bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic diagnostic support for diagnosis of pulmonary fibrosis
Authors: Pal Ravi , Barney Anna , Sgalla Giacomo , Walsh Simon L. F. , Sverzellati Nicola , Fletcher Sophie , Cerri Stefania , Cannesson Maxime , Richeldi Luca
Published: August 2024

Patients with pulmonary fibrosis (PF) often experience long waits before getting a correct diagnosis, and this delay in reaching specialized care is associated with increased mortality, regardless of the severity of the disease. Early diagnosis and timely treatment of PF can potentially extend life expectancy and maintain a better quality of life. Crackles present in the recorded lung sounds may be crucial for the early diagnosis of PF. This paper describes an automated system for differentiating lung sounds related to PF from other pathological lung conditions using the average number of crackles per breath cycle (NOC/BC). The system is divided into four main parts: (1) preprocessing, (2) separation of crackles from normal breath sounds, (3) crackle verification and counting, and (4) estimating NOC/BC. The system was tested on a dataset consisting of 48 (24 fibrotic and 24 non-fibrotic) subjects and the results were compared with an assessment by two expert respiratory physicians. The set of HRCT images, reviewed by two expert radiologists for the presence or absence of pulmonary fibrosis, was used as the ground truth for evaluating the PF and non-PF classification performance of the system. The overall performance of the automatic classifier based on receiver operating curve-derived cut-off value for average NOC/BC of 18.65 (AUC=0.845, 95 % CI 0.739-0.952, p<0.001; sensitivity=91.7 %; specificity=59.3 %) compares favorably with the averaged performance of the physicians (sensitivity=83.3 %; specificity=56.25 %). Although radiological assessment should remain the gold standard for diagnosis of fibrotic interstitial lung disease, the automatic classification system has strong potential for diagnostic support, especially in assisting general practitioners in the auscultatory assessment of lung sounds to prompt further diagnostic work up of patients with suspect of interstitial lung disease.
Association of Right Heart Structure and Function with Cognition and Brain MRI Measures in the Multi-Ethnic Study of Atherosclerosis
Authors: Kamel Hooman , Heckbert Susan R. , Hughes Timothy M. , Schaich Christopher L. , Lockhart Samuel N. , Jimenez Marcia Pescador , Longstreth W.T. , Austin Thomas R. , Bryan R. Nick , Erus Guray , Srinivasan Dhivya , Nasrallah Ilya M. , Iadecola Costantino , Shah Sanjiv J.
Published: August 2024

Background

Recent studies in selected populations suggest that impaired venous return may affect brain health. We examined associations of right heart structure and function with cognition and MRI markers of brain health in a community-based cohort.

Methods

The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal cohort study of individuals 45 to 84 years of age who were free of clinically apparent cerebrovascular or cardiovascular disease at baseline in 2000-2002. From echocardiograms performed at Exam 6 during 2016-2018, we measured: right atrial pressure and end-systolic area; pulmonary artery systolic pressure; and right ventricular free wall strain, fractional area change, and end-diastolic area. Outcome variables were the Cognitive Assessment Screening Instrument, Digit Span, and Digit Symbol Coding tests and MRI-determined volumes of total white matter, total gray matter, and white matter hyperintensity -- as well as fractional anisotropy. Cognitive measures were obtained at Exam 6, and MRI measures, within a median of 18 months of echocardiograms. Covariates were demographics,APOE-ε4 allele status, vascular risk factors, and echocardiographic markers of left heart function. We used general linear models to examine associations between each exposure and outcome variable.

Results

In 1,913 participants with cognitive testing and echocardiography data, we found no associations between any of the echocardiographic exposure variables and worse scores on any of the cognitive tests. Similarly, in 1,035 participants with echocardiography and MRI data, we found no associations between any of the echocardiographic exposure variables and any of the MRI variables.

Discussion

We found no associations in this cohort of right heart structure and function with cognition or brain MRI measures. These findings do not support the hypothesis that right heart dysfunction impedes venous return sufficiently to adversely affect brain health among people without clinically apparent heart failure.
A novel fusion method of 3D MRI and test results through deep learning for the early detection of Alzheimer’s disease
Authors: Atalar Arman , Adar Nihat , Okyay Savaş
Published: August 2024

Alzheimer’s disease (AD) is a prevalent form of dementia that impacts brain cells. Although its likelihood increases with age, there is no transitional period between its stages. In order to enhance diagnostic precision, physicians rely on clinical judgments derived from interpreting health data, considering demographics, clinical history, and laboratory results to detect AD at an early stage. While patient cognitive tests and demographic information are primarily presented in text, brain scan images are presented in graphic formats. Researchers typically use different classifiers for each data format and then merge the classifier outcomes to maximize classification accuracy and utilize all patient-related data for the final decision. However, this approach leads to low performance, diminishing predictive abilities and model effectiveness.

We propose an innovative approach that combines diverse textual health records (HR) with three-dimensional structural magnetic resonance imaging (3D sMRI) to achieve a similar objective in computer-aided diagnosis, utilizing a novel deep learning technique. Health records, encompassing demographic features like age, gender, apolipoprotein gene, and mini-mental state examination score, are fused with 3D sMRI, enabling a graphic-based deep learning strategy for early AD detection. The fusion of data is accomplished by representing textual information as graphic pipes and integrating them into 3D sMRI, a method referred to as the “pipe-laying” method.

Experimental results from over 4000 sMRI scans of 780 patients in the AD Neuroimaging Initiative (ADNI) dataset demonstrate that the pipe-laying method enhances recognition accuracy rates for Early and Late Mild Cognitive Impairment (MCI) patients, accurately classifying all AD patients. In a 4-class AD diagnosis scenario, accuracy improved from 86.87% when only 3D images were used to 90.00% when 3D sMRI and patient health records were included. Thus, the positive impact of combining 3D sMRI with HR on 4-class AD diagnosis was established.
Efficacy and safety of 10-day versus 14-day bismuth-containing quadruple therapy for H. pylori eradication: A systematic review and meta-analysis
Authors: Gohar Najam , Ejaz Zoya , Ahmed Faizan , Rafay Abdul , Humayun Abdullah , Nisar Momna , Mushtaq Ali , Ghouri Aanusha , Zafar Fatima , Khalid Hira , Afzal Sania , Khan Hammad , Cheema Huzaifa Ahmed , Shahzil Muhammad , Rashad Essam , Awan Rehmat Ullah , Jalal Prasun K
Published: August 2024

Background

Nearly half of the world population is infected byHelicobacter pylori (H. pylori).Bismuth-containing quadruple therapy (BQT) has shown favorable outcomes. This study compares 10-day and 14-day BQT regimens to evaluate their efficacy, safety, and compliance rates.

Methods

We searched electronic databases from their inception until May 2024 to retrieve all randomized controlled trials (RCTs) that compared 10-day and 14-day BQT regimens forH. pylorieradication. Meta-analysis was performed using Review Manager 5.4. Dichotomous outcomes were compared using risk ratio (RR).

Results

Seven RCTs and a total of 2,424 patients were included in the meta-analysis. There was no significant difference in the intention-to-treat eradication rate (RR 0.97; 95% CI 0.94, 1.01) and the per-protocol eradication rate (RR 0.96; 95% CI 0.93, 1.00) between the 10-day BQT and 14-day BQT groups. Commonly reported adverse events in both groups were epigastric pain and discomfort, nausea, and vomiting. There was no significant difference in the risk of adverse events between the two groups (RR 0.80; 95% CI 0.63, 1.02). There was no significant difference in the compliance rate between the two groups (RR 1.02; 95% CI 1.00, 1.04).

Conclusion

The eradication rates, risk of adverse events, and compliance rates were comparable between the two groups. Future research comparing similar drug doses with larger sample sizes and longer patient follow-ups can improve the quality of results.

Highlights

Our meta-analysis comprising 2424 patients showed that patients receiving 10-day bismuth-containing quadruple therapy had comparable eradication rates to those receiving 14-day bismuth-containing quadruple therapy forHelicobacter pylori.

Additionally, there was no significant difference between the two groups for compliance and risk of adverse events.

Antibiotic resistance was associated with lower eradication rates in both treatment groups.
Increased Risk of Alzheimer’s Disease Affected by Weight Changes but Not by Body Mass Index
Authors: Roh Jee Hoon , Jung Inha , Kim Hyun Jung
Published: August 2024

Background

Alzheimer’s disease (AD) is an intractable and multi-factorial neurodegenerative disorder. Given the globally rapid increase in obesity and its role in AD pathogenesis, understanding the impact of body weight, its changes, and the role of physical activity on AD development can provide important guidance for preventative strategies.

Methods

This population-based retrospective cohort study analyzed data from Korean national health and disability databases, including 3,741,424 individuals aged 30 to 80 years at baseline, who underwent health assessments between 2003 and 2006, followed by biennial check-ups over a decade. Exposures included BMI categories (underweight, normal, overweight, obese) and body weight changes (stable, acute increase, steady increase, weight cycling, acute decrease, steady decrease). Regular physical activity was defined as consistent weekly exercise over ten years. The primary outcome was AD incidence, identified by ICD-10 codes F00 or G30. Hazard ratios (HRs) were calculated using Cox proportional hazard models adjusted for multiple risk factors.

Results

Baseline BMI was not significantly associated with AD incidence after adjusting for confounders, except for underweight (adjusted HR [aHR], 1.10, 95% CI, 1.05-1.15). Weight changes were significantly linked to increased AD risk, particularly weight cycling (aHR, 1.37, 95% CI, 1.35-1.40), acute decrease (aHR, 1.78, 95% CI, 1.55-2.03), and steady decrease (aHR, 1.33, 95% CI, 1.30-1.35). Regular physical activity mitigated these risks, nullifying statistical significance.

Conclusion

Weight changes are significant risk factors for AD, and regular physical activity mitigates these risks. Public health strategies should focus on maintaining stable weight and promoting consistent physical activity.

Key messages

What is already known on this topic

Previous studies assessing the risk of Alzheimer’s disease (AD) in relation to body weight or body mass index (BMI) have shown inconsistent results, probably due to short periods of follow-up, limited assessment of AD risk factors, and lack of washout periods to exclude the potential reverse causation between weight changes and AD development.

What this study adds

In an 18-year cohort study with 3741424 adults in Korea, weight changes significantly impacted the risk of AD, while baseline BMI did not. Both increases and decreases in weight, as well as weight cycling, increased the risk of AD after controlling for AD risk factors. Regular physical activity, defined as at least one exercise per week over the 10-year period, mitigated these risks.

How this study might affect research, practice or policy

These findings suggest that maintaining stable body weight and engaging in regular physical activity may be crucial in reducing the risk of AD, emphasizing the need for public health strategies focusing on weight stability and consistent exercise rather than simple correction of body weight.
Analysis of Extraocular muscle volumes in idiopathic Hypertrophic Pachymeningitis patients
Authors: Kitkamolwat Suppakul , Soonthornpusit Supichaya , Eiamsamarng Akarawit , Rattanathamsakul Natthapon , Chirapapaisan Niphon , Ngamsombat Chanon
Published: August 2024

Background

Idiopathic hypertrophic pachymeningitis (HP) is a rare chronic inflammatory condition without an identifiable cause characterized by fibrous thickening of the dura mater, which can involve the extraocular muscles (EOM).

Objective

To evaluate volumetric changes of EOM in idiopathic HP patients compared with healthy controls (HC) and study the correlation with ocular motility disturbance.

Materials and methods

A retrospective study of 22 diagnosed idiopathic HP patients and 22 age-matched, sex-matched HC underwent a 3T MRI scan from January 1, 2017, to December 31, 2022. EOM was manually segmented from the T1W image using 3D Slicer software, and volume was calculated using FSL software. T-tests and Mann-Whitney U tests were used to compare EOM volumes between the idiopathic HP and control groups. Pearson’s correlation coefficient was then used to assess the correlation between ocular motility and EOM enlargement.

Results

In idiopathic HP patients, the average EOM volumes, including the medial rectus (MR), inferior rectus (IR), inferior oblique (IO), right lateral rectus (LR), right superior oblique (SO), and left superior rectus (SR) muscles, were significantly larger compared to those in HC, particularly in the left IR and both MR. However, there was no significant correlation between the enlargement of these 9 EOMs and the extraocular movement limitation.

Conclusion

In idiopathic HP patients, significantly larger EOM volumes were found compared to control subjects. This enlargement could be due to the diffuse infiltrative histopathology potentially involving microstructures in the EOM. Extraocular movement limitations may be related to cranial nerve involvement.
Low incidence of adverse events or construct failure of a novel high-strength No.2 round suture in rotator cuff repair: An IDEAL Stage 2a assessment retrospective cohort analysis
Authors: Moody Cooper , Scholes Corey , Fatima Manaal , Eng Kevin , Brown Graeme , Page Richard S
Published: August 2024

Background

Despite technical and material improvements in rotator cuff repair (RCR) clinical and radiological failure remains common. Following suture fixation, tension and footprint compression decrease from time zero. A novel suture (Dynacord, Depuy Synthes) has been designed to shorten when submerged in liquid to maintain tension and increase repair construct security.

Methods

A retrospective cohort analysis was performed on the PRULO (Patient Reported Outcomes in Upper Limb Surgery) registry for 12 months follow up after RCR using this suture regarding all cause failure, rates of common complications, Quick Disability of the Arm, Shoulder and Hand (QuickDASH), and Western Ontario Rotator Cuff Index (WORC). Summary statistics were generated for patient characteristics and patient-reported outcome measures (PROMs) analysed using multiple imputation and a linear model to assess changes over 12 months follow up.

Results

A cohort of 236 cases was included for analysis. Complication rates and functional improvements were comparable to literature on similar sutures. At 12 months follow up, all-cause failure occurred in 12% of cases, and mean scores for QuickDASH decreased by 37 and WORC increased by 44, both of which surpass the minimum clinically important difference. Our observed rates of complications are as follows: Infection 2.1%, stiffness/capsulitis 11% and retear 12%.

Conclusion

The novel suture demonstrated favourable safety and efficacy profiles, with outcomes comparable to those published for commonly used sutures. This study through an IDEAL 2a framework for surgical innovation highlights this suture as safe, effective in mitigating common failure mechanisms and having satisfactory outcomes in RCR.
Behaviourally-informed two-way text messaging to improve return to HIV care in South Africa: evidence from a randomised controlled trial
Authors: Njuguna Christine , Mistri Preethi , Long Lawrence , Chetty-Makkan Candice , Maughan-Brown Brendan , Buttenheim Alison , Schmucker Laura , Pascoe Sophie , Thirumurthy Harsha , O’Connor Cara , Mutasa Barry , Rees Kate
Published: August 2024

Introduction

One-way text messaging to re-engage people in HIV care has shown promise, but little is known about two-way messaging where the recipient is asked to respond. We evaluated a two-way text messaging intervention, informed by behavioural science, to increase re-engagement in care following missed antiretroviral therapy (ART) visits.

Methods

We conducted an individual-level randomised controlled trial between February and March 2023 in Capricorn District, South Africa. Adults aged ≥18 years who had missed an ART visit by >28 days were randomised to (1) a standard one-way text message, or (2) behaviourally informed two-way text messages. Two-way messages asked recipients to reply by selecting from a list of reasons for their missed visit. Those who responded received another text message tailored to their response and designed using behavioural economics principles (affect heuristic, availability heuristic, loss aversion, social norms, providing slack, expanding choice). The primary outcome was return to care within 45 days, analysed as 1) intention to treat, and 2) restricted to successful message delivery.

Results

3,695 participants were randomised: 1,845 to the one-way message group and 1,850 to the two-way message group. 27.9% (515/1845) of participants sent a one-way message and 27.2% (503/1850) sent a two-way message returned for an ART visit within 45 days (proportion difference:−0.7%, p-value: 0.622). In an analysis restricted to participants whose text message was delivered, 28.3% (310/1094) in the one-way message group compared to 28.3% (304/1076) in the two-way message group returned to care (proportion difference:−0.09%, p-value: 0.966). 19.5% (210/1076) responded to the two-way message. The two most commonly reported reasons for missed appointments were being out of town (41.0%) and still having medication (31.0%.). Among those who responded, 27.1% (95%CI: 21.3-33.7) returned for an ART visit. Clients ≥50 years were less likely to respond to the two-way text message, (AOR 0.4; 95%CI: 0.2-0.9)

Conclusions

Behaviourally informed two-way text messages did not improve return to care over one-way messages. However, they elicited reasons for disengagement, which could inform future outreach for missed visits. Additional research is needed on the mode, content and timing of two-way messages intended to increase return to care.

Clinical Trial Number

PACTR202202748760768 & DOH-27-042022-6703.
The LMSz method - an automatable scalable approach to constructing gene-specific growth charts in rare disorders
Authors: Low K.J. , Foreman J. , Hobson R.J. , Kwuo H. , Martinez-Cayuelas E. , Almoguera B. , Marin-Reina P. , Caraffi S.G. , Garavelli L. , Woods E. , Balasubramanian M. , Bayat A. , Ockeloen C.W. , Wright C.M. , Firth H.V. , Cole T.J.
Published: August 2024

Introduction

Children with monogenic neurodevelopmental disorders often grow abnormally. Gene-specific growth charts would be useful but require large samples to construct them using the conventional LMS method.

Methods

We transformed anthropometry to British 1990 reference z-scores for 328 UK and 264 international probands withANKRD11, ARID1B, ASXL3, DDX3X, KMT2AorSATB2-related disorders, and modelled mean and standard deviation (SD) of the z-scores as gene-specific linear age trends adjusted for sex. Back-transforming the mean ±2 SD lines provided gene-specific median, 2ndand 98thcentiles.

Results

The resulting z-score charts look plausible on several counts. OnlyKMT2Ashows a (rising) age trend in median height, while BMI and weight increase in several genes, possibly reflecting population trends. Apart fromSATB2andDDX3X,the gene-specific medians are all below the reference (range 0.1thcentile for heightKMT2Ato 36thcentile for BMIANKRD11). Median OFC shows no age trend, with medians ranging from 10th-30thcentile, andASXL3lowest, on the 3rdcentile. There are no sex differences in 19/24 cases.

Conclusions

Our LMSz method produces gene-specific growth charts for rare diseases, an essential clinical tool for paediatric care. We plan to automate it within the DECIPHER platform, enabling availability for all relevant genes.
Endogenous adenine is a potential driver of the cardiovascular-kidney-metabolic syndrome
Authors: Tamayo Ian , Lee Hak Joo , Aslam M. Imran , Liu Jian-Jun , Ragi Nagarjunachary , Karanam Varsha , Maity Soumya , Saliba Afaf , Treviño Esmeralda , Zheng Huili , Lim Su Chi , Lanzer Jan D. , Bjornstad Petter , Tuttle Katherine , Bedi Kenneth C. , Margulies Kenneth B. , Ramachandran Vasan , Abdel-Latif Ahmed , Saez-Rodriguez Julio , Iyengar Ravi , Bopassa Jean C. , Sharma Kumar
Published: August 2024

Mechanisms underlying the cardiovascular-kidney-metabolic (CKM) syndrome are unknown, although key small molecule metabolites may be involved. Bulk and spatial metabolomics identified adenine to be upregulated and specifically enriched in coronary blood vessels in hearts from patients with diabetes and left ventricular hypertrophy. Single nucleus gene expression studies revealed that endothelial methylthioadenosine phosphorylase (MTAP) was increased in human hearts with hypertrophic cardiomyopathy. The urine adenine/creatinine ratio in patients was predictive of incident heart failure with preserved ejection fraction. Heart adenine and MTAP gene expression was increased in a 2-hit mouse model of hypertrophic heart disease and in a model of diastolic dysfunction with diabetes. Inhibition of MTAP blocked adenine accumulation in the heart, restored heart dysfunction in mice with type 2 diabetes and prevented ischemic heart damage in a rat model of myocardial infarction. Mechanistically, adenine-induced impaired mitophagy was reversed by reduction of mTOR. These studies indicate that endogenous adenine is in a causal pathway for heart failure and ischemic heart disease in the context of CKM syndrome.
Deciphering ofGorilla gorilla gorillaImmunoglobulin Loci in Multiple Genome Assemblies and Enrichment of IMGT Resources
Authors: Debbagh Chahrazed , Folch Géraldine , Jabado-Michaloud Joumana , Giudicelli Véronique , Kossida Sofia
Published: August 2024

Through the analysis of immunoglobulin genes at the IGH, IGK, and IGL loci from fourGorilla gorilla gorillagenome assemblies, IMGT®provides an in-depth overview of these loci and their individual variations in a species closely related to humans. The similarity between gorilla and human IG gene organization allowed the assignment of gorilla IG gene names based on their human counterparts. This study revealed significant findings, including variability in the IGH locus, the presence of known and new copy number variations (CNVs), and the accurate estimation of IGHG genes. The IGK locus displayed remarkable homogeneity and lacked the gene duplication seen in humans, while the IGL locus showed a previously unconfirmed CNV in the J-C cluster. The curated data from these analyses, available on the IMGT website, enhance our understanding of gorilla immunogenetics and provide valuable insights into primate evolution.
Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus 1 CNS infection
Authors: Ding Xiangning , Lai Xin , Klæstrup Ida Hyllen , Jensen Sara R. N. , Nielsen Morten M , Thorsen Kasper , Romero-Ramos Marina , Luo Yonglun , Lin Lin , Reinert Line S , Paludan Søren R
Published: August 2024

Herpes Simplex Virus 1 (HSV-1) is a common human neurotropic virus with the majority of adults harboring latent-recurrent infections. In rare cases, HSV-1 infection can access the central nervous system through the neuronal route and develop into life-threatening encephalitis. Here, we used a mouse model for HSV-1 infection to describe the transcriptomic profile of the infected brain stem at the single-cell level and with temporal resolution. Among resident brain cells, microglia increased in proportion during the course of infection, while astrocytes, pericytes, and endothelial cell levels decrease. At the levels of peripheral immune cells, we found notably monocytes to strongly influx the infected brain. Large dynamic changes were found in the abundance of subpopulations of the different cell types following virus infection. For instance, we identify one subpopulation of microglia exhibiting very high type I interferon and chemokine expression early during infection. This population was also enriched for viral transcripts, suggesting localization at foci of infection, and orchestrating recruitment of other immune cells. In contrast, for the infiltrating monocytes, we identified a larger panel of unique subpopulations with antiviral and inflammatory phenotypes, and found not all of these being highly positive for viral transcripts, thus indicating monocyte activities beyond the infected brain areas. Finally, investigation of endothelial cell cross-talk with other cell types revealed that cytokines derived from microglia and monocyte, but also T cells, contribute to disturbance of the blood brain barrier. Our work thus reveals for the first time the complex nature of the cellular response in the virus-infected brain, which seeks to eliminate infection but can also prime for pathological changes.
Using lineage-specific patterns to understand convergence of enzymatic functions led to the identification of Moraceae-specific P450s involved in furanocoumarin biosynthesis
Authors: Bouillé Alexandre , Kumari Rashmi , Olry Alexandre , Charles Clément , Nelson David R , Larbat Romain , Thornton Janet , Villard Cloé , Hehn Alain
Published: August 2024

Specialized metabolites are molecules involved in plants interaction with their environment. Elucidating their biosynthetic pathways is a challenging but rewarding task, leading to societal applications and ecological insights. Furanocoumarins emerged multiple times in Angiosperms, raising the question of how different enzymes evolved into catalyzing identical reactions.

To identify enzymes producing lineage-specific metabolites, an evolutionary-based approach was developed and applied to furanocoumarin biosynthesis inFicus carica(Moraceae). This led to the characterization of CYP71B129-131a, three P450 enzymes whose evolution of the function was investigated using phylogenetics, structural comparisons and site-directed mutagenesis.

CYP71B129 and CYP71B130,131a were found to hydroxylate umbelliferone (coumarin) and xanthotoxin (furanocoumarin), respectively. Results suggest that CYP71Bs xanthotoxin hydroxylase activity results from duplications and functional divergence of umbelliferone hydroxylase genes. Structural comparisons highlighted an amino acid affecting CYP71Bs substrate specificity, which may play a key role in allowing xanthotoxin hydroxylation in several P450 subfamilies.

CYP71B130-131a characterization validates the proposed enzyme-discovery approach, which can be applied to different pathways and help to avoid the classic bottlenecks of specialized metabolism elucidation. The CYP71Bs also exemplify how furanocoumarin-biosynthetic enzymes can stem from coumarin-biosynthetic ones and provides insights into the molecular mechanisms underlying the multiple emergences of xanthotoxin hydroxylation in distant P450 subfamilies.
Tim-3 promotes viral infection by suppressing USP25-TRAF3-IRF7 signaling pathway
Authors: Du Lin , Chen Jinjie , Du Chunxiao , Chen Junrui , Wang Chaoxiang , Bao Bing , Lv Zhonglin , Xing Chen , Liang Meng , Wang Lanying , Xie Shun , Li Yuxiang , Wang Zhiding , Li Ge , Zhang Jun , Han Gencheng
Published: August 2024

Tim-3, an immune checkpoint inhibitor, plays key roles in maintaining immune homeostasis and is involved in viral evasion. However, the precise role of Tim-3 in viral infection remains to be determined. USP25 is one of the deubiquitinating enzymes that serves to initiate antiviral immunity by deubiquitinating TRAF3 and triggering the anti-viral signaling pathway. Here we found that Tim-3 specific knockout in myeloid cells leads to enhanced anti-viral immunity in mice with VSV encephalitis by increasing type I interferon response. Mechanistically, Tim-3 inhibits the expression of USP25 via STAT1, interacts with USP25 but does not regulate its post-translational modification, and as a result, Tim-3 inhibits USP25 mediated deubiquitination of TRAF3, promotes k48-linked ubiquitination and degradation of TRAF3, and then inhibits the phosphorylation of IRF7, finally down-regulates the interferon response. These findings provide new insights into the function of Tim-3 in antiviral immunity and its related clinical significance.
An extraordinary larval-like teleost fish from the Eocene of Bolca
Authors: Davesne Donald , Carnevale Giorgio
Published: August 2024

“Pegasus”volansis a highly unusual fossil teleost fish from the celebrated Eocene Bolca Lagerstatte. The fossil, known on the basis of two specimens, has been historically assigned to seamoths (Pegasidae), then to oarfish and relatives (Lampriformes). We describe its enigmatic skeletal anatomy in detail, and provide a new genus name. “Pegasus”volansis an extremely elongate and slender animal, with long anal and dorsal fins and a very well-developed first dorsal-fin ray reminiscent to the vexillum of some modern teleost larvae. Most striking is its extreme ventral projection of the pelvic girdle (basipterygium), associated with an element of the pectoral girdle (a long process of the coracoid) and developed pelvic-fin rays. The strongly reduced abdominal region suggests that “Pegasus”volanshad an external gut, once again reminiscent of those of certain larval teleosts. The unique character state combination displayed by “Pegasus”volansmake it impossible to assign it to a specific subclade within perch-like spiny-rayed fishes (Percomorpha). Nevertheless, it offers a valuable perspective on the diversity of morphologies and ecological niches occupied by teleost fishes of the early Eocene Bolca fauna.
Compressed higher-order structures facilitate human knowledge network learning
Authors: Ren Xiangjuan , Wang Muzhi , Qin Tingting , Fang Fang , Li Aming , Luo Huan
Published: August 2024

Knowledge seeking is innate to human nature, yet integrating vast and fragmented information into a unified network is a daunting challenge, especially in the information explosion era. Graph theory describes knowledge as a network characterising relationships (edges) between isolated data (nodes). Accordingly, knowledge learning could be abstracted as network navigation through random walks, where local connections are gradually learned and integrated to form the global picture. To facilitate network learning, we develop a novel “compressive learning” approach that decomposes network structures into substructures based on higher-order inhomogeneity properties and designs pre-learning paths highlighting key substructures. Large-scale behavioural experiments and magnetoencephalography (MEG) recordings demonstrate its effectiveness and better network formation in human brains. Hypergraph-based computational models reveal that the pre-learning path helps establish the core network skeleton to efficiently accommodate late inputs. Overall, higher-order network structures are crucial to network learning and can be utilised to better “connect the dots”.
Confidence over competence: Real-time integration of social information in human continuous perceptual decision-making
Authors: Schneider Felix , Calapai Antonino , Mundry Roger , Báez-Mendoza Raymundo , Gail Alexander , Kagan Igor , Treue Stefan
Published: August 2024

Human perception is susceptible to social influences. To determine if and how individuals opportunistically integrate real-time social information about noisy stimuli into their judgment, we tracked perceptual accuracy and confidence in social (dyadic) and non-social (solo) settings using a novel continuous perceptual report (CPR) task with peri-decision wagering. In the dyadic setting, most participants showed a higher degree of perceptual confidence. In contrast, average accuracy did not improve compared to solo performance. Underlying these net effects, partners in the dyad exhibit mutual convergence of accuracy and confidence, benefitting less competent or confident individuals, at the expense of the better performing partner. In conclusion, real-time social information asymmetrically shapes human perceptual decision-making, with dyads expressing more confidence without a matching gain in overall competence.
The multi-stage plasticity in the aggression circuit underlying the winner effect
Authors: Yan Rongzhen , Wei Dongyu , Varshneya Avni , Shan Lynn , Asencio Hector J. , Lin Dayu
Published: August 2024

Winning increases the readiness to attack and the probability of winning, a widespread phenomenon known as the “winner effect”. Here, we reveal a transition from target-specific to generalized aggression enhancement over 10 days of winning in male mice, which is supported by three stages of plasticity in the ventrolateral part of the ventromedial hypothalamus (VMHvl), a critical node for aggression. Over 10-day winning, VMHvl cells experience monotonic potentiation of long-range excitatory inputs, a transient local connectivity strengthening, and a delayed excitability increase. These plasticity events are causally linked. Optogenetically coactivating the posterior amygdala (PA) terminals and VMHvl cells potentiates the PA-VMHvl pathway and triggers the cascade of plasticity events as those during repeated winning. Optogenetically blocking PA-VMHvl synaptic potentiation eliminates all winning-induced plasticity. These results reveal the complex Hebbian synaptic and excitability plasticity in the aggression circuit during winning that ultimately leads to an increase in “aggressiveness” in repeated winners.
Ex situspawning, larval development, and settlement in the massive reef-building coralPorites lobatain Palau
Authors: Bennett Matthew-James , Grupstra Carsten G.B. , Da-Anoy Jeric , Andres Maikani , Holstein Daniel , Rossin Ashley , Davies Sarah W. , Meyer-Kaiser Kirstin S.
Published: August 2024

Reproduction, embryological development, and settlement of corals are critical for survival of coral reefs through larval propagation. Yet, for many species of corals, a basic understanding of the early life-history stages is lacking. In this study, we report our observations forex situreproduction in the massive reef-building coralPorites lobataacross two years. Spawning occurred in April and May, on the first day after the full moon with at least two hours of darkness between sunset and moonrise, on a rising tide. Only a small proportion of corals observed had mature gametes or spawned (17 – 35%). Eggs were 185 – 311 μm in diameter, spherical, homogenous, and provisioned with 95 – 155 Symbiodiniaceae algae. Males spawned before females, andex situfertilization rates were high for the first 2 hours after egg release.P. lobatalarvae were elliptical, approximately 300 μm long, and symbiotic. Just two days after fertilization, many larvae swam near the bottom of culture dishes and were competent to settle. Settlers began calcification two days after metamorphosis, and tentacles were developed 10 days after attachment. Our observations contrast with previous studies by suggesting an abbreviated pelagic larval period inP. lobata, which could lead to the isolation of some populations. The high thermal tolerance and a broad geographic range ofP. lobatasuggest this species could locally adapt to a wide range of environmental conditions, especially if larvae are locally retained. The results of this study can inform future work on reproduction, larval biology, dispersal, and recruitment ofP. lobata, which could have an ecological advantage over less resilient coral species under future climate change.
Abundant and active community members respond to the diel cycle in hot spring phototrophic mats
Authors: Shelton Amanda N , Yu Feiqiao B. , Grossman Arthur R , Bhaya Devaki
Published: August 2024

Photosynthetic microbial mats in hot springs can provide insights into the diel behaviors of communities in extreme environments. In this habitat, photosynthesis dominates during the day, leading to super-oxic conditions, with a rapid transition to fermentation and anoxia at night. Multiple samples were collected from two springs over several years to generate metagenomic and metatranscriptomic datasets. Metagenome assembled genomes (MAGs) comprised 71 taxa (in 19 different phyla), of which twelve core taxa were present at high abundance in both springs. The eight most active taxa identified by metatranscriptomics were an oxygenic cyanobacterium (Synechococcus sp.), five anoxygenic phototrophs from three different phyla, and two understudied heterotrophs from phylum Armatimonadota. Surprisingly, in all eight taxa, a significant fraction of genes exhibited a diel expression pattern although peak timing varied considerably. The two abundant heterotrophs exhibit starkly different peak timing of expression, which we propose is shaped by their metabolic and genomic potential to use carbon sources that become differentially available during the diel cycle. Network analysis revealed pathway expression patterns that had not previously been linked to diel cycles, including ribosome biogenesis and chaperones. This provides a framework for analyzing metabolically coupled communities and the dominant role of the diel cycle.
What did the dove sing to Pope Gregory? Ancestral melody reconstruction in Gregorian chant using Bayesian phylogenetics
Authors: Ballen Gustavo A. , Mühlová Klára Hedvika , Hajič Jan
Published: August 2024

An attractive goal in the study of Gregorian chant melodies is reconstructing unobserved melodies as they may have been transmitted along the history of chant, especially as early chant notation does not capture pitch exactly. We propose doing this computationally using Ancestral State Reconstruction (ASR) over phylogenetic trees. Bayesian phylogenetic trees have shown promise as a tool to study the evolution of chant melodies, by inferring a plausible topology of chant transmission. However, the inferred trees cannot be used as ASR inputs directly, because they are undirected, and their branch lengths conflate time and evolutionary rate. We therefore first apply Divergence Time Estimation (DTE) to separate them and represent the tree in a directed form on the time dimension. Using ASR, we then obtain reconstructions of melodies for each of the ancestral nodes, in addition to their distribution in time obtained from DTE, and thus we obtain a phylogeny of chant melody with a music-historical interpretation. We applied this method to the Christmas Vespers dataset, and compare the results against musicological knowledge and melodies reconstructed at Solesmes using methods of contemporary philology, which shows potential for reconstructing cultural transmission through time.
Differential interactions determine anisotropies at interfaces of RNA-based biomolecular condensates
Authors: Erkamp Nadia A. , Farag Mina , Qiu Yuanxin , Qian Daoyuan , Sneideris Tomas , Wu Tingting , Welsh Timothy J. , Ausserwӧger Hannes , Krug Tommy J. , Weitz David A. , Lew Matthew , Knowles Tuomas P. J. , Pappu Rohit V.
Published: August 2024

Biomolecular condensates form via macromolecular phase separation, giving rise to coexisting phases delineated by interfaces. Here, we characterize the structures of interfaces formed by phase separation driven by heterotypic interactions in ternary mixtures of two types of RNA molecules and polyethylene glycol. We find that purine-rich RNAs are scaffolds that drive phase separation via strong heterotypic interactions. Conversely, pyrimidine-rich RNA molecules are defined by weaker heterotypic interactions. They function as adsorbents that accumulate at and wet the interfaces of coexisting phases formed by phase separation of scaffolds. Our computations predict that scaffolds and adsorbents have different non-random orientational preferences at interfaces. We tested these predictions using single-molecule super resolution imaging that tracks the motions of fluorogenic probes that are bound to RNA molecules. Motions parallel to the interface were found to be faster than motions perpendicular to the interface. These findings support previous predictions regarding anisotropies of motions at interfaces.
MAASTY: A (dis)ordered copolymer for structural determination of human membrane proteins in native nanodiscs
Authors: Pugh Ciara Frances , Præstegaard Kaia Fiil , Feilen Lukas Peter , Živković Dušan , Borthwick Neil Jean , de Lichtenberg Casper , Bolla Jani R. , Autzen Anton Allen Abbotsford , Autzen Henriette Elisabeth
Published: August 2024

Amphiphilic copolymers capable of extracting membrane proteins directly from lipid bilayers into ”native nanodiscs” offer a simplified approach for preparing membrane proteins in lipid nanodiscs compared to approaches that rely on detergent. Amphiphilicity, length, and composition influence the performance of copolymers, in addition to the protein itself and the purification conditions used. Here, we report a copolymer composed of methacrylic acid and styrene, which we term MAASTY, leveraging the inherent monomer reactivity ratios to create an anionic copolymer with a statistical distribution of monomers. We show that MAASTY can be used for high-resolution structural determination of a human membrane protein with single particle cryo-electron microscopy, preserving endogenous lipids. Moreover, MAASTY copolymers effectively solubilize a broad range of lipid species and a wide range of different, eukaryotic membrane proteins from mammalian cells. We find that MAASTY copolymers are promising as effective solubilizers of membrane proteins and offer a new chemical platform for structural and functional characterization of membrane proteins in native nanodiscs.
Clusters of deep intronic RbFox motifs regulate mammalian alternative splicing
Authors: Tomassoni-Ardori Francesco , Palko Mary Ellen , Galloux Melissa , Tessarollo Lino
Published: August 2024

The RbFox RNA binding proteins regulate alternative splicing of genes governing mammalian development and organ function. They bind to the RNA sequence GCAUG with high affinity but also non-canonical secondary motifs in a concentration dependent manner. However, the hierarchical requirement of RbFox motifs, which are widespread in the genome, is still unclear. Here we show that deep intronic, tightly clustered RbFox1 motifs cooperate and are necessary in regulating splicing of alternative exons. By employing recombineering mutagenesis in bacterial artificial chromosomes we found that tightly clustered (U)GCAUG motifs in the middle of 50 Kb introns are necessary for RbFox regulation of gene isoforms expression. Bioinformatic analysis revealed that (U)GCAUG-clusters are widely present in both mouse and human genes and are embedded in sequences binding the large assembly of splicing regulators. Integrative data analysis from eCLIP and RNAseq experiments showed a global increase in RNA isoform modulation of genes with Rbfox1 eCLIP-peaks associated with these clusters. These data suggest that clustered distal intronic Rbfox-binding motifs are important determinants of RbFox1 function in the mammalian genome and provide a target for identification of pathogenic mutations.
The ZIP8 A391T Crohn’s disease-linked risk variant induces colonic metal ion dyshomeostasis, microbiome compositional shifts, and inflammation
Authors: Yang Julianne C. , Zhao Matthew , Chernikova Diana , Arias-Jayo Nerea , Zhou Yi , Situ Jamilla , Gutta Arjun , Chang Candace , Liang Fengting , Lagishetty Venu , Jacobs Jonathan P.
Published: August 2024

The pathogenesis of Crohn’s disease involves genetic and environmental factors, with the gut microbiome playing a crucial role. The Crohn’s disease-associated variant rs13107325 in the SLC39A8 gene results in an A391T substitution in the ZIP8 metal ion transporter and has previously been linked to alterations in the colonic microbiome in variant carriers. We hypothesized that the A391T substitution alters metal ion homeostasis in the colonic mucosal-luminal interface, thereby inducing dysbiosis which may promote intestinal inflammation. To evaluate this hypothesis, we generated a SLC39A8 A393T mouse model (matching human A391T). Consistent with an effect of the variant on ZIP8 function, homozygous A393T mice exhibited increased cobalt in the colonic mucosa, but reduced iron, zinc, manganese, cobalt, copper, and cadmium in the colonic lumen. We performed 16S rRNA gene sequencing of colon samples and histological scoring of colon tissue collected from the SLC39A8 A393T mouse model at different ages. We identified variant-linked effects on microbiome beta diversity in 2-month, 3-4 month, and 12-month old mice and spontaneous intestinal inflammation in 10-month but not 5-month old mice. Predicted pathway analysis of the microbiome samples revealed differential enrichment of iron-, zinc- and cobalt-dependent pathways in A393T mice compared to wild-type controls. These results suggest that the variant in SLC39A8 primarily restricts metal availability to the microbiota, resulting in compositions that can adapt to the environment, and that A393T-linked dysbiosis occurs prior to the onset of inflammation. This study paves the way for future studies investigating risk variants as microbiome-disease modifiers.

NEW & NOTEWORTHY

Mice recapitulating the human A391T Crohn’s disease-linked risk variant in the SLC39A8-encoded ZIP8 transporter exhibit reduced luminal trace metals and an altered microbiome composition. The microbiome compositional shift occurs prior to the onset of spontaneous colonic inflammation. This study supports an emerging paradigm by which genetic risk for inflammatory bowel disease may confer disease susceptibility through modulation of the gut microbiome.
Technical Assessment on Proteonano™: A Robust Platform for Deep Plasma Proteomics Study
Authors: Wang Yi , Zhang Yonghao , Ouyang Xiehua , Wu Hao
Published: August 2024

Complete profiling of human plasma proteome is an immerse source for disease biomarker discovery. Cutting-edge mass spectrometers, like ThermoFisher’s Orbitrap Astral, have promised unprecedented insights into the exploration of multiple protein biomarkers from human plasma samples. However, large-scale, deep profiling of the human plasma proteome, especially low-abundant proteins (LAPs, <10 ng mL−1), in a robust and fast way remains challenging. This is largely due to the lack of standardized and automated workflows including LAPs enrichment, reduction, and enzymatic digestion procedures. Until now, these complex procedures have not been incorporated into a streamlined workflow to achieve reproducibility, high-throughput, and deep proteome coverage.

Here we report the Proteonano™ Ultraplex Proteomics Platform for large cohort plasma proteomics studies with robustness and high throughput by standardizing workflow by incorporating the Proteonano™ platform and high-resolution mass spectrometers, including Orbitrap Exploris™ 480, Orbitrap Astral™, and timsTOF Pro 2. This pipeline demonstrates excellent stability and reproducibility, with tunable balance between detection depth and throughput. We further demonstrate the utility of this platform for biomarker discovery in an Alzheimer disease related cohort. This harmonized platform enables robust, fast and large-cohort plasma proteomics studies to meet the need to discovering new biomarkers.