bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional traits and phylogeny predict vertical foraging in terrestrial mammals and birds
Authors: Jantz Patrick , Abraham Andrew , Scheffers Brett , Gaillard Camille , Harfoot Mike , Goetz Scott , Doughty Christopher E.
Published: April 2024

Earth’s ecosystems are characterized by numerous gradients related to the distribution of environmental conditions and resources. Niche theory predicts that animals will evolve traits to exploit changing resource availability and environmental conditions across these gradients. Much work has been done examining how animal traits like body mass and diet change across gradients from regional to global scales. Environmental and resource gradients in the vertical dimension tend to exhibit strong changes over relatively short distances due to the influence of elevation and vegetation. Vegetation structure may be an especially important vertical axis as it contributes to strong gradients in micro- climate, food resources, and predation risk. To investigate interrelationships between the vertical niche and its presumed drivers, we use functional traits, phylogenies, and predation risk to predict the vertical foraging niche for 4,828 mammals and 9,437 birds globally. To provide biogeographic context to the predictive analysis, we use species ranges to map geographic distributions of the vertical foraging niche and relationships between the niche and its presumed drivers. Linking trait databases with species range maps revealed distinct global distributions of vertical foraging niches for mammals and birds. The most important predictors of these niches varied by taxon but there were several systematic relationships. Diet, body mass, and phylogeny were strong predictors of vertical foraging niche across mammal and bird species. Percent fruit in diet exhibited progressively more positive relationships with higher canopy foraging positions. Predation pressure was relatively unimportant in predicting most vertical foraging niches for birds and mammals but displayed a positive trend with arboreal foraging. Geographic hotspots for the importance of fruit in both mammal and bird diets included the Andes-Amazon transition zone, the Amazon Basin, and New Guinea. Our results provide support for the theory of resource driven vertical niche partitioning but also reveal that vertical niches are strongly associated with phylogeny, suggesting niche conservatism in numerous mammal and bird families. Geographic patterns in variable importance values suggest multiple mechanisms behind spatial structure in eco- evolutionary relationships, including latitudinal gradients in vegetation structure and composition, historical patterns of island isolation (in Southeast Asia), and the influence of habitat heterogeneity driven by tectonic processes (in South America).
Smpd1regulates chitin-clearance for tracheal gas-filling in theDrosophilaembryo in a ceramide-specific manner
Authors: Hull Alexander J , Atilano Magda L , Hallqvist Jenny , Heywood Wendy , Kinghorn Kerri J
Published: April 2024

Type A and B Niemann Pick (NPD) is an inherited multisystem lysosomal storage disorder caused by mutations in theSMPD1gene. Respiratory dysfunction is a key hallmark of NPD, although the precise mechanisms underlying these pathologies is underexplored. Here we present aDrosophilamodel ofSmpd1loss-of-function that displays significant respiratory defects.Smpd1is expressed in the late-embryonic fly respiratory network, the trachea, and is secreted into the tracheal lumen. Loss ofSmpd1results in embryonic lethality, and although tracheal morphology appears normal, trachea fail to fill with gas prior to eclosion. We demonstrate that clearance of luminal constituents through endocytosis prior to gas-filling is defective inSmpd1mutants. This is coincident with autophagic, but not lysosomal defects. Finally, we show that although bulk sphingolipids are unchanged, dietary loss of lipids in combination with genetic and pharmacological block of ceramide synthesis is sufficient to rescue gas-filling defects. In summary, we present a novel NPD model amenable to genetic and pharmacological screens, and highlight myriocin, an inhibitor of ceramide synthesis, as a potential therapeutic drug for the treatment of NPD.
New role for cardiomyocyteBmal1in the regulation of sex-specific heart transcriptomes
Authors: Zhang Xiping , Procopio Spencer B. , Ding Haocheng , Semel Maya G. , Schroder Elizabeth A. , Seward Tanya S. , Du Ping , Wu Kevin , Johnson Sidney R. , Prabhat Abhilash , Schneider David J. , Stumpf Isabel G , Rozmus Ezekiel R , Huo Zhiguang , Delisle Brian P. , Esser Karyn A.
Published: April 2024

It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice. Here, we show that the the core clock genes are expressed in common in both sexes but the circadian transcriptome of the mouse heart is very sex-specific. Hearts from female mice expressed significantly more rhythmically expressed genes (REGs) than male hearts and the temporal pattern of REGs was distinctly different between sexes. We next used a cardiomyocyte-specific knock out of the core clock gene,Bmal1, to investigate its role in sex-specific gene expression in the heart. All sex differences in the circadian transcriptomes were significantly diminished with cardiomyocyte-specific loss ofBmal1. Surprisingly, loss of cardiomyocyteBmal1also resulted in a roughly 8-fold reduction in the number of all the differentially expressed genes between male and female hearts. We conclude that cardiomyocyte-specificBmal1, and potentially the core clock mechanism, is vital in conferring sex-specific gene expression in the adult mouse heart.
Machine learning methods for predicting guide RNA effects in CRISPR epigenome editing experiments
Authors: Mu Wancen , Luo Tianyou , Barrera Alejandro , Bounds Lexi R. , Klann Tyler S. , Weele Maria ter , Bryois Julien , Crawford Gregory E. , Sullivan Patrick F. , Gersbach Charles A. , Love Michael I. , Li Yun
Published: April 2024

CRISPR epigenomic editing technologies enable functional interrogation of non-coding elements. However, current computational methods for guide RNA (gRNA) design do not effectively predict the power potential, molecular and cellular impact to optimize for efficient gRNAs, which are crucial for successful applications of these technologies.

We present “launch-dCas9” (machine LeArning based UNified CompreHensive framework for CRISPR-dCas9) to predict gRNA impact from multiple perspectives, including cell fitness, wild-type abundance (gauging power potential), and gene expression in single cells. Our launch-dCas9, built and evaluated using experiments involving >1 million gRNAs targeted across the human genome, demonstrates relatively high prediction accuracy (AUC up to 0.81) and generalizes across cell lines. Method-prioritized top gRNA(s) are 4.6-fold more likely to exert effects, compared to other gRNAs in the same cis-regulatory region. Furthermore, launch-dCas9 identifies the most critical sequence-related features and functional annotations from >40 features considered. Our results establish launch-dCas9 as a promising approach to design gRNAs for CRISPR epigenomic experiments.
Dynamic reconfiguration of aperiodic brain activity supports cognitive functioning in epilepsy: a neural fingerprint identification
Authors: Lopez Emahnuel Troisi , Corsi Marie-Constance , Danieli Alberto , Antoniazzi Lisa , Angiolelli Marianna , Bonanni Paolo , Sorrentino Pierpaolo , Duma Gian Marco
Published: April 2024

Background

Temporal lobe epilepsy (TLE) is characterized by alterations of brain dynamic at large scale associated with altered cognitive functioning. Interindividual variability of brain activity is a source of heterogeneity in this disorder. Here, we aimed at analyzing dynamical reconfiguration of brain activity, using the neural fingerprint approach, to delineate subject-specific characteristics and their cognitive correlates in TLE.

Methods

We collected 10 minutes of resting state electroencephalography (128 channels), free from epileptiform activity, from 68 TLE patients and 34 healthy controls. The functional network was defined by the spatio-temporal spreading, across cortical regions, of aperiodic bursts of activations (neuronal avalanches). This metric allowed encapsulating brain reconfiguration patterns into the avalanche transition matrix (ATM). We used a neural fingerprint approach to differentiate across controls and patients diagnosis, linking altered brain dynamic with cognitive outcome.

Findings

Patients’ brain dynamics were more stereotyped as compared to controls. The neural fingerprint using ATMs differentiated, in a data-driven fashion, patients with respect to healthy controls, being sensitive not only to the pathology but also to the subtype (unilateral vs. bilateral TLE). Notably, in unilateral TLE patients, a better memory performance was associated with a larger similarity of the brain dynamic configuration with controls.

Interpretation

TLE is characterized by reduced variability and more stereotyped brain dynamics, implicating widespread alterations across the brain. These alterations correlate with cognitive function in patients with unilateral TLE. This study underscores the utility of brain fingerprinting in elucidating disease-specific brain dynamics, offering novel metrics for personalized patient care.
A novel food frequency questionnaire for Brazilian adults based on the Nova classification system: development, reproducibility and validation
Authors: Frade Evelyn Oliveira da Silva , Gabe Kamila Tiemann , Costa Caroline dos Santos , Neri Daniela , Steele Euridice Martinez , Rauber Fernanda , Steluti Josiane , Levy Renata Bertazzi , Louzada Maria Laura da Costa
Published: April 2024

The Nova system categorizes foods according to processing levels, and dietary intake instruments not developed to assess this criteria may introduce bias in epidemiological studies. To address this gap, we developed and validated the Nova Food Frequency Questionnaire (NovaFFQ) for Brazilian adults. The NovaFFQ includes commonly consumed foods and drinks based on 2017-2018 National Food Survey data. Reproducibility was assessed by comparing NovaFFQ estimates on two occasions. Criterion validity was assessed by comparing the mean dietary contribution of Nova groups obtained from the first NovaFFQ against two Nova24h. Strong reproducibility was observed with an intraclass correlation coefficient (ICC) of 0.91 for all Nova groups. Criterion validity showed a moderate ICC, ranging from 0.61 to 0.65, and substantial agreement in ranking individuals, as indicated by prevalence and bias-adjusted kappa, ranging from 0.70 to 0.74. The NovaFFQ is a valid instrument for assessing food consumption according to food processing.
Enhanced network synchronization connectivity following transcranial direct current stimulation (tDCS) in bipolar depression: effects on EEG oscillations and deep learning-based predictors of clinical remission
Authors: Xiao Wenyi , Moncy Jijomon C. , Ghazi-Noori Ali-Reza , Woodham Rachel D. , Rezaei Hakimeh , Bramon Elvira , Ritter Philipp , Bauer Michael , Young Allan H. , Fu Cynthia H.Y.
Published: April 2024

Aim

To investigate oscillatory networks in bipolar depression, effects of a home-based tDCS treatment protocol, and potential predictors of clinical response.

Methods

20 participants (14 women) with bipolar disorder, mean age 50.75 ± 10.46 years, in a depressive episode of severe severity (mean Montgomery-Åsberg Rating Scale (MADRS) score 24.60 ± 2.87) received home-based transcranial direct current stimulation (tDCS) treatment for 6 weeks. Clinical remission defined as MADRS score < 10. Resting-state EEG data were acquired at baseline, prior to the start of treatment, and at the end of treatment, using a portable 4-channel EEG device (electrode positions: AF7, AF8, TP9, TP10). EEG band power was extracted for each electrode and phase locking value (PLV) was computed as a functional connectivity measure of phase synchronization. Deep learning was applied to pre-treatment PLV features to examine potential predictors of clinical remission.

Results

Following treatment, 11 participants (9 women) attained clinical remission. A significant positive correlation was observed with improvements in depressive symptoms and delta band PLV in frontal and temporoparietal regional channel pairs. An interaction effect in network synchronisation was observed in beta band PLV in temporoparietal regions, in which participants who attained clinical remission showed increased synchronisation following tDCS treatment, which was decreased in participants who did not achieve clinical remission. Main effects of clinical remission status were observed in several PLV bands: clinical remission following tDCS treatment was associated with increased PLV in frontal and temporal regions and in several frequency bands, including delta, theta, alpha and beta, as compared to participants who did not achieve clinical remission. The highest deep learning prediction accuracy 69.45% (sensitivity 71.68%, specificity 66.72%) was obtained from PLV features combined from theta, beta, and gamma bands.

Conclusions

tDCS treatment enhances network synchronisation, potentially increasing inhibitory control, which underscores improvement in depressive symptoms. Baseline EEG-based measures might aid predicting clinical response.
Short-term stability of diluted treprostinil sodium for subcutaneous administration
Authors: Sketch Margaret R. , Sauerstrom Daniel , Lange Allison Marie , Diehl Jane Hall
Published: April 2024

Background

The Remunity Pump for Remodulin (treprostinil) Injection is an infusion system indicated for use with subcutaneous treprostinil.

Objective

The objective was to assess the stability of diluted treprostinil sodium stored in Remunity pump cassettes.

Methods

Treprostinil’s chemical and physical stability were assessed over a 76-hour period at 40 degrees Celsius and 75% relative humidity after dilution to 0.01 mg/mL in sterile water for injection and 0.9% sodium chloride. Analyses were conducted via visual inspection, pH measurement, and a stability-indicating high-performance liquid chromatographic assay.

Results

At all time points, the treprostinil samples were consistently clear, colorless, and free of visible particulate matter, with pH levels 6.0-7.0. All assays were within 90.0%-110.0% of the label claim, with minimal variation.

Conclusions

Treprostinil diluted to 0.01 mg/mL was stable in Remunity pump cassettes for up to 76 hours at elevated temperature and humidity. No notable changes from label claim concentration values were observed.
Deep Learning for Polygenic Risk Prediction
Authors: Georgantas Costa , Kutalik Zoltán , Richiardi Jonas
Published: April 2024

Polygenic risk scores (PRS) are relative measures of an individual’s genetic propensity to a particular trait or disease. Most PRS methods assume that mutation effects scale linearly with the number of alleles and are constant across individuals. While these assumptions simplify computation, they increase error, particularly for less-represented racial groups. We developed and provide Delphi (deep learning for phenotype inference), a deep-learning method that relaxes these assumptions to produce more predictive PRS. In contrast to other methods, Delphi can integrate up to hundreds of thousands of SNPs as input. We compare our results to a standard, linear PRS model, lasso regression, and a gradient-boosted trees-based method. We show that deep learning can be an effective approach to genetic risk prediction. We report a relative increase in the percentage variance explained compared to the state-of-the-art by 11.4% for body mass index, 18.9% for systolic blood pressure, 7.5% for LDL, 35% for C-reactive protein, 16.2% for height, 29.6 % for pulse rate; in addition, Delphi provides 2% absolute explained variance for blood glucose while other tested methods were non-predictive. Furthermore, we show that Delphi tends to increase the weight of high-effect mutations. This work demonstrates an effective deep learning method for modeling genetic risk that also showed to generalize well when evaluated on individuals from non-European ancestries.
Accurate cross-platform GWAS analysis via two-stage imputation
Authors: Greenberg Anya , Reynolds Kaylia , McNulty Michelle T. , Sampson Matthew G. , Kang Hyun Min , Lee Dongwon
Published: April 2024

In genome-wide association studies (GWAS), combining independent case-control cohorts has been successful in increasing power for meta and joint analyses. This success sparked interest in extending this strategy to GWAS of rare and common diseases using existing cases and external controls. However, heterogeneous genotyping data can cause spurious results. To harmonize data, we propose a new method, two-stage imputation (TSIM), where cohorts are imputed separately, merged on intersecting high-quality variants, and imputed again. We show that TSIM minimizes cohort-specific bias while controlling imputation-derived errors. Merging arthritis cases and UK Biobank controls using TSIM, we replicated known associations without introducing false positives. Furthermore, GWAS using TSIM performed comparably to the meta-analysis of nephrotic syndrome cohorts genotyped on five different platforms, demonstrating TSIM’s ability to harmonize heterogeneous genotyping data. With the plethora of publicly available genotypes, TSIM provides a GWAS framework that harmonizes heterogeneous data, enabling analysis of small and case-only cohorts.
Predictive Modeling and Deep Phenotyping of Obstructive Sleep Apnea and Associated Comorbidities through Natural Language Processing and Large Language Models
Authors: Ahmed Awwal , Rispoli Anthony , Wasieloski Carrie , Khurram Ifrah , Zamora-Resendiz Rafael , Morrow Destinee , Dong Aijuan , Crivelli Silvia
Published: April 2024

Obstructive Sleep Apnea (OSA) is a prevalent sleep disorder associated with serious health conditions. This project utilized large language models (LLMs) to develop lexicons for OSA sub-phenotypes. Our study found that LLMs can identify informative lexicons for OSA sub-phenotyping in simple patient cohorts, achieving wAUC scores of 0.9 or slightly higher. Among the six models studied, BioClinical BERT and BlueBERT outperformed the rest. Additionally, the developed lexicons exhibited some utility in predicting mortality risk (wAUC score of 0.86) and hospital readmission (wAUC score of 0.72). This work demonstrates the potential benefits of incorporating LLMs into healthcare.

Data and Code Availability

This paper uses the MIMIC-IV dataset (Johnson et al., 2023a), which is available on the PhysioNet repository (Johnson et al., 2023b). We plan to make the source code publicly available in the future.

Institutional Review Board (IRB)

This research does not require IRB approval.
The role of pulmonary metastasectomy (PM) for non-primary lung cancer: Umbrella review of meta-analyses
Authors: Woo Wongi , Park Brandon , Ahadi Awranoos , Chung Liam il-young , Jung Chan Mi , Bharat Ankit , Chae Young Kwang
Published: April 2024

Introduction

Due to heterogeneous characteristics of primary cancers, the efficacy of pulmonary metastasectomy(PM) in non-primary lung cancers has not been investigated other than colorectal cancers. This study aims to investigate the clinical outcomes of PM for non-primary lung cancer.

Methods

A systematic search for meta-analyses on PM for non-primary lung cancers was conducted, encompassing publications up to January 3, 2024. The analysis included seven primary cancer types: renal cell, breast, adrenocortical, head and neck cancers, melanoma, germ cell tumors, and sarcoma. Primary outcomes, overall survival, and recurrence rates post-PM were assessed using random-effect models to account for study heterogeneity.

Results

This study included 16 systematic-review articles and 101 individual studies, involving 10,277 patients who underwent PM for non-primary lung cancer. Patients had a mean age of 48.0 years, with 68.4% being male. About half of the patients(47.1% [95%CI 40.8-53.5] presented with multiple metastatic lesions, and complete R0 resection achieved in 87.2% [95%CI 83.0-90.8]. The pooled 5-year overall survival (OS) rate post-PM was 41.2% [95%CI, 37.1-45.4%]. Patients with germ cell tumors demonstrated significantly higher survival rate than other cancers(p<0.05), while patients with melanoma exhibited the poorest outcome(p<0.05). During follow-up, 57.6%[95%CI 46.4-68.1] had recurrence; 48% of them had intrathoracic-only recurrence and 52% had extra-thoracic recurrence.

Conclusion

This study underscores the survival benefits associated with PM. Overall survival rates following PM do not significantly differ based on primary cancer types, except for germ cell tumors and melanoma. These findings highlight the importance of recognizing and incorporating PM into clinical practice when appropriate.

Synopsis

Surgical resection for pulmonary metastasis from cancers other than lung cancer still holds a significant role in improving a patient’s prognosis. Though the recurrence rate is high, it could improve the chance of survival regardless of the primary cancer types.
Comparative gene regulatory networks modulatingAPOEexpression in microglia and astrocytes
Authors: Brase Logan , Yu Yanbo , McDade Eric ,   Dominantly Inherited Alzheimer Network (DIAN), Harari Oscar , Benitez Bruno A.
Published: April 2024

Background

Single-cell technologies have unveiled various transcriptional states in different brain cell types. Transcription factors (TFs) regulate the expression of related gene sets, thereby controlling these diverse expression states. Apolipoprotein E (APOE), a pivotal risk-modifying gene in Alzheimer’s disease (AD), is expressed in specific glial transcriptional states associated with AD. However, it is still unknown whether the upstream regulatory programs that modulate its expression are shared across brain cell types or specific to microglia and astrocytes.

Methods

We used pySCENIC to construct state-specific gene regulatory networks (GRNs) for resting and activated cell states within microglia and astrocytes based on single-nucleus RNA sequencing data from AD patients’ cortices from the Knight ADRC-DIAN cohort. We then identified replicating TF using data from the ROSMAP cohort. We identified sets of genes co-regulated withAPOEby clustering the GRN target genes and identifying genes differentially expressed after the virtual knockout of TFs regulatingAPOE. We performed enrichment analyses on these gene sets and evaluated their overlap with genes found in AD GWAS loci.

Results

We identified an average of 96 replicating regulators for each microglial and astrocyte cell state. Our analysis identified the CEBP, JUN, FOS, and FOXO TF families as key regulators of microglial APOE expression. The steroid/thyroid hormone receptor families, including the THR TF family, consistently regulated APOE across astrocyte states, while CEBP and JUN TF families were also involved in resting astrocytes. AD GWAS-associated genes (PGRN,FCGR3A,CTSH,ABCA1,MARCKS,CTSB,SQSTM1,TSC22D4,FCER1G, and HLA genes) are co-regulated with APOE. We also uncovered that APOE-regulating TFs were linked to circadian rhythm (BHLHE40,DBP,XBP1,CREM,SREBF1,FOXO3, andNR2F1).

Conclusions

Our findings reveal a novel perspective on the transcriptional regulation ofAPOEin the human brain. We found a comprehensive and cell-type-specific regulatory landscape forAPOE, revealing distinct and shared regulatory mechanisms across microglia and astrocytes, underscoring the complexity ofAPOEregulation.APOE-co-regulated genes might also affect AD risk. Furthermore, our study uncovers a potential link between circadian rhythm disruption andAPOEregulation, shedding new light on the pathogenesis of AD.
Quantitative Magnetic Resonance Cerebral Spinal Fluid Flow Properties and Executive Function Cognitive Outcomes in Congenital Heart Disease
Authors: Lee Vincent Kyu , Reynolds William T. , Wallace Julia , Beluk Nancy , Badaly Daryaneh , Lo Cecilia W , Ceschin Rafael , Panigrahy Ashok
Published: April 2024

Cerebrospinal fluid (CSF) circulation has recently been shown to be important in nutrient distribution, waste removal, and neurogenesis. Increased CSF volumes are frequently observed in congenital heart disease (CHD) and are associated with neurodevelopmental deficits. This suggests prolonged perturbation to the CSF system and possible interference to its homeostatic function, which may contribute to the neurodevelopmental deficits in CHD. CSF flow has yet to be studied in CHD patients, but the pulsatile flow of CSF throughout the brain is driven mainly by cardiopulmonary circulation. Given the underlying heart defects in CHD, the cardiopulmonary circulatory mechanisms in CHD might be impaired with resultant perturbation on the CSF circulation. In this study, we determine whether CSF flow, using MRI measurements of static and dynamic pulsatile flow, is abnormal in youths with CHD compared to healthy controls in relation to executive cognitive function. CSF flow measurements were obtained on a total of 58 child and young adult participants (CHD=20, healthy controls = 38). The CSF flow was measured across the lumen of the Aqueduct of Sylvius using cardiac-gated phase-contrast MRI at 3.0T. Static pulsatility was characterized as anterograde and retrograde peak velocities, mean velocity, velocity variance measurements, and dynamic pulsatility calculated as each participant’s CSF flow deviation from the study cohort’s consensus flow measured with root mean squared deviation (RMSD) were obtained. The participants had neurocognitive assessments for executive function with focus on inhibition, cognitive flexibility, and working memory domains. The CHD group demonstrated greater dynamic pulsatility (higher overall flow RMSD over the entire CSF flow cycle) compared to controls (p=0.0353), with no difference detected in static pulsatility measures. However, lower static CSF flow pulsatility (anterograde peak velocity: p=0.0323) and lower dynamic CSF flow pulsatility (RMSD: p=0.0181) predicted poor inhibitory executive function outcome. Taken together, while the whole CHD group exhibited higher dynamic CSF flow pulsatility compared to controls, the subset of CHD subjects with relatively reduced static and dynamic CSF flow pulsatility had the worst executive functioning, specifically the inhibition domain. These findings suggest that altered CSF flow pulsatility may be central to not only brain compensatory mechanisms but can also drive cognitive impairment in CHD. Further studies are needed to investigate possible mechanistic etiologies of aberrant CSF pulsatility (i.e. primary cardiac hemodynamic disturbances, intrinsic brain vascular stiffness, altered visco-elastic properties of tissue, or glial-lymphatic disturbances), which can result in acquired small vessel brain injury (including microbleeds and white matter hyperintensities).
Safety of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: role of the standardized definition of complications
Authors: van Leusden F.J. , Staal D.P. , van Thor M.C.J. , Rensing B.J.M.W. , van Kuijk J.P. , Mulder B.J.M. , van den Heuvel D. , Boerman S. , Boomars K.A. , Peper J. , Mager J.J. , Post M.C.
Published: April 2024

Literature reports high complication rates in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who undergo balloon pulmonary angioplasty (BPA), especially in patients with poor pulmonary hemodynamics. Here we describe complications of BPA based on the new definitions.

All patients with CTEPH who completed BPA treatment before September 15th, 2023, were selected from the CTEPH database. Peri-procedural complications were collected and classified according to the 2023 consensus paper on BPA treatment. Complications were analyzed in subgroups of patients with pulmonary vascular resistance (PVR) ≤ or > 6.6 WU and mean pulmonary artery pressure (mPAP) ≤ or > 45 mmHg at first BPA.

In this analysis, 87 patients (63% women; mean age 61.1±14.0 years; 62% on dual PH targeted medical therapy) underwent 426 (mean 4.9±1.6 per patient) BPAs. Only non-severe complications occurred in 14% of BPA treatments; in 47% of the patients; 31% patients had a thoracic complication. The thoracic complications were mild (71%) or moderate (29%). Patients with a PVR >6.6 WU (n=8) underwent more BPA treatments (6.6±1.5 versus 4.6±1.5, p=0.002), had more complications (88% versus 41% of patients, p=0.020), and more thoracic complications (17% vs 7% of BPAs, p=0.013) than patients with PVR ≤6.6 WU. Patients with mPAP >45 mmHg (n=13) also had more BPA-treatments (6.5±1.7 versus 4.6±1.4, p<0.001), more complications (77% versus 44% of patients, p=0.027) and more thoracic complications (14% versus 8% of BPAs, p=0.039) than patients with mPAP ≤45 mmHg.

Complications occurred in 14% of BPAs and were mostly mild. Patients with severe pulmonary hemodynamics suffered more (thoracic) complications.

What is known?

BPA is an effective treatment in improving pulmonary hemodynamics in patients with CTEPH.

BPAs are associated with a high complication rate.

In 2023 a consensus statement was published concerning the definition of complications of BPAs.

Patients with poor pulmonary hemodynamics may be more susceptible to suffer from complications.

What does this study add?

For the first time, complications are categorized according to the consensus statement on BPA treatments in patients with CTEPH.

Thoracic complication rates in patients with severe pulmonary hemodynamics are significantly higher compared to complication rates in patients with lower pulmonary hemodynamic values.
Aurodox, a polyketide fromStreptomyces goldiniensis, inhibits transcription of the type III secretion system of multiple Gram-negative pathogens
Authors: Mark David , O’Boyle Nicky , Wale Kabo R , Tucker Samantha K , McHugh Rebecca E , Roe Andrew J
Published: April 2024

Gram-negative pathogens pose a significant threat due to their propensity for causing various infections, often coupled with formidable resistance to conventional antibiotic treatments. In light of this challenge, the development of antivirulence (AV) compounds emerges as a promising alternative strategy, aiming to disrupt key virulence mechanisms rather than directly targeting bacterial viability. One such compound, aurodox, derived fromStreptomyces goldiniensis, has exhibited promising AV properties in our prior studies. Specifically, aurodox caused a marked downregulation in the expression and function of theE. colitype 3 secretion system (T3SS), a needle-like injectosome structure which is deployed to translocate effector proteins from the cytoplasm to the host target cells.

However, the broader spectrum of aurodox’s efficacy against T3SS across diverse pathogens remained unanswered, prompting the focus of this work. Using quantitative real-time PCR, we show that aurodox exerts inhibitory effects on selected T3SS in various pathogens, including Salmonella typhimurium,Yersinia pseudotuberculosis, andVibrio parahaemolyticus. However, aurodox was not a universal blocker of all secretion systems, showing selectivity in its mode-of-action, even within a single strain. This finding was verified using transcriptomics which demonstrated that aurodox selectively blocks the expression of the Salmonella typhimurium SPI-2 type T3SS whilst other pathogenicity islands, including the SPI-1 system were not inhibited. To delve deeper into the mechanisms governing aurodox’s efficacy against these pathogens, we analysed transcriptomic datasets from bothE. coliand S. Typhimurium treated with aurodox. By identifying orthologous genes exhibiting differential expression in response to aurodox treatment across these pathogens, our study sheds light on the potential mechanisms underlying the action of this rediscovered antibiotic.
A delta-tubulin/epsilon-tubulin/Ted protein complex is required for centriole architecture
Authors: Pudlowski Rachel , Xu Lingyi , Milenkovic Ljiljana , Kumar Chandan , Hemsworth Katherine , Aqrabawi Zayd , Stearns Tim , Wang Jennifer T.
Published: April 2024

Centrioles have a unique, conserved architecture formed by three linked “triplet” microtubules arranged in nine-fold symmetry. The mechanisms by which these triplet microtubules are formed are not understood and likely involve the noncanonical tubulins delta-tubulin and epsilon-tubulin. Previously, we found that human cells deficient in delta-tubulin or epsilon-tubulin form abnormal centrioles, characterized by an absence of triplet microtubules, lack of central core protein POC5, and a futile cycle of centriole formation and disintegration (Wang et al., 2017). Here, we show that human cells lacking either of the associated proteins TEDC1 and TEDC2 have these same phenotypes. Using ultrastructure expansion microscopy, we find that mutant centrioles elongate to the same length as control centrioles in G2-phase. These mutants fail to recruit inner scaffold proteins of the central core and have an expanded proximal region. During mitosis, the mutant centrioles elongate further before fragmenting and disintegrating. All four proteins physically interact and TEDC1 and TEDC2 are capable forming a subcomplex in the absence of the tubulins. These results support an AlphaFold Multimer model of the tetramer in which delta-tubulin and epsilon-tubulin are predicted to form a heterodimer. TEDC1 and TEDC2 localize to centrosomes and are mutually dependent on each other and on delta-tubulin and epsilon-tubulin for localization. Our results demonstrate that delta-tubulin, epsilon-tubulin, TEDC1, and TEDC2 function together to promote robust centriole architecture. This work also lays the groundwork for future molecular studies of this complex, providing a basis for determining the mechanisms that underlie the assembly and interplay between the triplet microtubules and inner centriole structure.
A conserved genetic basis for commensal-host specificity through live imaging of colonization dynamics
Authors: Gutiérrez-García Karina , Aumiller Kevin , Dodge Ren , Obadia Benjamin , Deng Ann , Agrawal Sneha , Yuan Xincheng , Wolff Richard , Garud Nandita , Ludington William B
Published: April 2024

Animals throughout the metazoa selectively acquire specific symbiotic gut bacteria from their environment that aid host fitness. Current models of colonization suggest these bacteria use weakly specific receptors to stick to host tissues and that colonization results when they stick in a region of the host gut that overlaps with their nutritional niche. An alternative model is that unique receptor-ligand binding interactions provide specificity for target niches. Here we use live imaging of individual symbiotic bacterial cells colonizing the gut of livingDrosophila melanogasterto show thatLactiplantibacillus plantarumspecifically recognizes a distinct physical niche in the host gut. We find that recognition is controlled by a colonization island that is widely conserved in commensals and pathogens from the Lactobacillales to the Clostridia. Our findings indicate a genetic mechanism of host specificity that is broadly conserved.

One-Sentence Summary

Host-symbiont specificity is encoded by a conserved colonization island that provides molecular precision to host niche access.
Highly diverse – low abundance methanogenic communities in hypersaline microbial mats of Guerrero Negro B.C.S., assessed through microcosm experiments
Authors: Ramírez-Arenas Patricia J. , Latisnere-Barragán Hever , García-Maldonado José Q , López-Cortés Alejandro
Published: April 2024

Methanogenic communities of hypersaline microbial mats of Guerrero Negro, Baja California Sur, Mexico, have been recognized to be dominated by methylotrophic methanogens. However, recent studies of environmental samples have evidenced the presence of hydrogenotrophic and methyl-reducing methanogenic members, although at low relative abundances. Physical and geochemical conditions that stimulate the development of these groups in hypersaline environments, remains elusive. Thus, in this study the taxonomic diversity of methanogenic archaea of two sites of Exportadora de Sal S.A was assessed by mcrA gene high throughput sequencing from microcosm experiments with different substrates (both competitive and non-competitive). Results confirmed the dominance of the order Methanosarcinales in all treatments, but an increase in the abundance of Methanomassiliiccocales was also observed, mainly in the treatment without substrate addition. Moreover, incubations supplemented with hydrogen and carbon dioxide, as well as the mixture of hydrogen, carbon dioxide and trimethylamine, managed to stimulate the richness and abundance of other than Methanosarcinales methanogenic archaea. Several OTUs that were not assigned to known methanogens resulted phylogenetically distributed into at least nine orders. Environmental samples revealed a wide diversity of methanogenic archaea of low relative abundance that had not been previously reported for this environment, suggesting that the importance and diversity of methanogens in hypersaline ecosystems may have been overlooked. This work also provided insights into how different taxonomic groups responded to the evaluated incubation conditions.
The Energetic Stress Marker GDF15 is Induced by Acute Psychosocial Stress
Authors: Huang Qiuhan , Monzel Anna S. , Rausser Shannon , Haahr Rachel , Devine Jack , Liu Cynthia C. , Kelly Catherine , Thompson Elizabeth , Kurade Mangesh , Michelson Jeremy , Li Shufang , Engelstad Kris , Tanji Kurenai , Lauriola Vincenzo , Wang Tian , Wang Shuang , Marsland Anna L , Kaufman Brett A , St-Onge Marie-Pierre , Sloan Richard , Juster Robert-Paul , Gouspillou Gilles , Hirano Michio , Picard Martin , Trumpff Caroline
Published: April 2024

GDF15 (growth differentiation factor 15) is a marker of cellular and mitochondrial energetic stress linked to physical-mental illness, aging, and mortality. Here, we describe the psychobiological regulation of plasma and saliva GDF15 in four human studies including 3,599 samples from 148 healthy individuals. We report two main observations establishing GDF15 as a novel tractable biomarker of psychosocial stress. 1) In two experimental laboratory studies, socio-evaluative stress rapidly elevates GDF15 and lactate, two molecular markers of energetic/reductive stress. 2) Similar to other stress-related metabolic hormones, we also find that saliva GDF15 exhibit a robust awakening response, being highest at the time of waking up and declining by ∼42-92% within 30-45 minutes. These data position GDF15 as a dynamic biomarker of psychosocial stress accessible in human blood and saliva, pointing towards a shared psychobiological pathway linking mental and mitochondrial energetic stress. These foundational observations open the door to large-scale studies using GDF15 to non-invasively probe how acute psychosocial factors promote cellular and mitochondrial and energetic stress contributing to the stress-disease cascade across the lifespan.

Significance statement

This study uncovers the dynamic psychobiological regulation of plasma and saliva GDF15, establishing it as a biomarker of acute psychosocial stress. Using over 3,500 samples we demonstrate that acute socio-evaluative stress increases within minutes both GDF15 and lactate, reflecting reductive stress. High-intensity sampling over multiple weeks also confirms novel dynamics around the saliva GDF15 awakening response. These findings highlight a connection between acute psychosocial stress and mitochondrial energetic stress, offering new opportunities to investigate how stress becomes biologically embedded and contributes to health trajectories across the human lifespan.
Examining Intercage Transmission ofChlamydia muridarum: Impact of Barrier Husbandry and Cage Sanitization
Authors: Palillo Michael B , Mishkin Noah , Aydin Mert , Mourino Anthony , Ricart Arbona Rodolfo J , Lipman Neil S
Published: April 2024

Chlamydia muridarum(Cm) has reemerged as a prevalent bacterial contaminant of academic research mouse colonies. A study was conducted to assess the effectiveness of husbandry and cage sanitization methods in preventing intercage transmission of Cm. To assess intercage transmission during cage change, a cage housing 2 Cm-free Swiss Webster (Tac:SW; SW) sentinel mice was placed randomly on each of 12 individually ventilated cage racks, housing cages with Cm-shedding mice, located in 1 of 2 animal holding rooms. Husbandry staff blinded to the study cages, changed all cages in the animal holding rooms weekly using microisolator cage technique. PCR testing performed 180 days post-placement confirmed all mice remained negative for Cm. To assess the effectiveness of cage sanitization to eliminate Cm, we investigated transmission of Cm to a naïve Cm-free SW and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mouse co-housed for 7 days (repeated weekly for 4 weeks) in cages assigned to 1 of 3 groups (n=10 pairs of mice/group). Cages that previously housed 2 Cm-shedding BALB/c mice were either washed in a tunnel washer (82.2°C [180°F] final rinse for an average of 16 seconds per run; n=10) with and without post-washing autoclaving (121°C for 20 minutes; n=10), or were untreated (bedding change only; n=10). Pre- and post-sanitization swabs of each cage were assayed for Cm by PCR. All pre-treatment swabs tested positive, while post-treatment swabs from all cages (excluding bedding change) tested negative. All SW and NSG mice, irrespective of group, remained negative for Cm as determined by PCR. These findings suggest that infectious Cm does not persist in untreated cages nor after mechanical washing with and without autoclaving. Collectively, these findings suggest that neither our husbandry protocols nor inadequate cage sanitization methods likely contributed to the observed prevalence of Cm in contemporary research mouse colonies.
Hierarchical dynamic coding coordinates speech comprehension in the brain
Authors: Gwilliams Laura , Marantz Alec , Poeppel David , King Jean-Remi
Published: April 2024

Speech comprehension requires the human brain to transform an acoustic waveform into meaning. To do so, the brain generates a hierarchy of features that converts the sensory input into increasingly abstract language properties. However, little is known about how these hierarchical features are generated and continuously coordinated. Here, we propose that each linguistic feature is dynamically represented in the brain to simultaneously represent successive events. To test this ‘Hierarchical Dynamic Coding’ (HDC) hypothesis, we use time-resolved decoding of brain activity to track the construction, maintenance, and integration of a comprehensive hierarchy of language features spanning acoustic, phonetic, sub-lexical, lexical, syntactic and semantic representations. For this, we recorded 21 participants with magnetoencephalography (MEG), while they listened to two hours of short stories. Our analyses reveal three main findings. First, the brain incrementally represents and simultaneously maintains successive features. Second, the duration of these representations depend on their level in the language hierarchy. Third, each representation is maintained by a dynamic neural code, which evolves at a speed commensurate with its corresponding linguistic level. This HDC preserves the maintenance of information over time while limiting the interference between successive features. Overall, HDC reveals how the human brain continuously builds and maintains a language hierarchy during natural speech comprehension, thereby anchoring linguistic theories to their biological implementations.
Sex-specific competitive social feedback amplifies the role of early life contingency in male mice
Authors: Zipple Matthew N , Kuo Daniel Chang , Meng Xinmiao , Reichard Tess M , Guess Kwynn , Vogt Caleb C , Moeller Andrew H , Sheehan Michael J
Published: April 2024

Contingency (or ‘luck’) in early life plays an important role in shaping individuals’ development. When individuals live within larger societies, social experiences may cause the importance of early contingencies to be magnified or dampened. Here we test the hypothesis that competition magnifies the importance of early contingency in a sex-specific manner by comparing the developmental trajectories of genetically identical, free-living mice who either experienced high levels of territorial competition (males) or did not (females). We show that male territoriality results in a competitive feedback loop that magnifies the importance of early contingency and pushes individuals onto divergent, self-reinforcing life trajectories, while the same process appears absent in females. Our results indicate that the strength of sexual selection may be self-limiting, as within-sex competition increases the importance of early life contingency, thereby reducing the ability of selection to lead to evolution. They also demonstrate the potential for contingency to lead to dramatic differences in life outcomes, even in the absence of any underlying differences in ability (‘merit’).
Emergence of multiple foraging strategies under competition
Authors: Kim Hyunjoong , Subedi Manoj , Josić Krešimir
Published: April 2024

Foraging strategies are shaped by interactions with the environment, and evolve under metabolic constraints. Optimal strategies for isolated and competing organisms have been studied extensively in the absence of evolution. Much less is understood about how metabolic constraints shape the evolution of an organism’s ability to detect food and move through its environment to find it. To address this question, we introduce a minimal agent-based model of the coevolution of two phenotypic attributes critical for successful foraging in crowded environments: movement speed and perceptual acuity. Under competition higher speed and acuity lead to better foraging success, but at higher metabolic cost. We derive the optimal foraging strategy for a single agent, and show that this strategy is no longer optimal for foragers in a group. We show that mutation and selection can lead to the coexistence of two strategies: A metabolically costly strategy with high acuity and velocity, and a metabolically cheap strategy. Generally, in evolving populations speed and acuity co-vary. Therefore, even under metabolic constraints, trade-offs between metabolically expensive traits are not guaranteed.