomes
Authors: Mallawaarachchi Sudaraka , Tonkin-Hill Gerry , Pöntinen Anna K. , Calland Jessica K. , Gladstone Rebecca A. , Arredondo-Alonso Sergio , MacAlasdair Neil , Thorpe Harry A. , Top Janetta , Sheppard Samuel K. , Balding David , Croucher Nicholas J. , Corander Jukka
Published: August 2023

Population genomics has revolutionised our ability to study bacterial evolution by enabling data-driven discovery of the genetic architecture of trait variation. Genome-wide association studies (GWAS) have more recently become accompanied by genome-wide epistasis and co-selection (GWES) analysis, which offers a phenotype-free approach to generating hypotheses about selective processes that simultaneously impact multiple loci across the genome. However, existing GWES methods only consider associations between distant pairs of loci within the genome due to the strong impact of linkage-disequilibrium (LD) over short distances. Based on the general functional organisation of genomes it is nevertheless expected that the majority of co-selection and epistasis will act within relatively short genomic proximity, on co-variation occurring within genes and their promoter regions, and within operons. Here we introduce LDWeaver, which enables an exhaustive GWES across both short- and long-range LD, to disentangle likely neutral co-variation from selection. We demonstrate the ability of LDWeaver to efficiently generate hypotheses about co-selection using large genomic surveys of multiple major human bacterial pathogen species and validate several findings using functional annotation and phenotypic measurements. Our approach will facilitate the study of bacterial evolution in the light of rapidly expanding population genomic data.
Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates
Authors: Chocarro Julia , Rico Alberto J. , Ariznabarreta Goiaz , Roda Elvira , Honrubia Adriana , Collantes María , Peñuelas Iván , Vázquez Alfonso , Rodríguez-Pérez Ana I. , Labandeira-García José L. , Vila Miquel , Lanciego José L.
Published: August 2023

Although neuromelanin (NMel) is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta (SNpc), its potential role in the pathogenesis of Parkinson’s disease (PD) has often been neglected since most commonly used laboratory animals lack NMel. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent NMel accumulation within SNpc dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, NMel accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of NMel-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous alpha-synuclein is triggered by NMel accumulation, therefore any therapeutic approach intended to decrease NMel levels may provide appealing choices for the successful implementation of novel PD therapeutics.
PoxiPred: An artificial intelligence-based method for the prediction of potential antigens and epitopes to accelerate vaccine development efforts against poxviruses
Authors: Martinez Gustavo Sganzerla , Dutt Mansi , Kumar Anuj , Kelvin David J.
Published: August 2023

Motivation

Poxviridaeis a family of large, complex, enveloped, and double-stranded DNA viruses. Members of this family are ubiquitous and well known to cause contagious diseases in humans and other types of animals as well. Despite significant progress in Artificial intelligence (AI) based methods, limited methods are available to predict the epitopes. In this study, we have proposed a unique method to predict the potential antigens and T-cell epitopes for multiple poxviruses.

Results

With PoxiPred, we developed an AI-based tool that was trained and tested with antigens and epitopes ofPoxviruses. Our tool was able to locate 1,675 antigen proteins from 25 distinctpoxviruses. From these antigenic proteins, PoxiPred also located 6,579 T-cell epitopes. PoxiPred is able to, on a single run, identify antigens and T-cell epitopes for poxviruses with one single input, i.e., the proteome file of any poxvirus.

Availability

The code that implements PoxiPred and the predicted antigens/T-cell epitopes is publicly available athttps://github.com/gustavsganzerla/poxipred.
Measuring phase-amplitude coupling opposition in neurophysiological signals with the Mean Opposition Vector Index (MOVI)
Authors: Saint-Amour di Chanaz Ludovico , Pérez-Bellido Alexis , Fuentemilla Lluís
Published: August 2023

Background

The phase–amplitude coupling (PAC) opposition between distinct neural oscillations is critical to understanding brain functions. Available methods to assess phase-preference differences between conditions rely on density of occurrences. Other methods like the Kullback-Leibler Divergence (DKL) assess the distance between two conditions by transforming neurophysiological data into probabilistic distributions of phase-preference and assessing the distance between them. However, these methods have limitations such as susceptibility to noise and bias.

New Method

We propose the “Mean Opposition Vector Index” (MOVI), a parameter-free, data-driven algorithm for unbiased estimation of PAC opposition. MOVI establishes a unified framework that integrates the strength of PAC to account for reliable unimodal differences in phase-specific amplitude coupling between neurophysiological datasets.

Results

We found that MOVI accurately detected phase opposition, was resistant to noise and gave consistent results with low or asymmetrical number of trials, therefore in conditions more similar to experimental studies.

Comparison with existing methods

MOVI outperformed Jensen-Shannon Divergence (JSD), an adaptation of the DKL, in terms of sensitivity, specificity, and accuracy to detect phase opposition.

Conclusions

MOVI provides a novel and useful approach to study of phase-preference opposition in neurophysiological datasets.
Genome and transcriptome mining revealed evolutionary insights and tissue-specific expression patterns of Cytochrome P450 superfamily inAquilaria sinensis
Authors: Das Ankur , Begum Khaleda , Ahmed Raja , Akhtar Suraiya , Banu Sofia
Published: August 2023

The Cytochrome P450 (CYPs) enzyme superfamily has evolved and expanded in plants to play a significant role in the biosynthesis of valuable secondary metabolites. InAquilariaplant, the process of wounding and fungal infection results in the accumulation of distinct aromatic metabolites which contribute to the formation of resinous agarwood. The members of CYPs in plants genomes have diversified to catalyze a wide array of fragrant metabolites. Therefore, this study aimed to identify and provide insights into the evolution and expansion of the CYP superfamily members inAquilaria sinensisand elucidate their tissue-specific functional role through mapping and expression analyses. In total, 179 AsCYPs were identified and subsequently classified into 8 clans and 42 families which were found to be dispersed in the 8 chromosomes. Duplication analysis highlights slow segmental events as a major force, coupled with negative selection pressure, behind the expansion of theAsCYPs. We observed their participation in the biosynthesis of various secondary metabolites, particularly sesquiterpenoids. Expression analysis showed variation in the expression pattern of the genes in different tissues, revealing that the diversification of the AsCYP superfamily occurred to carry out tissue-specific functional role. Additionally, molecular docking of a sesquiterpene oxidase which is specifically expressed in wounded wood, indicated its potential to generate sesquiterpenoids derivatives in agarwood. This study sheds light on the evolution and expansion of theAsCYPsin the genome ofA. sinensisand highlights their crucial role in the biosynthesis of various secondary metabolites found in different parts of the plant. Further functional exploration may pave the way for advancements in the field ofAquilaria-based fragrance development and natural product synthesis.
Decoding Glycomics: Differential Expression Reimagined
Authors: Lundstrøm Jon , Urban James , Bojar Daniel
Published: August 2023

Glycomics, the comprehensive study of all glycan structures in a sample, is a rapidly expanding field with substantial relevance for understanding physiology and disease mechanisms. However, the complexity of glycan structures and glycomics data interpretation present significant challenges, especially when it comes to differential expression analysis. Here, we present a novel computational framework for differential glycomics expression analysis. Our methodology encompasses specialized and domain-informed methods for data normalization and imputation, glycan motif extraction and quantification, differential expression analysis, motif enrichment analysis, time series analysis, and meta-analytic capabilities, allowing for synthesizing results across multiple studies. All methods are integrated into our open-source glycowork package, facilitating performant workflows and user-friendly access. We demonstrate these methods using dedicated simulations and various glycomics datasets. Our rigorous approach allows for more robust, reliable, and comprehensive differential expression analyses in glycomics, contributing to the advancement of glycomics research and its translation to clinical and diagnostic applications.
Transitions in sex determination mechanisms through parental antagonism
Authors: Schenkel Martijn A.
Published: August 2023

Parental antagonism (PA) occurs when the fitness effects of a gene depend on the parent from which it is inherited. Such genes may become enriched on sex chromosomes, due to their biased inheritance patterns. Although various sex determination (SD) genes exhibit parent-of-origin effects themselves, and between-parent conflict over offspring sex may affect SD, PA itself has not been considered as a driver of SD transitions. Here, I present a model to investigate the scope for transitions in SD mechanisms through PA. My model assumes an ancestral SD locus linked to a PA gene, as well as an autosomal PA gene in whose vicinity a novel SD gene arises. Transitions between functionally-homologous genes are found to depend on the fitness effects of both PA genes and their linkage to nearby SD genes. Transitions between male and female heterogamety by the invasion of a dominant SD gene are however nearly unconstrained. This also allows for back-and-forth dynamics where the ancestral SD and novel SD genes constantly evolve to be dominant over each other. These results further underline the malleability of SD mechanisms, and the need to consider parent-of-origin effects in driving transitions in SD, through proximate and/or ultimate means.
Low prevalence of HLA-G antibodies in lung transplant patients detected by MAIPA adapted protocol
Authors: Pedini Pascal , Hubert Lucas , Carlini Federico , Baudey Jean Baptiste , Tous Audrey , Jordier Francois , Basire Agnès , Bagnis Claude , Reynaud-Gaubert Martine , Coiffard Benjamin , Chiaroni Jacques , Silvy Monique , Picard Christophe
Published: August 2023

Lung transplantation is often complicated by acute and/or chronic rejection leading to graft function loss. In addition to the HLA donor-specific antibodies (HLA-DSA), a few autoantibodies are correlated with the occurrence of these complications. Recently, antibodies directed against non-classical HLA molecules, HLA-G, -E, and -F have been detected in autoimmune diseases, like systemic lupus erythematosus. Non-classical HLA molecules are crucial in the immunological acceptance of the lung graft, and some of their isoforms, like HLA-G*01:04 and -G*01:06, are associated with a negative clinical outcome. The aim of this study is to determine the frequency of detection of HLA-G antibodies in lung transplant recipients (LTRs) and their impact on the occurrence of clinical complications. After incubating the cell lines SPI-801, with and without 3 different HLA-G isoforms expression, with sera from 90 healthy blood donors and 35 LTRs (before and after transplantation), HLA-G reactivity was revealed by using reagents from commercial monoclonal antibody immobilization of platelet antigen assay (MAIPA ApDIA®). Only one serum from one blood donor had specific reactivity against the HLA-G transduced lines. Non-specific reactivity in many sera from LTRs was observed with transduced and wild type cell lines, which may suggest recognition of an autoantigen expressed by the SPI-801 cell line. In conclusion, this study allowed the development of a specific detection tool for non-denatured HLA-G antibodies. These antibodies seem uncommon, both in healthy subjects and in complicated LTRs. This study should be extended to patients suffering from autoimmune diseases as well as kidney and heart transplant recipients.
Induction of antiviral Interferon-Stimulated Genes (ISGs) by neuronal STING promotes the resolution of pain
Authors: Defaye Manon , Bradaia Amyaouch , Abdullah Nasser S. , Agosti Francina , Iftinca Mircea , Soubeyre Vanessa , Svendsen Kristofer , Gill Gurveer , Cuménal Mélissa , Gheziel Nadine , Martin Jérémy , Poulen Gaetan , Lonjon Nicolas , Vachiery-Lahaye Florence , Bauchet Luc , Basso Lilian , Bourinet Emmanuel , Chiu Isaac M. , Altier Christophe
Published: August 2023

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein Stimulator of Interferon Genes (STING) in DRG nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an interferon-beta (IFNβ) response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes (IRGs) and KChIP1 downstream of STING, in the resolution of inflammatory pain.
Leach’s Storm-Petrels fledge on the full moon and throughout the lunar cycle
Authors: Collins Sydney M. , Hedd April , Montevecchi William A. , Burt Tori , Wilson David R. , Fifield David A.
Published: August 2023

Many seabirds are attracted to anthropogenic light, and the risk is greater for recent fledglings. Lunar phase predicts the probability of stranding, but it remains uncertain whether lunar phase is associated with when young seabirds fledge. Fledging behaviour of nocturnal, burrowing seabirds can be difficult to monitor using traditional methods but can provide insight into environmental factors that influence the risk of stranding. We used passive integrated transponder tags to monitor the fledging dates and times of Leach’s Storm-Petrel chicks from four breeding seasons at a major colony in Newfoundland and Labrador, Canada. We also assessed whether lunar phase associated with fledging date. The median fledge time was 2.4 h after sunset (1.4 - 12.4 h). The median fledge date was 10 October, and fledging dates ranged from 13 September to 13 November. Most importantly, Leach’s Storm-Petrels chicks did fledge during the full moon. These results provide insight into why storm-petrels are less attracted to anthropogenic light during high levels of natural illumination and can be used to inform periods of higher risk for stranding, thus allowing better concentration of conservation efforts.
PDBe CCDUtils: an RDKit-based toolkit for handling and analysing small molecules in the Protein Data Bank
Authors: Kunnakkattu Ibrahim Roshan , Choudhary Preeti , Pravda Lukas , Nadzirin Nurul , Smart Oliver S. , Yuan Qi , Anyango Stephen , Nair Sreenath , Varadi Mihaly , Velankar Sameer
Published: August 2023

While the Protein Data Bank (PDB) contains a wealth of structural information on ligands bound to macromolecules, their analysis can be challenging due to the large amount and diversity of data. Here, we present PDBe CCDUtils, a versatile toolkit for processing and analysing small molecules from the PDB in PDBx/mmCIF format.

PDBe CCDUtils provides streamlined access to all the metadata for small molecules in the PDB and offers a set of convenient methods to compute various properties using RDKit, such as 2D depictions, 3D conformers, physicochemical properties, scaffolds, common fragments and cross-references to small molecule databases using UniChem. The toolkit also provides methods for identifying all the covalently attached chemical components in a macromolecular structure and calculating similarity among small molecules. By providing a broad range of functionality, PDBe CCDUtils caters to the needs of researchers in cheminformatics, structural biology, bioinformatics and computational chemistry.
A chromosome-level genome for the nudibranch gastropodBerghia stephanieaehelps parse clade-specific gene expression in novel and conserved phenotypes
Authors: Goodheart Jessica A. , Rio Robin A. , Taraporevala Neville F. , Fiorenza Rose A. , Barnes Seth R. , Morrill Kevin , Jacob Mark Allan C. , Whitesel Carl , Masterson Park , Batzel Grant O. , Johnston Hereroa T. , Ramirez M. Desmond , Katz Paul S. , Lyons Deirdre C.
Published: August 2023

How novel phenotypes originate from conserved genes, processes, and tissues remains a major question in biology. Research that sets out to answer this question often focuses on the conserved genes and processes involved, an approach that explicitly excludes the impact of genetic elements that may be classified as clade-specific, even though many of these genes are known to be important for many novel, or clade-restricted, phenotypes. This is especially true for understudied phyla such as mollusks, where limited genomic and functional biology resources for members of this phylum has long hindered assessments of genetic homology and function. To address this gap, we constructed a chromosome-level genome for the gastropodBerghia stephanieae(Valdés, 2005) to investigate the expression of clade-specific genes across both novel and conserved tissue types in this species. The final assembled and filteredBerghiagenome is comparable to other high quality mollusk genomes in terms of size (1.05 Gb) and number of predicted genes (24,960 genes), and is highly contiguous. The proportion of upregulated, clade-specific genes varied across tissues, but with no clear trend between the proportion of clade-specific genes and the novelty of the tissue. However, more complex tissue like the brain had the highest total number of upregulated, clade-specific genes, though the ratio of upregulated clade-specific genes to the total number of upregulated genes was low. Our results, when combined with previous research on the impact of novel genes on phenotypic evolution, highlight the fact that the complexity of the novel tissue or behavior, the type of novelty, and the developmental timing of evolutionary modifications will all influence how novel and conserved genes interact to generate diversity.
Limitations of fluorescent timer protein maturation kinetics to isolate transcriptionally synchronized cortically differentiating human pluripotent stem cells
Authors: Peter Manuel , Shipman Seth , Macklis Jeffrey D.
Published: August 2023

Differentiation of human pluripotent stem cells (hPSC) into distinct neuronal populations holds substantial potential for disease modelingin vitro, toward both elucidation of pathobiological mechanisms and screening of potential therapeutic agents. For successful differentiation of hPSCs into subtype-specific neurons usingin vitroprotocols, detailed understanding of the transcriptional networks and their dynamic programs regulating endogenous cell fate decisions is critical. One major roadblock is the heterochronic nature of neurodevelopment, during which distinct cells and cell types in the brain and duringin vitrodifferentiation mature and acquire their fates in an unsynchronized manner, hindering pooled transcriptional comparisons. One potential approach is to “translate” chronologic time into linear developmental and maturational time. Attempts to partially achieve this using simple binary promotor-driven fluorescent proteins (FPs) to pool similar cells have not been able to achieve this goal, due to asynchrony of promotor onset in individual cells. Toward solving this, we generated and tested a range of knock-in hPSC lines that express five distinct dual FP timer systems or single time-resolved fluorescent timer (FT) molecules, either in 293T cells or in human hPSCs driving expression from the endogenous paired box 6 (PAX6) promoter of cerebral cortex progenitors. While each of these dual FP or FT systems faithfully reported chronologic time when expressed from a strong inducible promoter in 293T cells, none of the tested FP/FT constructs followed the same fluorescence kinetics in developing human neural progenitor cells, and were unsuccessful in identification and isolation of distinct, developmentally synchronized cortical progenitor populations based on ratiometric fluorescence. This work highlights unique and often surprising expression kinetics and regulation in specific cell types differentiating from hPSCs.
Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability
Authors: Drexler Richard , Khatri Robin , Sauvigny Thomas , Mohme Malte , Maire Cecile L. , Ryba Alice , Zghaibeh Yahya , Dührsen Lasse , Salviano-Silva Amanda , Lamszus Katrin , Westphal Manfred , Gempt Jens , Wefers Annika K. , Neumann Julia , Bode Helena , Hausmann Fabian , Huber Tobias B. , Bonn Stefan , Jütten Kerstin , Delev Daniel , Weber Katharina J. , Harter Patrick N. , Onken Julia , Vajkoczy Peter , Capper David , Wiestler Benedikt , Weller Michael , Snijder Berend , Buck Alicia , Weiss Tobias , Keough Michael B. , Ni Lijun , Monje Michelle , Silverbush Dana , Hovestadt Volker , Suvà Mario L. , Krishna Saritha , Hervey-Jumper Shawn L. , Schüller Ulrich , Heiland Dieter H. , Hänzelmann Sonja , Ricklefs Franz L.
Published: August 2023

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients’ survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formationin vitroandin vivoand show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.