bluuebunny/crossref_metadata_2025 huggingface dataset:
Automated, Objective Speech and Language Markers of Longitudinal Changes in Psychosis Symptoms
Authors: Tang Sunny X. , Spilka Michael J. , John Majnu , Birnbaum Michael L. , Saito Ema , Berretta Sarah A. , Behbehani Leily M. , Liberman Mark Y. , Malhotra Anil K. , Simpson William , Kane John M.
Published: July 2024

Background and Hypotheses

We sought to evaluate the ability of automated speech and language features to track fluctuations in the major psychosis symptoms domains:Thought Disorder, Negative Symptoms, andPositive Symptoms.

Study Design

Sixty-six participants with psychotic disorders were longitudinally assessed soon after inpatient admission, at discharge, and at 3- and 6-months. Psychosis symptoms were measured with semi-structured interviews and standardized scales. Recordings were collected from paragraph reading, fluency, picture description, and open-ended tasks. Longitudinal relationships between psychosis symptoms and 357 automated speech and language features were analyzed using a single component score and as individual features, using linear mixed models.

Study Results

All three psychosis symptom domains demonstrated significant longitudinal relationships with the single component score.Thought Disorderwas particularly related to features describing more subordinated constructions, less efficient identification of picture elements, and decreased semantic distance between sentences.Negative Symptomswas related to features describing decreased speech complexity.Positive Symptomsappeared heterogeneous, withSuspiciousnessrelating to greater use of nouns, andHallucinationsrelated to decreased semantic distances. These relationships were largely robust to interactions with gender and race. However, interactions with timepoint revealed variable relationships during different phases of illness (acute vs. stable).

Conclusions

Automated speech and language features show promise as scalable, objective markers of psychosis severity. The three symptom domains appear to be distinguishable with different features. Detailed attention to clinical setting and patient population is needed to optimize clinical translation; there are substantial implications for facilitating differential diagnosis, improving psychosis outcomes and enhancing therapeutic discovery.
Evaluating the Potential of Wearable Technology in Early Stress Detection: A Multimodal Approach
Authors: Darwish Basil A. , Salem Nancy M. , Kareem Ghada , Mahmoud Lamees N. , Sadek Ibrahim
Published: July 2024

Stress can adversely impact health, leading to issues like high blood pressure, heart diseases, and a compromised immune system. Consequently, using wearable devices to monitor stress is essential for prompt intervention and effective management. This study investigates the efficacy of wearable devices in the early detection of psychological stress, employing both binary and five-class classification models. Significant correlations were observed between stress levels and physiological signals, including Electrocardiogram (ECG), Electrodermal Activity (EDA), and Respiration (RESP), establishing these modalities as reliable biomarkers for stress detection. Utilizing the publicly available Wearable Stress and Affect Detection (WESAD) dataset, we employed two ensemble methods, Majority Voting (MV) and Weighted Averaging (WA), to integrate these signals, achieving maximum accuracies of 99.96% for binary classification and 99.59% for five-class classification. This integration significantly enhances the accuracy and robustness of the stress detection system. Furthermore, ten different classifiers were evaluated, and hyperparameter optimization and K-fold cross-validation ranging from 3-fold to 10-fold were applied. Both time-domain and frequency-domain features were examined separately. A review of commercially available wearable devices supporting these modalities was also conducted, resulting in recommendations for optimal configurations for practical applications. Our findings highlight the potential of multimodal wearable devices in advancing the early detection and continuous monitoring of psychological stress, with significant implications for future research and the development of improved stress detection systems.
Accurate Predictions of Liquid-Liquid Phase Separating Proteins at Single Amino Acid Resolution
Authors: Monti Michele , Fiorentino Jonathan , Miltiadis-Vrachnos Dimitrios , Bini Giorgio , Cotrufo Tiziana , de Groot Natalia Sanchez , Armaos Alexandros , Tartaglia Gian Gaetano
Published: July 2024

Liquid-liquid phase separation (LLPS) is a molecular mechanism that leads to the formation of membraneless organelles inside the cell. Despite recent advances in the experimental probing and computational prediction of proteins involved in this process, the identification of the protein regions driving LLPS and the prediction of the effect of mutations on LLPS are lagging behind.

Here, we introduce catGRANULE 2.0 ROBOT (R - Ribonucleoprotein, O - Organization, in B - Biocondensates, O - Organelle, T - Types), an advanced algorithm for predicting protein LLPS at single amino acid resolution. Integrating physico-chemical properties of the proteins and structural features derived from AlphaFold models, catGRANULE 2.0 ROBOT significantly surpasses traditional sequence-based and state-of-the-art structure-based methods in performance, achieving an Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.76 or higher. We present a comprehensive evaluation of the algorithm across multiple organisms and cellular components, demonstrating its effectiveness in predicting LLPS propensities at the single amino acid level and the impacts of mutations on LLPS. Our results are robustly supported by experimental validations, including immunofluorescence microscopy images from the Human Protein Atlas.

catGRANULE 2.0 ROBOT’s potential in protein design and mutation control can improve our understanding of proteins’ propensity to form subcellular compartments and help develop strategies to influence biological processes through LLPS. catGRANULE 2.0 ROBOT is freely available athttps://tools.tartaglialab. com/catgranule2.
ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers
Authors: O’Neill Kathryn , Shaw Regina , Bolger Isobel ,   NYGC ALS Consortium, Tam Oliver , Phatnani Hemali , Hammell Molly Gale
Published: July 2024

Amyotrophic Lateral Sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this general heterogeneity, several common factors have been identified. For example, nearly all patients show pathological accumulations of phosphorylated TDP-43 protein in affected regions of the motor cortex and spinal cord. Moreover, large patient cohort studies have revealed that most patient samples can be grouped into a small number of ALS subtypes, as defined by their transcriptomic profiles. These ALS molecular subtypes can be grouped by whether postmortem motor cortex samples display signatures of: mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or dense TDP-43 pathology and associated transposable element de-silencing (ALS-TE). In this study, we have built a deep layer ALS neural network classifier (DANcer) that has learned to accurately assign patient samples to these ALS subtypes, and which can be run on either bulk or single-cell datasets. Upon applying this classifier to an expanded ALS patient cohort from the NYGC ALS Consortium, we show that ALS Molecular Subtypes are robust across clinical centers, with no new subtypes appearing in a cohort that has quadrupled in size. Signatures from two of these molecular subtypes strongly correlate with disease duration: ALS-TE signatures in cortex and ALS-Glia signatures in spinal cord, revealing molecular correlates of clinical features. Finally, we use single nucleus RNA sequencing to reveal the cell type-specific contributions to ALS subtype, as determined by our single-cell classifier (scDANCer). Single-cell transcriptomes reveal that ALS molecular subtypes are recapitulated in neurons and glia, with both ALS-wide shared alterations in each cell type as well as ALS subtype-specific alterations. In summary, ALS molecular subtypes: (1) are robust across large cohorts of sporadic and familial ALS patient samples, (2) represent a combination of cellular, genetic, and pathological features, and (3) correlate with clinical features of ALS.

Abstract Figure

Figure 0:

Graphical Abstract - ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers.
Enhanced Visualization of Influenza A Virus Entry Using Virus-View Atomic Force Microscopy
Authors: Yoshida Aiko , Uekusa Yoshitsugu , Suzuki Takeshi , Bauer Michael , Sakai Nobuaki , Yamauchi Yohei
Published: July 2024

Virus entry begins with attachment of virions to the cell surface, multivalent binding of viral proteins to receptors, signaling, and endocytosis. Using ViViD-AFM (Virus-View Dual confocal and Atomic Force Microscopy), we visualized the nanoscale morphology of influenza A virus (IAV) virions interacting with the cell membrane during virus entry. Following attachment to the cell surface, spherical IAV (90-100 nm in diameter) diffused in a sialic acid- and neuraminidase-dependent manner. Reduced diffusion signified the onset of clathrin coat assembly, followed by formation of actin-rich ruffles that promoted pit closure and IAV endocytosis. Cell surface ruffles sheared filamentous IAV (>1µm in length) into shorter fragments that became internalized. ViViD-AFM is a powerful tool that provides nanoscale morphological insights of virus-cell membrane interplay in living cells.
Structures of TGF-β with betaglycan and the signaling receptors reveal the mechanism whereby betaglycan potentiates receptor complex assembly and signaling
Authors: Wieteska Łukasz , Taylor Alexander B. , Punch Emma , Coleman Jonathan A. , Conway Isabella O. , Lin Yeu-Farn , Byeon Chang-Hyeock , Hinck Cynthia S. , Krzysiak Troy , Ishima Rieko , López-Casillas Fernando , Cherepanov Peter , Bernard Daniel J. , Hill Caroline S. , Hinck Andrew P.
Published: July 2024

Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-β (TGF-β) family of signaling ligands. It is essential for embryonic development and tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-β isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-βs and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-β bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed novel binding interfaces that differ from those described for the closely related co-receptor of the TGF-β family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-β signal potentiation.
High-throughput method rapidly characterizes hundreds of novel antibiotic resistance mutations
Authors: Jago Matthew J. , Soley Jake K. , Denisov Stepan , Walsh Calum J. , Gifford Danna R. , Howden Benjamin P. , Lagator Mato
Published: July 2024

A fundamental obstacle to tackling the antimicrobial resistance crsisis is identifying mutations that lead to resistance in a given genomic background and environment. We present a high-throughput technique – Quantitative Mutational Scan Sequencing (QMS-Seq) – that enables quantitative comparison of which genes are under antibiotic selection and captures how genetic background influences resistance evolution. We compared fourE. colistrains exposed to ciprofloxacin, cycloserine, or nitrofurantoin and identified 975 resistance mutations, many in genes and regulatory regions not previously associated with resistance. QMS-Seq revealed that multi-drug and antibiotic-specific resistance are acquired through categorically different types of mutations, and that minor genotypic differences significantly influence evolutionary routes to resistance. By quantifying mutation frequency with single base pair resolution, QMS-Seq informs about the underlying mechanisms of resistance and identifies mutational hotspots within genes. Our method provides a way to rapidly screen for resistance mutations while assessing the impact of multiple confounding factors.
Synthesis of K+channel radioligand [18F]5-methyl-3-fluoro-4-aminopyridine and PET imaging in mice
Authors: Sun Yang , Ramos-Torres Karla M. , Takahashi Kazue , Zhang Lauren L. , Brugarolas Pedro
Published: July 2024

Abstract and Graphical abstract

[18F]3-fluoro-4-aminopyridine ([18F]3F4AP) is the first positron emission tomography (PET) radioligand that targets voltage-gated potassium (K+) channels in the brain for imaging demyelination. [18F]3F4AP exhibits high brain penetration, favorable kinetics for PET imaging, and high sensitivity to demyelinating lesions. However, recent studies in awake human subjects indicate lower metabolic stability than in anesthetized animals, resulting in reduced brain uptake. Therefore, there is a need for novel radioligands for K+channels with suitable pharmacological properties and enhanced metabolic stability. Recentin vitrostudies demonstrate that 5-methyl-3-fluoro-4-aminopyridine (5Me3F4AP) exhibits comparable binding affinity to K+channels, pKa, logD, and membrane permeability as 3F4AP, and a slower enzymatic metabolic rate, suggesting its potential as a K+channel PET tracer. In this study, we describe the radiochemical synthesis of [18F]5Me3F4AP using an isotope exchange method from the corresponding 3-fluoro-5-methyl-4-nitropyridine N-oxide, followed by a palladium on carbon mediated hydrogenation of the nitro and N-oxide groups. This method yielded [18F]5Me3F4AP with high purity and acceptable molar activity. PET/CT studies using naïve mice demonstrate that [18F]5Me3F4AP effectively crosses the blood-brain barrier and has comparable kinetics to [18F]3F4AP. These findings strongly suggest that [18F]5Me3F4AP is a promising candidate for neuroimaging applications and warrant further studies to investigate its sensitivity to lesions andin vivometabolic stability.

Abstract Figure
Basis of Glucose and Fructose Selectivity in Sugar Transport Proteins
Authors: Andersen Camilla Gottlieb , Bavnhøj Laust , Brag Søren , Driller Jan Heiner , Pedersen Bjørn Panyella
Published: July 2024

The distribution of sugars is crucial for plant energy, signaling, and defense mechanisms. Sugar Transport Proteins (STPs) are Sugar Porters that mediate proton-driven cellular uptake of glucose. Some STPs transport fructose, while others remain highly selective only glucose. What determines this selectivity, distinguishing between compounds with highly similar chemical composition remains unknown. Here, we present the structure ofArabidopsis thalianaSTP6 in an inward occluded conformational state with glucose bound and demonstrate its role as both a glucose and fructose transporter. We perform a comparative analysis of STP6 with the glucose-selective STP10 usingin-vivoandin-vitrosystems, demonstrating how different experimental setups strongly influence kinetic transport properties. Finally, we show that the position of a single methyl group in the binding site is sufficient to shuffle glucose and fructose specificity, providing detailed insights into the fine-tuned dynamics of affinity-induced specificity for sugar uptake. Altogether these findings enhance our understanding of sugar trafficking by Sugar Transport Proteins and lay the groundwork for the future advancements need to support plant engineering and enhance resistance towards pathogens.
Structural characterization of two full length γδ TCR/CD3 complexes
Authors: Hoque Mohammed , Grigg John Benji , Ramlall Trudy , Jones Jennifer , McGoldrick Luke L. , Olson William C. , Lin John C. , Smith Eric , Franklin Matthew C. , Zhang Tong , Saotome Kei
Published: July 2024

The T-cell receptor (TCR)/CD3 complex plays an essential role in the immune response and is a key player in cancer immunotherapies. There are two classes of TCR/CD3 complexes, defined by their TCR chain usage (αβ or γδ). Recently reported structures have revealed the organization of the αβ TCR/CD3 complex, but similar studies regarding the γδ TCR/CD3 complex have lagged behind. Here, we report cryoelectron microscopy (cryoEM) structural analysis of two full-length γδ TCRs, G115 (Vγ9Vδ2) and 9C2 (Vγ5Vδ1), in complex with CD3 subunits. Our results show that the overall subunit organization of the γδ TCR-CD3 complexes is similar to αβ TCRs. However, both γδ TCRs display highly mobile extracellular domains (ECDs), unlike αβ TCRs, which have TCR ECDs that are rigidly coupled to its transmembrane (TM) domains. We corroborate this finding in cells by demonstrating that a γδ T-cell specific antibody can bind a site that would be inaccessible in the more rigid αβ TCR/CD3 complex. Furthermore, we observed that a Vγ5Vδ1 complex forms a TCR γ5-chain mediated dimeric species whereby two TCR/CD3 complexes are assembled. Collectively, these data shed light on γδ TCR/CD3 complex formation and may aid the design of γδ TCR-based therapies.
High-Recovery Desalting Tip Columns for a Wide Variety of Peptides in Mass Spectrometry-based Proteomics
Authors: Kanao Eisuke , Tanaka Shunsuke , Tomioka Ayana , Tanigawa Tetsuya , Kubo Takuya , Ishihama Yasushi
Published: July 2024

In mass spectrometry-based proteomics, loss-minimized peptide purification techniques play a key role in improving sensitivity and coverage. We have developed a desalting tip column packed with thermoplastic polymer-coated chromatographic particles, named ChocoTip, to achieve high recoveries in peptide purification by pipette-tip-based LC with centrifugation (tipLC). ChocoTip identified more than twice as many peptides from 20 ng of tryptic peptides from Hela cell lysate compared to a typical StageTip packed with chromatographic particles entangled in a Teflon mesh in tipLC. The high recovery of ChocoTip in tipLC was maintained for peptides with a wide variety of physical properties over the entire retention time range of the LC/MS/MS analysis, and was especially noteworthy for peptides with long retention times. These excellent properties are attributable to the unique morphology of ChocoTip, in which the thermoplastic polymer covers the pores, thereby inhibiting irreversible adsorption of peptides into mesopores of the chromatographic particles.

ChocoTip is expected to find applications, especially in clinical proteomics and single-cell proteomics, where sample amounts are limited.
Validation of a novel, low-cost, portable MRI-compatible exercise device in healthy volunteers and patients with pulmonary hypertension
Authors: Virsinskaite Ruta , Brown James T. , Kotecha Tushar , Bower Darren , Steeden Jennifer A. , Montalt-Tordera Javier , Jaubert Olivier , Fontana Marianna , Coghlan J. Gerry , Knight Daniel S. , Muthurangu Vivek
Published: July 2024

Introduction

The value of exercise cardiovascular magnetic resonance (CMR) has been shown in many clinical scenarios. We have developed a MR-compatible exercise apparatus and aim to validate it against the reference standard MR-conventional ergometer.

Methods

The novel device consisted of two half-pipes fixed to a wooden base, with participants wearing knee-length socks with a 0.5kg weight in each sock. Increased workload was achieved by increasing the rate of alternating leg flexion and extension in time with a bleep sound of increasing frequency.

Twenty subjects (10 healthy volunteers, 10 patients with pulmonary hypertension) performed two CMR-augmented cardiopulmonary exercise tests (CMR-CPET) using the novel exercise apparatus and a conventional ergometer in a randomised order.

Results

Comparing peak metrics elicited on both exercise devices, there was a moderate correlation in peak oxygen consumption (VO2, r=0.86, P<0.001), cardiac output (CO, r=0.66, P=0.002), stroke volume (SV, r=0.75, P<0.001), peak heart rate (HR, r=0.65, P=0.002) and peak arteriovenous oxygen content gradient (ΔavO2, r=0.71, P<0.001). However, all metrics (except peak SV) were significantly lower from the novel device. Both devices were able to elicit statistically significant differences in VO2, HR and RVEF between patients and healthy subjects (P≤0.036).

Conclusions

We have created a simple, easy to use and affordable exercise apparatus for CMR environment. This may encourage greater dissemination of exercise CMR in clinical and research practice.
A scalable genetic tool for the functional analysis of the signal recognition particle
Authors: Long Lawton F. , Biskunda Shivani , Yang Ming “Peter” , Wu George C. , Simas Cassidy , Bruner Steven D. , Denard Carl A.
Published: July 2024

Mutations in theSRP54gene are linked to the pathophysiology of severe congenital neutropenia (SCN).SRP54is a key protein comprising one of the six protein subunits of the signal recognition particle responsible for co-translational targeting of proteins to the ER; mutations inSRP54disrupt this process. Crystal structures and biochemical characterization of a fewSRP54mutants provide insights into howSRP54mutations affect its function. However, to date, no scalable, flexible platform exists to study the sequence-structure-function relationships of SRP54 mutations and perform functional genomics and genome-wide association studies. In this work, we established a haploid model inSaccharomyces cerevisiaebased on inducible gene expression that allows these relationships to be studied. We employed this model to test the function of orthologous clinical mutations to demonstrate the model’s suitability for studying SCN. Lastly, we demonstrate the suspected dominant-negative phenotypes associated withSRP54mutants. In doing so, we discovered for the first time that the most common yeast orthologous clinical mutation, S125del (T117del human orthologue) displayed the least severe growth defect while the less common G234E mutant (G226E human orthologue) displayed the most severe growth defect. The ability of this haploid model to recapitulate these phenotypes while remaining amenable to high-throughput screening approaches makes it a powerful tool for studyingSRP54. Furthermore, the methodology used to create this model may also be used to study other human diseases involving essential and quasi-essential genes.

Takeaway

The constitutively expressed quasi-essential nativeSRP54gene in yeast is replaced with an aldosterone-inducible version, making a yeast haploid strain, LFL001, that requires aldosterone for growth.

Strains developed in this work corroborated that yeastSRP54mutations exhibit dominant-negative phenotypes.

The LFL000 and LFL001 yeast strains developed here are uniquely positioned to interrogate sequence-structure-function relationships ofSRP54.
Hierarchical Bayesian modeling of multi-region brain cell count data
Authors: Dimmock Sydney , Exley Benjamin M. S. , Moore Gerald , Menage Lucy , Delogu Alessio , Schultz Simon R. , Warburton E. Clea , Houghton Conor , O’Donnell Cian
Published: July 2024

We can now collect cell-count data across whole animal brains quantifying recent neuronal activity, gene expression, or anatomical connectivity. This is a powerful approach since it is a multi-region measurement, but because the imaging is done post-mortem, each animal only provides one set of counts. Experiments are expensive and since cells are counted by imaging and aligning a large number of brain sections, they are time-intensive. The resulting datasets tend to be under-sampled with fewer animals than brain regions. As a consequence, these data are a challenge for traditional statistical approaches. We demonstrate that hierarchical Bayesian methods are well suited to these data by presenting a ‘standard’ partially-pooled Bayesian model for multi-region cell-count data and applying it to two example datasets. For both datasets the Bayesian model outperformed standard parallel t-tests. Overall, the Bayesian approach’s ability to capture nested data and its rigorous handling of uncertainty in under-sampled data can substantially improve inference for cell-count data.

Significance Statement

Cell-count data is important for studying neuronal activation and gene expression relating to the complex processes in the brain. However, the difficulty and expense of data collection means that such datasets often have small sample sizes. Many routine analyses are not well-suited, especially if there is high variability among animals and surprising outliers in the data. Here we describe a multilevel, mixed effects Bayesian model for these data and show that the Bayesian approach improves inferences compared to the usual approach for two different cell-count datasets with different data characteristics.
N6-methyladenosine in DNA promotes genome stability
Authors: Conti Brooke A. , Novikov Leo , Tong Deyan , Xiang Qing , Vigil Savon , McLellan Thomas J. , Nguyen Chuong , De La Cruz Nancy , Veettil Reshma T. , Pradhan Prashant , Sahasrabudhe Parag , Arroyo Jason D. , Shang Lei , Sabari Benjamin R. , Shields David J. , Oppikofer Mariano
Published: July 2024

DNA base lesions, such as incorporation of uracil into DNA or base mismatches, can be mutagenic and toxic to replicating cells. To discover factors in repair of genomic uracil, we performed a CRISPR knockout screen in the presence of floxuridine, a chemotherapeutic agent that incorporates uracil and fluoro-uracil into DNA. We identified known factors, such as uracil DNA N-glycosylase (UNG), and unknown factors, such as the N6-adenosine methyltransferase, METTL3, as required to overcome floxuridine-driven cytotoxicity. Visualized with immunofluorescence, the product of METTL3 activity, N6-methyladenosine, formed nuclear foci in cells treated with floxuridine. The observed N6-methyladenosine was embedded in DNA, called 6mA, and these results were confirmed using an orthogonal approach, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). METTL3 and 6mA were required for repair of lesions driven by additional base damaging agents, including raltitrexed, gemcitabine, and hydroxyurea. Our results establish a role for METTL3 and 6mA in promoting genome stability in mammalian cells, especially in response to base damage.
Structural basis of long-range transcription-translation coupling
Authors: Wang Chengyuan , Molodtsov Vadim , Kaelber Jason T. , Blaha Gregor , Ebright Richard H.
Published: July 2024

Structures recently have been reported of molecular assemblies that mediate transcription-translation coupling inEscherichia coli. In these molecular assemblies, termed “coupled transcription-translation complexes” or “TTC-B”, RNA polymerase (RNAP) interacts directly with the ribosome, the transcription elongation factor NusG or its paralog RfaH forms a bridge between RNAP and ribosome, and the transcription elongation factor NusA optionally forms a second bridge between RNAP and ribosome. Here, we have determined structures of coupled transcription-translation complexes having mRNA spacers between RNAP and ribosome longer than the maximum-length mRNA spacer compatible with formation of TTC-B. The results define a new class of coupled transcription-translation complex, termed “TTC-LC,” where “LC” denotes “long-range coupling.” TTC-LC differs from TTC-B by a ∼60° rotation and ∼70 Å translation of RNAP relative to ribosome, resulting in loss of direct interactions between RNAP and ribosome and creation of a ∼70 Å gap between RNAP and ribosome. TTC-LC accommodates long mRNA spacers by looping out mRNA from the gap between RNAP and ribosome. We propose that TTC-LC is an intermediate in assembling and disassembling TTC-B, mediating pre-TTC-B transcription-translation coupling before a ribosome catches up to RNAP, and mediating post-TTC-B transcription-translation coupling after a ribosome stops moving and RNAP continues moving.
A high-resolution model of gene expression duringGossypium hirsutum(cotton) fiber development
Authors: Grover Corrinne E , Jareczek Josef J , Swaminathan Sivakumar , Lee Youngwoo , Howell Alexander H , Rani Heena , Arick Mark A , Leach Alexis G , Miller Emma R , Yang Pengcheng , Hu Guanjing , Xiong Xianpeng , Mallery Eileen L , Peterson Daniel G , Xie Jun , Haigler Candace H , Zabotina Olga A , Szymanski Daniel B , Wendel Jonathan F
Published: July 2024

Cotton fiber development relies on complex and intricate biological processes to transform newly differentiated fiber initials into the mature, extravagantly elongated cellulosic cells that are the foundation of this economically important cash crop. Here we extend previous research into cotton fiber development by employing controlled conditions to minimize variability and utilizing time-series sampling and analyses to capture daily transcriptomic changes from early elongation through the early stages of secondary wall synthesis (6 to 24 days post anthesis; DPA). A majority of genes are expressed in fiber, largely partitioned into two major coexpression modules that represent genes whose expression generally increases or decreases during development. Differential gene expression reveals a massive transcriptomic shift between 16 and 17 DPA, corresponding to the onset of the transition phase that leads to secondary wall synthesis. Subtle gene expression changes are captured by the daily sampling, which are discussed in the context of fiber development. Coexpression and gene regulatory networks are constructed and associated with phenotypic aspects of fiber development, including turgor and cellulose production. Key genes are considered in the broader context of plant secondary wall synthesis, noting their known and putative roles in cotton fiber development. The analyses presented here highlight the importance of fine-scale temporal sampling on understanding developmental processes and offer insight into genes and regulatory networks that may be important in conferring the unique fiber phenotype.
Long-Term Outcomes of Untreated Micropenis: Growth Patterns and Predictive Factors
Authors: Amirkashani Davoud , Abdollahi Mostafa , Masoumi Mostafa
Published: July 2024

Background

Micropenis, defined as a penile length more than 2.5 standard deviations below the mean for age and population, presents significant concerns for patients and parents. Despite current guidelines recommending multidisciplinary management, there is limited evidence on long-term outcomes, particularly in untreated patients.

Methods

This retrospective cohort study involved 46 male children aged 7 to 9 years presenting with micropenis at the Ali Asghar Endocrine Clinic from 2015 to 2023. Initial penile size, BMI, and other growth parameters were measured, with biannual follow-ups extending three years post-bone fusion to evaluate growth rates and influential factors.

Results

Initial mean stretched penile length (SPL) was 3.22 ± 0.21 cm. Significant increases in penile size were observed across all intervals, with the highest growth rates occurring between the first- and second-years post-fusion. BMI emerged as the most significant predictor of penile growth, while initial SPL was the least influential factor. By the third-year post-fusion, all subjects achieved penile lengths within the normal range.

Conclusion

Our findings indicate that most untreated micropenis patients attain normal penile size by adulthood, highlighting the importance of monitoring growth rates rather than focusing solely on initial penile size. This study provides critical insights for developing guidelines and management strategies for micropenis, emphasizing the necessity of continued follow-up to ensure optimal outcomes.
Connectivity of the Piriform Cortex and its Implications in Temporal Lobe Epilepsy
Authors: Lucas Alfredo , Jaskir Marc , Sinha Nishant , Pattnaik Akash , Mouchtaris Sofia , Josyula Mariam , Petillo Nina , Roth Rebecca W. , Dikecligil Gulce N. , Bonilha Leonardo , Gottfried Jay , Gleichgerrcht Ezequiel , Das Sandhitsu , Stein Joel M. , Gugger James J. , Davis Kathryn A.
Published: July 2024

Background

The piriform cortex has been implicated in the initiation, spread and termination of epileptic seizures. This understanding has extended to surgical management of epilepsy, where it has been shown that resection or ablation of the piriform cortex can result in better outcomes. How and why the piriform cortex may play such a crucial role in seizure networks is not well understood. To answer these questions, we investigated the functional and structural connectivity of the piriform cortex in both healthy controls and temporal lobe epilepsy (TLE) patients.

Methods

We studied a retrospective cohort of 55 drug-resistant unilateral TLE patients and 26 healthy controls who received structural and functional neuroimaging. Using seed-to-voxel connectivity we compared the normative whole-brain connectivity of the piriform to that of the hippocampus, a region commonly involved in epilepsy, to understand the differential contribution of the piriform to the epileptogenic network. We subsequently measured the inter-piriform coupling (IPC) to quantify similarities in the inter-hemispheric cortical functional connectivity profile between the two piriform cortices. We related differences in IPC in TLE back to aberrations in normative piriform connectivity, whole brain functional properties, and structural connectivity.

Results

We find that relative to the hippocampus, the piriform is functionally connected to the anterior insula and the rest of the salience ventral attention network (SAN). We also find that low IPC is a sensitive metric of poor surgical outcome (sensitivity: 85.71%, 95% CI: [19.12%, 99.64%]); and differences in IPC within TLE were related to disconnectivity and hyperconnectivity to the anterior insula and the SAN. More globally, we find that low IPC is associated with whole-brain functional and structural segregation, marked by decreased functional small-worldness and fractional anisotropy.

Conclusions

Our study presents novel insights into the functional and structural neural network alterations associated with this structure, laying the foundation for future work to carefully consider its connectivity during the presurgical management of epilepsy.
Identifying a ubiquitous gene expression variation pattern in the human brain
Authors: Lo Chien-Ming , Duncan Niall W
Published: July 2024

The availability of dense sampled gene expression data from across the human brain has allowed important investigations into fundamental brain principles. Correlated expression patterns of genes tied to microstructural properties have been studied for their relationships with diverse brain features. This work looks at the specificity of these relationships based on the sets of genes targeted. We find that the same spatial pattern emerges from any set with more than 180 genes in it. Looking at the association between this pattern and cortical myelination, as represented by a T1w/T2w map, we show that correlations between myelination and theoretically guided gene sets do not differ from random ones. This observation prompts a reevaluation of current methodologies and assumptions in the study of gene-brain associations. Additionally, our research highlights covariance characteristics within specific functional networks, underscoring their significant role in shaping the spatial transcription patterns in the brain. These findings contribute insights into the complex relationships governing brain organisation and gene expression patterns. They also highlight an important methodological factor influencing the validity of inferences made from gene expression covariance patterns.
Adaptor protein 2 sigma subunit (AP2S1) variants associated with neurodevelopmental disorders
Authors: Stevenson Mark , Bayliss Asha L. , Stokes Victoria J. , English Katherine A. , Kooblall Kreepa G. , Fischer Roman , Heilig Raphael , Vendrell Iolanda , Albers Maria E. W. A. , Bartos Meghan , Begtrup Amber , Bourgois Alexia , Buchert Rebecca , Carey David J. , Carere Deanna A. , Carnevale Amanda , Claeys Kristl G. , Cogne Benjamin , Costain Gregory , de Leeuw Nicole , Denommé-Pichon Anne-Sophie , Donner Elizabeth J. , Drogouti Eftychia , Dyment David A. , Gangaram Balram , Haack Tobias B. , Haley Jeremy S. , Heide Solveig , Husain Ralf A. , Isidor Bertrand , Izatt Louise , Jacquinet Adeline , Juusola Jane , Kahle Juliette J. , Keren Boris , Klee Eric W. , Kokosali Evgenia , Lanpher Brendan C. , Macke Erica L. , Marco Elysa J. , McWalter Kirsty , Mendelsohn Bryce A. , Milunsky Aubrey , Osmond Matthew , Piton Amelie , Riess Angelika , Ruault Valentin , Rump Patrick , Schuhmann Sarah , Shillington Amelle L. , Smelser Diane T. , Snijders Blok Lot , Tran Mau-Them Frederic , Tsakalidis Christos , Turnwald Abigail , Van Gassen Koen L. I. , Van Schil Kristof , Vasileiou Georgia , Vawter-Lee Marissa , Willems Marjolaine , Willemsen Marjolein H. , Wong-Kisiel Lily C. , Wonneberger Antje , Zaganas Ioannis ,   Genomics England Research Consortium, Hannan Fadil M. , Lines Kate E. , Thakker Rajesh V.
Published: July 2024

Adaptor-Related Protein Complex 2 Sigma-1 Subunit(AP2S1) encodes AP2σ2, which forms part of the heterotetrameric AP2 complex that is composed of α, β2, μ2, and σ2 subunits and has a pivotal role in clathrin-mediated endocytosis (CME)1–3.AP2S1variants involving the Arg15 residue are associated with familial hypocalciuric hypercalcaemia type 3 (FHH3)1,4–6. Here, we report 5 differentAP2S1variants (AP2σ2: p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His) in 26 patients with neurodevelopmental delay, of whom >70% had epilepsy, 50% had brain abnormalities, and none had hypercalcaemia. All 5 variants decreased cell viability, 4 reduced CME transferrin uptake, and 4 disrupted interactions with other AP2 complex subunits, thereby affecting AP2 formation. Furthermore, AP2σ2 p.Arg10Trp had reduced interactions with 44 human proteins including intersectin 1, a component required for clathrin-coated pit formation and synaptic vesicle dynamics in neurones. Thus, our results show that AP2σ2 variants may disrupt CME and be associated with neurodevelopmental disorders.
Brains Under Stress: Unravelling the Effects of the COVID-19 Pandemic on Brain Ageing
Authors: Mohammadi-Nejad Ali-Reza , Craig Martin , Cox Eleanor , Chen Xin , Jenkins R. Gisli , Francis Susan , Sotiropoulos Stamatios N. , Auer Dorothee P.
Published: July 2024

The impact of SARS-CoV-2 and the COVID-19 pandemic on cognitive and mental health is recognised, yet specific effects on brain health remain understudied. We investigated the pandemic’s impact on brain ageing using longitudinal neuroimaging data from the UK Biobank. Brain age prediction models were trained from hundreds of multi-modal imaging features using a cohort of 15,334 healthy participants. These models were then applied to an independent cohort of 1,336 participants with two MRI scans: either both collected before the pandemic (“Control” groups), or one before and one after the pandemic onset (“Pandemic” group). Our findings reveal that, even with initially matched brain age gaps (predicted brain age vs. chronological age), the pandemic significantly accelerated brain ageing. The “Pandemic” group showed on average 11-month higher deviation of brain age gap at the second time point compared with controls. Accelerated brain ageing was more pronounced in males and those from deprived socio-demographic backgrounds, with average increases of 3.3 and 7 months, respectively. These deviations existed regardless of SARS-CoV-2 infection. However, accelerated brain ageing correlated with reduced cognitive performance only in COVID-infected participants. Our study highlights the pandemic’s significant impact on brain health, beyond direct infection effects, emphasising the need to consider broader social and health inequalities.
Micronutrient-deficient diets and possible environmental enteric dysfunction in Buruli ulcer endemic communities in Ghana: lower dietary diversity and reduced serum zinc and vitamin C implicate micronutrient status a possible susceptibility factor
Authors: Loglo Aloysius Dzigbordi , Antwi Philemon Boasiako , Abass Kabiru Mohammed , Osei-Mireku Samuel , Amofa George , Ofori Elizabeth , Adjei Jonathan , Oppong Michael Ntiamoah , Phillips Richard Odame , Annan Reginald , Engel Barbara , Simmonds Rachel E.
Published: July 2024

Background

The nutritional status of communities susceptible to Buruli ulcer (BU, a skin NTD caused by infection withMycobacterium ulcerans) remains almost completely obscure. We have assessed the diets of BU patients vs. controls from the same BU-endemic communities, and compared their circulating biomarkers of nutrients and inflammation.

Methods/Principal Findings

We investigated two cohorts of BU patients and controls. The first were administered food frequency and multi-pass 24-hour recall questionnaires to determine patterns of foods consumed, nutrient intake and nutrient adequacy. The second used archived serum samples collected as baseline to measure the circulating concentration of zinc, vitamin C, CRP, IL-1β, IFN-γ, TNF-α and IL-6. Stunted growth was more prevalent than expected (31%), while 18% of participants were underweight and most had inadequate intake of all micronutrients except for carbohydrate. BU patients had a lower intake of, selenium, vitamin B12and zinc, and for selenium and vitamin B12a higher proportion had dietary insufficiency (40% vs. 15% and 80% vs. 55%, respectively). In line with this, BU patients had significantly lower levels of zinc in their serum, and more had levels below the normal range (72% vs. 43%). Despite many participants having a good intake of vitamin C, serum levels were low, and lower amongst the BU patients. As expected, there was little evidence of systemic inflammation (CRP <0.6 mg/L). Elevated IL-6 levels were present in several participants suggesting that environmental enteric dysfunction may be prevalent in these communities, however this was similar in cases vs. controls.

Conclusions/Significance

Diet and nutritional status may be a contributing factor to BU pathogenesis. Protein and the micronutrients zinc, selenium, vitamin B12and vitamin C may be of particular importance. Nutritional interventions may have potential for both prophylaxis and treatment of BU, which may be a cost-effective approach to achieving the NTD Roadmap goals.
Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters
Authors: Depta Laura , Bryce-Rogers Hogan P. , Dekker Nienke J. , Bønke Anna Wiehl , Camporese Nicolo’ , Qian Mingxing , Xu Yuanjian , Covey Douglas F. , Laraia Luca
Published: July 2024

Sterol transport proteins (STPs) play a pivotal role in cholesterol homeostasis and therefore are essential for healthy human physiology. Despite recent advances in dissecting functions of STPs in the human cell, there is still a significant knowledge gap regarding their specific biological functions and a lack of suitable selective probes for their study. Here, we profile fluorescent steroid-based probes across ten STPs, uncovering substantial differences in their selectivity, aiding the retrospective and prospective interpretation of biological results generated with those probes. These results guided the establishment of an STP screening panel combining diverse biophysical assays, enabling the evaluation of 41 steroid-based natural products and derivatives. Combining this with a thorough structural analysis revealed the molecular basis for STP specific selectivity profiles, leading to the uncovering of several new potent and selective Aster-B inhibitors, and supporting the role of this protein in steroidogenesis.
Membranous translation platforms in the chloroplast ofChlamydomonas reinhardtii
Authors: Sun Yi , Bakhtiari Shiva , Valente-Paterno Melissa , Jiang Heng , Zerges William
Published: July 2024

A small genome in chloroplasts encodes polypeptide subunits of the photosynthetic electron transport complexes in the membranes of thylakoid vesicles in the chloroplast stroma. Trans-membrane subunits of these complexes undergo co-translational membrane insertion during their synthesis by ribosomes of the bacterial-like genetic system of this semiautonomous organelle. While thylakoid membranes are sites of translation, evidence in the unicellular algaChlamydomonas reinhardtiisupports translation also on non-canonical membranes in a discrete translation-zone in the chloroplast. To characterize the membranous platforms for translation and the biogenesis of thylakoid membrane, we profiled membranes during chloroplast development, using theyellow-in-the-dark 1mutant, and carried out proteomic analyses on membranes of interest. The results support roles of two membrane types in preliminary and ongoing stages of translation: a “low-density membrane” and a denser “chloroplast translation membrane”, respectively. These roles are based on correlations of the relative levels of each membrane type and the translational status of the chloroplast before, during and after chloroplast differentiation and results of proteomic analyses. Our results support a model of photosynthesis complex biogenesis in a spatiotemporal “assembly line” involving LDM and CTM as sequential stages leading to photosynthetic thylakoid membranes.
Global compositional and functional states of the human gut microbiome in health and disease
Authors: Lee Sunjae , Portlock Theo , Le Chatelier Emmanuelle , Garcia-Guevara Fernando , Clasen Frederick , Oñate Florian Plaza , Pons Nicolas , Begum Neelu , Harzandi Azadeh , Proffitt Ceri , Rosario Dorines , Vaga Stefania , Park Junseok , von Feilitzen Kalle , Johansson Fredric , Zhang Cheng , Edwards Lindsey A. , Lombard Vincent , Gauthier Franck , Steves Claire J. , Gomez-Cabrero David , Henrissat Bernard , Lee Doheon , Engstrand Lars , Shawcross Debbie L. , Proctor Gordon , Almeida Mathieu , Nielsen Jens , Mardinoglu Adil , Moyes David L. , Ehrlich Stanislav Dusko , Uhlen Mathias , Shoaie Saeed
Published: July 2024

The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identifiedFusobacterium nucleatumandAnaerostipes hadruswith the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts.