bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Harmful Alcohol Use Prevalence in Sub-Saharan Africa between 2015 and 2019: Evidence from Population-based HIV Impact Assessment
Authors: Goma Mtumbi , Ng’ambi Wingston Felix , Zyambo Cosmas
Published: March 2024

Introduction

Harmful alcohol use is associated with significant risks to public health outcomes worldwide. Although data on harmful alcohol use have been collected by population-based HIV Impact Assessment (PHIA), there is a dearth of analysis on the effect of HIV/ART status on harmful alcohol use in the SSA countries with PHIA surveys. This study uses data from the national representative PHIA to predict the harmful alcohol use prevalence.

Methods

A secondary analysis of the PHIA surveys: Namibia (n=27,382), Tanzania (n=1807), Zambia (n=2268), Zimbabwe (n=3418), Malawi (n=2098), Namibia (n=27,382), and Eswatini (n=2762). Using R version 4.2, the outcome variable and the descriptive variables were tested for association using chi square. Multivariable logistic regression analysis was used identify significant variables associated with harmful alcohol use. We employed to test and apply machine learning (ML) methods through Super Learner, Decision Tree, Random Forest (RF), Lasso Regression, Sample mean and Gradient boosting. Evaluation metrics methods specifically confusion matrix, accuracy, precision, recall, F1 score, and Area under the Receiver Operating Characteristics (AUROC) were used to evaluate the performance of predictive models. The cutoff point for statistically significant was P<0.05.

Results

Of the 12,460 persons, 15% used alcohol harmfully. Harmful alcohol use varied by countries and ranged from 8.7% in Malawi to 26.1% in Namibia (P<0.001). Females were less likely to use alcohol in a harmful way (AOR = 0.32, 95% CI: 0.29-0.35, P< 0.001). Compared to those HIV negative, persons that were with HIV-positive and on ART were less likely to use alcohol in a harmful way (AOR = 0.65, 95% CI: 0.57-0.73, P<0.001) however persons that were HIV-positive and not on ART were more likely to use alcohol in a harmful way (OR = 1.49, 95% CI: 1.32-1.69, P<0.001). Being married or formally married was protective to harmful use of alcohol. The best performing models were Lasso or Super Learner or Random Forest were the best performing models while gradient boosting models or sample mean did not perform well.

Conclusion

The findings highlight concerning variations in harmful alcohol use prevalence across surveyed countries, with Namibia reporting the highest rate. Males, older individuals, those HIV positive and not yet on ART, and unmarried persons demonstrated a higher likelihood of engaging in harmful alcohol use. These findings collectively contribute to a comprehensive understanding of the multiple factors influencing harmful alcohol use within the surveyed populations, the importance of targeted interventions at country and individual levels.
Impact of Lactobacillus GG on weight loss in post-bariatric surgery patients: a randomized, double-blind clinical trial
Authors: Nasir Myra , Stone Samuel , Mahoney Ian , Chang Justin , Kim Julie , Shah Sajani , McDermott Laura A. , Sebastiani Paola , Tighiouart Hocine , Snydman David R. , Doron Shira
Published: March 2024

Introduction and Objectives

There is increasing evidence suggesting the impact of human gut microbiota on digestion and metabolism. It is hypothesized that the microbiome in obese subjects is more efficient than that in lean subjects in absorbing energy from food, thus predisposing to weight gain. A transformation in gut microbiota has been demonstrated in patients who have undergone bariatric surgery which has been positively associated with post-surgical weight loss. However, there is lack of studies investigating the impact of probiotics on weight loss in post-bariatric surgery patients. The objectives of our study were to investigate the impact of a probiotic, Lactobacillus GG (LGG), on weight loss and quality of life in patients who have undergone bariatric surgery.

Methods

The study was registered withClinicalTrials.govNCT01870544. Subjects were randomized to receive either LGG or placebo capsules. Percent total weight loss at their post-operative visits was calculated and differences between the two groups were tested using a t-test with unequal variances. The effect of LGG on Gastrointestinal Quality of Life Index (GIQLI) scores was estimated using a mixed model repeated measures model.

Results

The mean rate of change in percent total weight loss at the ‘30-day’ post-operative visit for the placebo and treatment groups was 0.098 and 0.079 (p = 0.41), respectively, whereas that at the ‘90-day’ post-operative visit was 0.148 and 0.126 (p = 0.18), respectively. The difference in GIQLI scores on ‘30-day’ and ‘90-day’ visits were 0.5 (−7.1, 8.0), p=0.91 and 3.7 (−4.9, 12.3), p=0.42, respectively. LGG was recovered from the stools of 3 out of 5 subjects in the treatment group.

Conclusion

We did not appreciate a significant difference in the mean rate of weight loss or GIQLI scores between the groups who received LGG versus placebo. This study demonstrated survival of lactobacillus during transit through the gastrointestinal tract.
Enteric glutamatergic interneurons regulate intestinal motility
Authors: Hamnett Ryan , Bendrick Jacqueline L. , Robertson Keiramarie , Zhao Eric Tianjiao , Kaltschmidt Julia A.
Published: March 2024

The enteric nervous system (ENS) controls digestion autonomously via a complex neural network within the gut wall. Enteric neurons expressing glutamate have been identified by transcriptomic studies as a distinct subpopulation, and glutamate can affect intestinal motility by modulating enteric neuron activity. However, the nature of glutamatergic neurons, their position within the ENS circuit, and their function in regulating gut motility are unknown.

Here, we identify glutamatergic neurons as longitudinally projecting descending interneurons in the small intestine and colon, in addition to a novel class of circumferential neurons only in the colon. Both populations make synaptic contact with diverse neuronal subtypes, and signal with a variety of neurotransmitters and neuropeptides in addition to glutamate, including acetylcholine and enkephalin. Knocking out the glutamate transporter VGLUT2 from enkephalin neurons profoundly disrupts gastrointestinal transit, whileex vivooptogenetic stimulation of glutamatergic neurons initiates propulsive motility in the colon. This motility effect is reproduced when stimulating only the descending interneuron class, marked by Calb1 expression. Our results posit glutamatergic neurons as key interneurons that regulate intestinal motility.
Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules
Authors: Thienger Phillip , Rubin Philip D. , Yao Xiaosai , Benjak Andrej , Shah Sagar R. , Leung Alden King-Yung , de Brot Simone , Naveed Alina , Shi Minyi , Tremblay Julien , Triscott Joanna , Cassanmagnago Giada , Bolis Marco , Mela Lia , Beltran Himisha , Chen Yu , Piscuoglio Salvatore , Yu Haiyuan , Ng Charlotte K Y , Yauch Robert L. , Rubin Mark A.
Published: March 2024

The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex is frequently deregulated during progression to castration-resistant prostate cancer (CRPC). Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent CRPC (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF ATPase targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT), which accounts for about 10% of all clinical CRPC cases. In CRPC-WNT models, we discovered that SWI/SNF ATPase SMARCA4 depletion interfered with WNT signaling via the master transcriptional regulator TCF7L2 (TCF4). Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC by forming a complex with β-Catenin and AP-1 transcription factor c-JUN. These data suggest a mechanistic rationale for MAPK inhibition or interventions that disrupt the formation of the pro-proliferative TCF7L2-β-Catenin-JUN complex in the CRPC-WNT subclass of advanced prostate cancer.
A molecular switch orchestrates the nuclear export of human messenger RNA
Authors: Hohmann Ulrich , Graf Max , Schellhaas Ulla , Pacheco-Fiallos Belén , Fin Laura , Riabov-Bassat Daria , Pühringer Thomas , Szalay Michael-Florian , Tirián László , Handler Dominik , Brennecke Julius , Plaschka Clemens
Published: March 2024

The nuclear export of messenger RNA (mRNA) is a key step in eukaryotic gene expression (Köhler and Hurt, 2007). Despite recent insights into the packaging of newly transcribed mRNAs into ribonucleoprotein complexes (mRNPs) (Pacheco-Fiallos et al., 2023; Bonneau et al., 2023), the subsequent events that govern mRNA export are poorly understood. Here, we elucidate the molecular basis of human mRNA export licensing, which involves the remodeling of mRNP-bound transcription-export complexes (TREX), the formation of export-competent mRNPs, the docking of mRNPs at the nuclear pore complex (NPC), and the release of mRNPs at the NPC to initiate export. Our biochemical and structural data uncover the ATPase DDX39/UAP56 as a central molecular switch that directs mRNPs through the TREX and the NPC-anchored TREX-2 complexes using its ATPase and mRNA-binding cycle. Collectively, these findings establish a mechanistic framework for a general and conserved mRNA export pathway.
Multi-drug interaction target-controlled infusion from simultaneous optimization of pharmacometric models
Authors: Martinez-Vazquez Pablo , Abad-Torrent Ana
Published: March 2024

Background

Accurately controlling drug delivery is crucial for safe anesthesia. Target-controlled infusion (TCI) systems use pharmacokinetic and pharmacodynamic (PK/PD) models to administer intravenous agents to reach target concentrations. However, TCI’s operation is restricted to a single-drug and a linear PK/PD model, not accounting for drug interactions. Dose-response interaction (DRI) models quantify such interactions by representing shared effects as a function of agents’ concentrations. For example, the co-administration of an analgesic and a hypnotic with TCI leads to an uncontrolled synergy.

Methods

We introduce a new administering methodology for multi-drug infusions, interaction target-controlled infusion (iTCI), that combines the PK/PD models of the co-administered drugs and their interactions into a single optimal non-linear dynamic control problem with terminal constraints.

Results

Incorporating DRI and PK/PD models allows novel administration procedures. Simulations of iTCI in different clinical scenarios under propofol and remifentanil co-administrations are presented. These show that: (1) iTCI requires lower administered volumes than TCI to reach simultaneously the same target concentrations. (2) It offers optimal interdependent administrations that address not only concentration targets but also effect targets. (3) iTCI comes with additional constraints on the administration, including controlled titrations along iso-effect conditions (isoboles) or (5) directly limiting plasma concentration levels. (6) Unlike TCI, iTCI can include different exerted effects (ke0) per drug, particularly relevant for opioids.

Conclusion

The iTCI is a versatile multi-drug infusion paradigm where effects and interactions play a relevant role - providing better delivery profiles than current TCI while opening the door for using non-linear PK/PD descriptions in anesthesia.
A structured coalescent model reveals deep ancestral structure shared by all modern humans
Authors: Cousins Trevor , Scally Aylwyn , Durbin Richard
Published: March 2024

1

Understanding the series of admixture events and population size history leading to modern humans is central to human evolutionary genetics. Using a coalescence-based hidden Markov model, we present evidence for an extended period of structure in the history of all modern humans, in which two ancestral populations that diverged ∼1.5 million years ago came together in an admixture event ∼300 thousand years ago, in a ratio of ∼80:20 percent. Immediately after their divergence, we detect a strong bottleneck in the major ancestral population. We inferred regions of the present-day genome derived from each ancestral population, finding that material from the minority correlates strongly with distance to coding sequence, suggesting it was deleterious against the majority background. Moreover, we found a strong correlation between regions of majority ancestry and human-Neanderthal or human-Denisovan divergence, suggesting the majority population was also ancestral to those archaic humans.
A*PA2: up to 20 times faster exact global alignment
Authors: Groot Koerkamp Ragnar
Published: March 2024

Methods

We introduce A*PA2, an exact global pairwise aligner with respect to edit distance. The goal of A*PA2 is to unify the near-linear runtime of A*PA on similar sequences with the efficiency of dynamic programming (DP) based methods. Like Edlib, A*PA2 uses Ukkonen’s band doubling in combination with Myers’ bitpacking. A*PA2 1) extends this with SIMD (single instruction, multiple data), 2) uses large block sizes inspired by BlockAligner, 3) avoids recomputation of states where possible as suggested before by Fickett, 4) introduces a new optimistic technique for traceback based on diagonal transition, and 5) applies the heuristics developed in A*PA and improves them usingpre-pruning.

Results

The average runtime of A*PA2 is 19×faster than the exact aligners BiWFA and Edlibon>500 kbp long ONT reads of a human genome having 6% divergence on average. On shorter ONT reads of 11% average divergence the speedup is 5.6×(avg. length 11 kbp) and 0.81×(avg. length 800 bp). On all tested datasets, A*PA2 is competitive with or faster than approximate methods.

Availability

github.com/RagnarGrootKoerkamp/astar-pairwise-aligner

Contact

ragnar.grootkoerkamp@inf.ethz.ch
TestingAnopheleslarvae and adults using standard bioassays reveals susceptibility to chlorfenapyr (pyrrole) while highlighting variability between species
Authors: Bouaka Calmes , Ambadiang Marilene , Ashu Fred , Fouet Caroline , Kamdem Colince
Published: March 2024

A standard test is available for assessing the susceptibility of adultAnophelesmosquitoes to chlorfenapyr, a new active ingredient in insecticide-treated nets. However, for a new insecticide with a unique mode of action, testing both larvae and adults using different routes of exposure is crucial to a comprehensive evaluation of susceptibility and to identifying potential selection pressures that may drive resistance. We followed WHO guidelines to assess the lethal toxicity of chlorfenapyr and monitorAnophelessusceptibility. Based on the median lethal concentration (LC50), larvae of the pyrethroid-susceptible colonized strainAn. coluzziiNgousso were 16-fold more susceptible to chlorfenapyr than immature stages of another susceptible colony:An. gambiaeKisumu. Larval bioassays indicated 99.63 ± 0.2% mortality after 24 h at a discriminating concentration of 100 ng/ml inAnopheles gambiaeandAn. coluzziilarvae collected from seven locations in urban and rural areas of Yaoundé, Cameroon. By contrast, exposing emerging female adults from these populations to the recommended discriminating concentration (100 µg Active Ingredient (AI)/bottle) in bottle bioassays revealed variable mortality after 72 h, with values below the threshold of susceptibility (98%) in several tests.Anopheles coluzziilarvae and adults were fully susceptible, but mortality rates were slightly lower inAn. gambiaeadults compared to larvae (94 ± 1.5% vs 100%, Fisher’s exact test,p< 0.001). Piperonyl butoxide antagonized the activity of chlorphenapyr inAn. gambiaeadults. 100 ng/ml provides sufficient discriminative power for assessing the susceptibility ofAn. gambiaeandAn. coluzziilarvae to chlorfenapyr. TestingAn. gambiaeadults with 100 µg AI/bottle is likely to reveal inconsistent mortality values making it difficult to detect any emergence of resistance. Exploring different tests and accounting for variability between species are key to a reliable monitoring ofAnophelessusceptibility to chlorfenapyr.
Estimating Ejection Fraction from the 12 Lead ECG among Patients with Acute Heart Failure
Authors: Pokhrel Bhattarai Sunita , Dzikowicz Dillon J , Xue Ying , Block Robert , Tucker Rebecca G. , Bhandari Shilpa , Boulware Victoria E , Stone Breanne , Carey Mary G
Published: March 2024

Background

Identifying patients with low left ventricular ejection fraction (LVEF) in the emergency department using an electrocardiogram (ECG) may optimize acute heart failure (AHF) management. We aimed to assess the efficacy of 527 automated 12-lead ECG features for estimating LVEF among patients with AHF.

Method

Medical records of patients >18 years old and AHF-related ICD codes, demographics, LVEF %, comorbidities, and medication were analyzed. Least Absolute Shrinkage and Selection Operator (LASSO) identified important ECG features and evaluated performance.

Results

Among 851 patients, the mean age was 74 years (IQR:11), male 56% (n=478), and the median body mass index was 29 kg/m2(IQR:1.8). A total of 914 echocardiograms and ECGs were matched; the time between ECG-Echocardiogram was 9 hours (IQR of 9 hours);<30% LVEF (16.45%, n=140). Lasso demonstrated 42 ECG features important for estimating LVEF<30%. The predictive model of LVEF<30% demonstrated an area under the curve (AUC) of 0.86, a 95% confidence interval (CI) of 0.83 to 0.89, a specificity of 54% (50% to 57%), and a sensitivity of 91 (95% CI: 88% to 96%), accuracy 60% (95% CI:60 % to 63%) and, negative predictive value of 95%.

Conclusions

An explainable machine learning model with physiologically feasible predictors may be useful in screening patients with low LVEF in AHF.

Clinical Perspective

What is new?

Among 527 ECG features, 42 were important in estimating<30% reduced left ventricular ejection fraction (LVEF), showing the model’s high diagnostic accuracy (AUC of 0.86).

The model exhibits exceptional sensitivity (91%) in predicting<30% LVEF

ECG-derived metrics offer the potential for early detection of reduced LVEF, especially in settings with limited advanced diagnostic tools.

What are the clinical implications?

Enhanced diagnostic accuracy allows for the earlier detection of reduced LVEF through ECG analysis, which is critical in an environment where an echocardiogram is unavailable.

ECG features enable patient risk stratification for reduced LVEF, facilitating targeted management and optimization of healthcare resources.

The findings underscore the importance of integrating ECG features into AI-based diagnostic models for rapid, accurate LVEF estimation, supporting more informed clinical decisions and enabling effective remote patient monitoring.
Development of cell-free platforms for discovering, characterizing, and engineering post-translational modifications
Authors: Wong Derek A. , Shaver Zachary M. , Cabezas Maria D. , Daniel-Ivad Martin , Warfel Katherine F. , Prasanna Deepali V. , Sobol Sarah E. , Fernandez Regina , Nicol Robert , DeLisa Matthew P. , Balskus Emily P. , Karim Ashty S. , Jewett Michael C.
Published: March 2024

Post-translational modifications (PTMs) are important for the stability and function of many therapeutic proteins and peptides. Current methods for studying and engineering PTM installing proteins often suffer from low-throughput experimental techniques. Here we describe a generalizable,in vitroworkflow coupling cell-free protein synthesis (CFPS) with AlphaLISA for the rapid expression and testing of PTM installing proteins. We apply our workflow to two representative classes of peptide and protein therapeutics: ribosomally synthesized and post-translationally modified peptides (RiPPs) and conjugate vaccines. First, we demonstrate how our workflow can be used to characterize the binding activity of RiPP recognition elements, an important first step in RiPP biosynthesis, and be integrated into a biodiscovery pipeline for computationally predicted RiPP products. Then, we adapt our workflow to study and engineer oligosaccharyltransferases (OSTs) involved in conjugate vaccine production, enabling the identification of mutant OSTs and sites within a carrier protein that enable high efficiency production of conjugate vaccines. In total, we expect that our workflow will accelerate design-build-test cycles for engineering PTMs.
Characterization of a cytokinin-binding protein locus inMycobacterium tuberculosis
Authors: Yoo Jin Hee , Santarossa Cristina , Thomas Audrey , Ekiert Damian , Darwin K. Heran
Published: March 2024

Cytokinins are adenine-based hormones that have been well-characterized in plants but are also made by bacteria, including the human-exclusive pathogenMycobacterium tuberculosis. InM. tuberculosis, cytokinins activate transcription of an operon that affects the bacterial cell envelope. In plants, cytokinins are broken down by dedicated enzymes called cytokinin oxidases into adenine and various aldehydes. In proteasome degradation-deficientM. tuberculosis, the cytokinin-producing enzyme Log accumulates, resulting in the buildup of at least one cytokinin-associated aldehyde. We therefore hypothesized thatM. tuberculosisencodes one or more cytokinin oxidases. Using a homology-based search for homologs of a plant cytokinin oxidase, we identified Rv3719 and a putative cytokinin-specific binding protein, Rv3718c. Deletion of the locus encoding these proteins did not have a measurable effect onin vitrogrowth. Nonetheless, Rv3718c bound a cytokinin with high specificity. Our data thus support a model whereby cytokinins play one or more roles in mycobacterial physiology.

IMPORTANCE

Numerous bacterial species encode cytokinin-producing enzymes, the functions of which are almost completely unknown. This work contributes new knowledge to the cytokinin field for bacteria, and also revealed further conservation of cytokinin-associated proteins between plants and prokaryotes.
Dramatic Changes in Mitochondrial Subcellular Location and Morphology Accompany Activation of the CO2Concentrating Mechanism
Authors: Findinier Justin , Joubert Lydia-Marie , Schmid Michael F. , Malkovskiy Andrey , Chiu Wah , Burlacot Adrien , Grossman Arthur R.
Published: March 2024

Dynamic changes in intracellular ultrastructure can be critical for the ability of organisms to acclimate to environmental conditions. Microalgae, which are responsible for ∼50% of global photosynthesis, compartmentalize their Rubisco into a specialized structure known as the pyrenoid when the cells experience limiting CO2conditions; this compartmentalization appears to be a component of the CO2Concentrating Mechanism (CCM), which facilitates photosynthetic CO2fixation as environmental levels of inorganic carbon (Ci) decline. Changes in the spatial distribution of mitochondria in green algae have also been observed under CO2limiting conditions, although a role for this reorganization in CCM function remains unclear. We used the green microalgaeChlamydomonas reinhardtiito monitor changes in the position and ultrastructure of mitochondrial membranes as cells transition between high CO2(HC) and Low/Very Low CO2(LC/VLC). Upon transferring cells to VLC, the mitochondria move from a central to a peripheral location, become wedged between the plasma membrane and chloroplast envelope, and mitochondrial membranes orient in parallel tubular arrays that extend from the cell’s apex to its base. We show that these ultrastructural changes require protein and RNA synthesis, occur within 90 min of shifting cells to VLC conditions, correlate with CCM induction and are regulated by the CCM master regulator CIA5. The apico-basal orientation of the mitochondrial membrane, but not the movement of the mitochondrion to the cell periphery, is dependent on microtubules and the MIRO1 protein, which is involved in membrane-microtubule interactions. Furthermore, blocking mitochondrial electron transport in VLC acclimated cells reduces the cell’s affinity for inorganic carbon. Overall, our results suggest that CIA5-dependent mitochondrial repositioning/reorientation functions in integrating cellular architecture and energetics with CCM activities and invite further exploration of how intracellular architecture can impact fitness under dynamic environmental conditions.
3D imaging of neuronal inclusions and protein aggregates in human neurodegeneration by multiscale X-ray phase-contrast tomography
Authors: Reichmann Jakob , Franz Jonas , Eckermann Marina , Schulz Katja , Mollenhauer Brit , Stadelmann Christine , Salditt Tim
Published: March 2024

This study leverages X-ray phase-contrast tomography for detailed analysis of neurodegenerative diseases focusing on the 3D visualization and quantification of neuropathological features within fixed human postmortem tissue. X-ray phase-contrast tomography with synchrotron radiation offers micrometer and even sub-micron resolution, enabling us to examine intra- and extraneuronal aggregates and inclusions such as Lewy bodies, granulovacuolar degeneration, Hirano bodies, neurofibrillary tangles, β-amyloid plaques and vascular amyloid deposits in three dimensions (3D). In the reconstructions, we identified the highest electron densities in Hirano bodies and Lewy bodies while neurofibrillary tangles exhibit only slight alterations in X-ray phase-contrast tomography contrast. Using cutting edge high-resolution X-ray synchrotron beamlines we are now able to even detect subcellular differences of electron densities found in granulovacuolar degeneration. Small scale inhomogeneities of the electron density are also detected in Lewy bodies potentially relating to inclusions of organelles. Additionally, we reveal a peculiar 3D geometry of Hirano bodies and demonstrate the co-occurence with granulovacuolar degeneration in the same neuron. Utilizing X-ray phase-contrast tomography in a complementary fashion to traditional technologies, a quantitative, systematic and disease-overarching understanding of inclusions and aggregates in neurodegeneration can be achieved.
Genetic and phenotypic architecture of human myocardial trabeculation
Authors: McGurk Kathryn A , Qiao Mengyun , Zheng Sean L , Sau Arunashis , Henry Albert , Ribeiro Antonio Luiz P , Ribeiro Antônio H , Ng Fu Siong , Lumbers R Thomas , Bai Wenjia , Ware James S , O’Regan Declan P
Published: March 2024

Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart. Their development depends on multiscale morphogenetic processes and, while highly conserved across vertebrate evolution, their role in the pathophysiology of the mature heart is not fully understood. We report variant associations across the allele frequency spectrum for trabecular morphology in 47,803 participants of the UK Biobank using fractal dimension analysis of cardiac imaging. We identified an association between trabeculation and rare variants in 56 genes that regulate myocardial contractility and ventricular development. Genome-wide association studies identified 68 novel loci in pathways that regulate sarcomeric function, differentiation of the conduction system, and cell fate determination. We found that trabeculation-associated variants were modifiers of cardiomyopathy phenotypes with opposing effects in hypertrophic and dilated cardiomyopathy. Together, these data provide insights into mechanisms that regulate trabecular development and plasticity, and identify a potential role in modifying monogenic disease expression.
MMA athletes demonstrate different brain vital sign profiles compared to matched controls at baseline
Authors: Munce Thayne A. , Fickling Shaun D. , Nijjer Shaquile , Poel Daniel N. , D’Arcy Ryan C.N.
Published: March 2024

We investigated objective brain vital signs derived from event-related potentials (ERPs) for mixed martial arts (MMA) athletes and matched controls (N=24). Brain vital sign scans were acquired from 9 MMA athletes and 15 age- and sex-matched controls. Our analysis specifically compared differences in brain vital signs between MMA athletes and controls at baseline. We predicted that MMA athletes would show significant differences relative to controls due to their ongoing exposure to repetitive head impacts. Participants were scanned to extract three well-established ERPs: N100 for auditory sensation; P300 for basic attention; and N400 for cognitive processing. Scans were verified using automated reports, with N100, P300, and N400 amplitudes and latencies manually identified by a blinded reviewer. Groups were evaluated at the waveform level with a mass-univariate analysis using non-parametric resampling. Brain vital signs were compared across groups with a Kruskal-Wallis H-test for independent samples, with FDR correction for multiple comparisons. We identified significant differences between MMA athletes and controls. Specifically, there were significant N400 amplitude reductions, indicating that exposure to repetitive head impacts in MMA may be associated with changes in brain function.
Ultrasonic Texture Analysis for Acute Myocardial Infarction Risk Stratification: A Pilot Study
Authors: Hathaway Quincy A. , Jamthikar Ankush D. , Chaitman Bernard R. , Carson Jeffery , Yanamala Naveena , Sengupta Partho P.
Published: March 2024

Background

Current risk stratification tools for acute myocardial infarction (AMI) have limitations, particularly in predicting mortality. This study utilizes cardiac ultrasound radiomics (i.e., ultrasomics) to risk stratify AMI patients when predicting all-cause mortality.

Methods

The study included 197 patients: a) retrospective internal cohort (n=155) of non-ST-elevation myocardial infarction (n=63) and ST-elevation myocardial infarction (n=92) patients, and b) external cohort from the multicenter Door-To-Unload in ST-segment–elevation myocardial infarction [DTU-STEMI] Pilot Trial (n=42). Echocardiography images of apical 2, 3, and 4-chamber were processed through an automated deep-learning pipeline to extract ultrasomic features. Unsupervised machine learning (topological data analysis) generated AMI clusters followed by a supervised classifier to generate individual predicted probabilities. Validation included assessing the incremental value of predicted probabilities over the Global Registry of Acute Coronary Events (GRACE) risk score 2.0 to predict 1-year all-cause mortality in the internal cohort and infarct size in the external cohort.

Results

Three phenogroups were identified: Cluster A (high-risk), Cluster B (intermediate-risk), and Cluster C (low-risk). Cluster A patients had decreased LV ejection fraction (P=0.004) and global longitudinal strain (P=0.027) and increased mortality at 1-year (log rank P=0.049). Ultrasomics features alone (C-Index: 0.74 vs. 0.70, P=0.039) and combined with global longitudinal strain (C-Index: 0.81 vs. 0.70, P<0.001) increased prediction of mortality beyond the GRACE 2.0 score. In the DTU-STEMI clinical trial, Cluster A was associated with larger infarcts size (>10% LV mass, P=0.003), compared to remaining clusters.

Conclusions

Ultrasomics-based phenogroup clustering, augmented by TDA and supervised machine learning, provides a novel approach for AMI risk stratification.
A protocol for a scoping review on the role of whole-body and dedicated body-part magnetic resonance imaging for assessment of adult and juvenile idiopathic inflammatory myopathies
Authors: Essouma Mickael , de Araujo Daniel Brito , Day Jessica , Gupta Latika , Knight Adina Kay , Reed Ann , Naddaf Elie , Elias Sallum Adriana Maluf , Marrani Edoardo , Conticini Edoardo , Appenzeller Simone , Knight Adina Kay , Dimachkie Mazen , Abou Tamima Mohamad , Gibson Daren , Kirkhus Eva , van der Koi Anneke J , Lilleker James B , Lucchini Matteo , Machado Pedro , Riopel Mary Anne , Sanner Helga , Schiffenbauer Adam , Guimarães Julio Brandão , Saad-Magalhaes Claudia , O’Hanlon Susan , Omori Clarissa Harumi , Phaneuf Susan , Sanner Helga , Moghadam-Kia Siamak , Tolend Mirkamal , Ventura Iazsmin Bauer , Rider Lisa G , Christopher-Stine Lisa , Paik Julie J , Feldman Brian , Shinjo Samuel Katsuyuki , Doria Andrea Schwarz
Published: March 2024

Background

Currently, there is lack of standardization of magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults among treatment centres across the globe. Therefore, we will perform scoping reviews of the literature to inform available semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs with the final goal of providing evidence-based information for the future development of a universal standardized MRI scoring system in specific research and clinical settings in this population.

Methods

Electronic databases (PubMed, EMBASE, and Cochrane) will be searched to select relevant articles published from January 2000 to October 2023. Data will be synthesized narratively.

Discussion

This scoping review will extensively map evidence on the indications, utility for diagnosis and assessment of disease activity and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for MRI assessment of skeletal muscle changes in patients with IIMs.
An efficient inducible model for the control of gene expression in renin cells
Authors: Medrano Silvia , Yamaguchi Manako , Yamaguchi Hiroki , de Almeida Lucas Ferreira , Sigmund Curt D. , Sequeira-Lopez Maria Luisa S. , Ariel Gomez R.
Published: March 2024

Background

Fate mapping and genetic manipulation of renin cells have relied on either non-inducibleCrelines that can introduce developmental effects of gene deletion or BAC transgene-based inducible models that may be prone to spurious and/or ectopic gene expression.

Methods

We generated an inducible mouse model in whichCreERT2is under the control of the endogenousAkr1b7gene, an independent marker of renin cells.

Results

We evaluated the pattern ofCreexpression inAkr1b7CreERT2/+;R26RmTmG/+mice in which Akr1b7+/renin+cells become GFP+ upon tamoxifen administration. At E18.5 and P5, GFP was found in Juxtaglomerular cells, along the arterioles, and in the glomerular mesangium. In adult kidneys, GFP was present mainly in Juxtaglomerular cells. In mice treated with captopril and a low sodium diet to induce recruitment of renin cells, GFP extended along the afferent arterioles and in the mesangium. In addition, we deleted renin in adult mice and found a marked reduction in kidney renin expression and mean arterial pressure in mutant animals. When subjected to a homeostatic threat, mutant mice were unable to recruit renin+cells. Most importantly, mice with renin deletion induced in the adult developed concentric vascular hypertrophy ruling out potential developmental effects on the vasculature due to the lack of renin.

Conclusions

Renin can be efficiently and specifically deleted in renin cells in adult life using our conditional model.Akr1b7CreERT2mice constitute an excellent model for the fate mapping of renin cells and for the spatial and temporal control of gene expression in renin cells.
MAC3A and MAC3B modulateFLMsplicing to repress photoperiod-dependent floral transition
Authors: Huang Yu-Wen , Tseng Chih-Yen , Tu Yi-Tsung , Hsieh Hsin-Yu , Wang Yu-Sen , Ly Yun-Tung , Chen Yu-Zhen , Tu Shih-Long , Lee Chin-Mei
Published: March 2024

Plants adjust their flowering time by integrating environmental cues through complex regulatory networks. RNA splicing plays a crucial role in modulating gene expression in response to flowering signals. The MOS4-associated complex (MAC), consisting of the evolutionarily conserved E3 ubiquitin ligases MAC3A and MAC3B, is pivotal in splicing regulation. However, their involvement in floral transition remained unclear. This study observed thatmac3a/mac3bmutants flowered significantly earlier under short-day (SD) conditions, a phenotype absent under long-day (LD) conditions. This early flowering correlated with upregulation ofFLOWERING LOCUS T(FT) andSUPPRESSOR OF OVEREXPRESSION OF CO 1(SOC1) compared to wild-type plants. Transcriptomic analysis revealed alterations in transcript levels and splicing profiles of key floral regulators across different flowering pathways. Further investigation identified the thermosensory flowering regulatorFLOWERING LOCUS M(FLM) as being influenced byMAC3AandMAC3B. Subsequently, we found thatMAC3AandMAC3Bexhibited higher expression and were associated withFLMtranscripts to modulate their splicing in SD. This study elucidates how the MAC complex, through RNA splicing regulation, integrates environmental signals to modulate flowering, unveiling a new layer of complexity in flowering pathways crosstalk under non-inductive photoperiods.
Ligand-induced CaMKIIα hub Trp403 flip, hub domain stacking and kinase inhibition
Authors: Narayanan Dilip , Larsen Anne Sofie G. , Gauger Stine Juul , Adafia Ruth , Hammershøi Rikke Bartschick , Hamborg Louise , Bruus-Jensen Jesper , Griem-Krey Nane , Gee Christine L. , Frølund Bente , Stratton Margaret M. , Kuriyan John , Kastrup Jette Sandholm , Langkilde Annette E. , Wellendorph Petrine , Solbak Sara M. Ø.
Published: March 2024

γ-Hydroxybutyric acid (GHB) analogs are small molecules that bind competitively to a specific cavity in the oligomeric CaMKIIα hub domain. Binding affects conformation and stability of the hub domain, which may explain the neuroprotective action of some of these compounds. Here, we describe molecular details of interaction of the larger-type GHB analog 2-(6-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-yl)acetic acid (PIPA). Like smaller-type analogs, PIPA binding to the CaMKIIα hub domain promoted thermal stability. PIPA additionally inhibited CaMKIIα kinase activity by reducing CaM sensitivity. A high-resolution X-ray crystal structure of a stabilized CaMKIIα (6x mutant) hub construct revealed details of the binding mode of PIPA, which involved outward placement of tryptophan 403 (Trp403), a central residue in a flexible loop close to the upper hub cavity. Small-angle X-ray scattering (SAXS) solution structures and mass photometry of the CaMKIIα wildtype hub domain in the presence of PIPA revealed a high degree of ordered self-association (stacks of CaMKIIα hub domains). This stacking neither occurred with the smaller compound 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), nor when Trp403 was replaced with leucine (W403L). Additionally, CaMKIIα W403L hub was stabilized to a larger extent by PIPA compared to CaMKIIα hub wildtype, indicating that loop flexibility is important for holoenzyme stability. Thus, we propose that ligand-induced outward placement of Trp403 by PIPA, which promotes an unforeseen mechanism of hub domain stacking, may be involved in the observed reduction in CaMKIIα kinase activity. Altogether, this sheds new light on allosteric regulation of CaMKIIα activity via the hub domain.
The expression of integron arrays is shaped by the translation rate of cassettes
Authors: Carvalho André , Hipólito Alberto , da Roza Filipa Trigo , García-Pastor Lucía , Vergara Ester , Buendía Aranzazu , García-Seco Teresa , Escudero José Antonio
Published: March 2024

Integrons are key elements in the rise and spread of multidrug resistance in Gram-negative bacteria. These genetic platforms capture cassettes containing promoterless genes and stockpile them in arrays of variable length. In the current integron model, expression of cassettes is granted by the Pc promoter in the platform and is assumed to decrease as a function of its distance. Here we explored this model using a large collection of 136 antibiotic resistance cassettes and show that the effect of distance is in fact negligible. Instead, cassettes have a strong impact in the expression of downstream genes because their translation rate affects the stability of the whole polycistronic mRNA molecule. Hence, poorly translated cassettes decrease the expression and resistance phenotype of cassettes downstream. Our data puts forward a novel integron model in which expression is contingent on the translation of cassettes upstream, rather than on the distance to the Pc.
Genomic diversity inPaenibacillus polymyxa: Unveiling distinct species groups and functional variability
Authors: Wallner Adrian , Antonielli Livio , Mesguida Ouiza , Rey Patrice , Compant Stéphane
Published: March 2024

Paenibacillus polymyxais a bacterial species of high interest, as suggested by the increased number of publications on its functions in the past years. Accordingly, the number of described strains and sequenced genomes is also on the rise. While functional diversity was repeatedly suggested for this species, the available genomic data is now sufficient to confidently segregate strains affiliated toP. polymyxainto two major species groups. As these strains exhibit considerable potential in agriculture, medicine, and bioremediation, it is preferable to clarify their taxonomic affiliation to facilitate reliable and durable approval as active ingredients. Strains currently affiliated toP. polymyxacan be separated into two major species groups with differential potential in nitrogen fixation, plant interaction, secondary metabolism, and antimicrobial resistance, as inferred from genomic data.
Isolation and characterization of a phage collection againstPseudomonas putida
Authors: Brauer Age , Rosendahl Sirli , Kängsep Anu , Lewańczyk Alicja Cecylia , Rikberg Roger , Hõrak Rita , Tamman Hedvig
Published: March 2024

The environmental bacteriumPseudomonas putidahas a wide range of metabolic pathways and thus entails great promise both as cell factories in biotechnological production and for bioremediation approaches to degrade various aromatic pollutants. To thrive in the environment,P. putidahas to be able to endure the constant threat posed by bacteriophages. Surprisingly, up until now, only a few phages have been isolated for the common laboratory strainP. putidaKT2440, and no phage defence mechanisms have been characterized yet. Here, we introduce a novelCollection ofEnvironmentalPseudomonas putidaPhages fromEstonia (CEPEST), consisting of 67 dsDNA phages that belong to 22 phage species and nine phage genera. We show that most of the phages in the CEPEST collection are more infectious at lower temperatures, have a narrow host range, and require intact LPS forP. putidainfection. Additionally, we demonstrate that cryptic prophages in theP. putidachromosome strongly protect against the infection of many phages, whereas the chromosomal toxin-antitoxin systems play no role in phage defence ofP. putida.
Microbiome turnover during offspring development varies with maternal care, but not moult, in a hemimetabolous insect
Authors: Cheutin Marie-Charlotte , Boucicot Manon , Meunier Joël
Published: March 2024

The ecological success of insects often depends on their association with beneficial microbes. However, insect development involves repeated moults, which can have dramatic effects on their microbial communities. Here, we investigated whether and how moulting affects the microbiome of a hemimetabolous insect, and whether maternal care can modulate these effects. We reared European earwig juveniles with or without mothers and used 16S rRNA metabarcoding to analyse the prokaryotic fraction of the core microbiome of eggs, recently and old moulted individuals at four developmental stages and the resulting adults. The 218 samples obtained showed that the microbiome diversity changed non-linearly during development and that these changes were associated with bacterial biomarkers. Surprisingly, these changes did not occur during moulting, but rather between the beginning and end of certain developmental stages. We also found that access to maternal care affected the microbiome of both juveniles and adults, even when the last contact with mothers was two months before adulthood. Overall, these results provide new insights into our understanding of the (in)stability of the prokaryotic microbiome in hemimetabolous insects and its independence from moult. More generally, they question the role of microbiome acquisition through maternal care in maintaining family life in species where this behaviour is facultative.
Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST
Authors: Kraus Felix , He Yuchen , Swarup Sharan , Overmyer Katherine A. , Jiang Yizhi , Brenner Johann , Capitanio Cristina , Bieber Anna , Jen Annie , Nightingale Nicole M. , Anderson Benton J. , Lee Chan , Paulo Joao A. , Smith Ian R. , Plitzko Jürgen M. , Gygi Steven P. , Schulman Brenda A. , Wilfling Florian , Coon Joshua J. , Harper J. Wade
Published: March 2024

Lysosomal storage diseases (LSDs) comprise ∼50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multi-omic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially inNPC1-/-andNPC2-/-mutants, where lysosomes accumulate cholesterol. Autophagic and endocytic cargo delivery failures correlated with elevated lyso-phosphatidylcholine species and multi-lamellar structures visualized by cryo-electron tomography. Loss of mitochondrial cristae, MICOS- complex components, and OXPHOS components rich in iron-sulfur cluster proteins inNPC2-/-cells was largely alleviated when iron was provided through the transferrin system. This study reveals how lysosomal dysfunction affects mitochondrial homeostasis and underscores nMOST as a valuable discovery tool for identifying molecular phenotypes across LSDs.
Diurnal Regulation of SOS Pathway and Sodium Excretion Underlying Salinity Tolerance ofVigna marina
Authors: Noda Yusaku , Wang Fanmiao , Chankaew Sompong , Ariga Hirotaka , Muto Chiaki , Iki Yurie , Ohashi Haruko , Takahashi Yu , Sakai Hiroaki , Iseki Kohtaro , Ogiso-Tanaka Eri , Suzui Nobuo , Yin Yong-Gen , Miyoshi Yuta , Enomoto Kazuyuki , Kawachi Naoki , Somta Prakit , Furukawa Jun , Tomooka Norihiko , Naito Ken
Published: March 2024

Vigna marina(Barm.) Merr. is adapted to tropical marine beaches and has an outstanding tolerance to salt stress. Given there are growing demands for cultivating crops in saline soil or with saline water, it is important to understand how halophytic species are adapted to the saline environments. Here we revealed by positron emitting tracer imaging system (PETIS) thatV. marinaactively excretes sodium from the root during the light period but not in the dark period. The following whole genome sequencing accompanied with forward genetic study identified a QTL region harboringSOS1, encoding plasma membrane Na+/H+antiporter, which was associated with not only salt tolerance but also ability of sodium excretion. We also found the QTL region contained a large structural rearrangement that suppressed recombination across ∼20 Mbp, fixing multiple gene loci potentially involved in salt tolerance. RNA-seq and promoter analyses revealedSOS1inV. marinawas highly expressed even without salt stress and its promoter shared commoncis-regulatory motifs with those exhibiting similar expression profile. Interestingly, thecis-regulatory motifs seemed installed by a transposable element (TE) insertion. Though not identified by genetic analysis, the transcriptome data also revealedSOS2transcription was under diurnal regulation, explaining the pattern of sodium excretion together with up-regulated expression ofSOS1. Furthermore, we demonstrated that, under a condition of mild salt stress, the plants with the diurnally regulated SOS pathway outperformed those with the constitutively activated one.