bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconstruction of Extensive Scalp and Skull Defects with Dural Exposure: Report of a Series of Cases and Literature Review
Authors: Nassar Aref , Abou Zeid Samer , El Feghaly Charbel , Kassouf Elia , Naba Joy , Nasr Marwan , Sleilati Fadi
Published: October 2024

Background:

Large scalp and calvarial defects pose significant challenges for reconstruction. Successful reconstruction necessitates soft tissue restoration capable of withstanding radiation following tumor resection. Free flaps allow preserving and maintaining the structural and functional status of the reconstructed area. This article presents our experience with microsurgical free tissue transfer for scalp and calvarial defects as well as a literature review on the subject.

Methods:

A retrospective study was conducted to retrieve the files of all the extensive scalp/forehead defects with dural exposure treated in the plastic surgery department of Hotel Dieu de France University Hospital from September 2006 to December 2023.

Results:

Twelve free tissue transfers were performed in 11 patients between 2006 and 2023. In 3 cases, a 2-stage procedure was performed with the transfer of the free flap in the first stage and the ablative surgery in the second stage 1 week later. A muscular latissimus dorsi flap was used in 9 cases. In 3 patients, the defect involved the forehead and required cutaneous flaps: 2 radial forearm flaps and 1 parascapular flap. Complications included 1 flap venous thrombosis, 2 hematomas, 1 subdural hematoma, and 2 cases of distal flap necrosis.

Conclusions:

Free tissue transfer is indispensable for addressing large defects of the scalp and calvaria. A 2-stage operation is warranted for debilitated patients with a high risk of complications. The latissimus dorsi muscle flap is the flap of choice to cover extensive defects. Delayed cranioplasty is preferable in contaminated wounds.
ROLE OF VISUAL EVOKED POTENTIAL AND OCULAR TRAUMA SCORE AS PREDICTORS OF VISUAL RECOVERY IN EYE GLOBE INJURIES
Authors: Vofo Brice N. , Katzir Ayala , Homiedat Mohammad , Rivera Antonio , Estrella Fernando , Khateb Samer , Jaouni Tareq
Published: October 2024

Purpose:

Evaluate visual evoked potential (VEP) and ocular trauma score efficacy in predicting visual potential in globe trauma without optic nerve involvement.

Methods:

A retrospective cohort study analyzed clinical data from eye globe injury cases undergoing flash VEP between January 2000 and May 2021. Inclusion criteria: flash VEP completion within 48 hours and presurgical intervention. Exclusion criteria: head trauma and optic nerve injuries. Abnormal VEP: amplitudes <7 µV and latencies >120 milliseconds. The ocular trauma score was computed, and penetrating injuries were categorized.

Results:

Of 85 eyes meeting the criteria (mean age: 31.9 ± 20.6 years, 82.4% male), the median follow-up was 22 months. Ocular trauma score directly correlated with the amount of Early Treatment Diabetic Retinopathy Study letters gained at follow-up and was inversely correlated with ocular penetration extent and VEP signal amplitude. Visual evoked potential amplitude is inversely correlated with maintaining/improving visual acuity. Positive predictive value for normal VEP predicting maintained/improved visual acuity: 75.6%, negative predictive value: 21.3%. In blunt trauma, baseline VEP amplitude had superior predictive value compared with penetrating injury.

Conclusion:

This study highlights a correlation between VEP signal amplitude and ocular trauma score with visual outcomes in traumatic eye injuries without optic nerve involvement. Ocular trauma score emerges as a reliable VEP substitute, particularly in blunt trauma cases, where baseline VEP amplitude predicts visual recovery more accurately than penetrating injuries.
Screening for hemoglobin disorders and investigating their hematological and demographic profile among patients attending a tertiary-care hospital in southern India—a descriptive study
Authors: Kuppusamy Dheebika , Vinod Kolar Vishwanath , Kar Rakhee
Published: October 2024

Background:

Hemoglobinopathies and thalassemias are widely prevalent autosomal inherited recessive disorders of the structure and synthesis of hemoglobin, respectively. Given the regional heterogeneity of these disorders, this study was undertaken to elucidate the patterns and prevalence of these disorders from this region.

Methods:

This was a tertiary-care hospital-based study in southern India over 4 years. Screening for hemoglobin (Hb) disorders was done using Hb high-performance liquid chromatography in patients based on initial screening of complete blood count parameters and for clinically indicated cases.

Results:

A normal Hb HPLC pattern was observed in 404 (72.1%) and abnormal in 156 (27.9%) of 560 cases studied. The abnormalities seen were heterozygous β-thalassemia in 73 (46.8%), homozygous β-thalassemia in 19 (12.2%), heterozygous α-thalassemia in 7 (4.5%), HbH disease and heterozygous δβ-thalassemia in 1 (0.6%) each, sickle cell trait in 9 (5.8%), sickle cell anemia in 8 (5.1%), sickle β-thalassemia in 17 (10.9%), HbS+ Hb D-Punjab in 1 (0.6%), heterozygous HbE in 6 (3.8%), homozygous HbE in 2 (1.3%), HbE β-thalassemia in 3 (1.9%), Hb J-Meerut in 1 (0.6%), Hb Kirksey in 4 (2.6%), unknown α-hemoglobinopathy in 2 (1.3%), and Hb Lepore in 2 (1.3%) cases. Most of the patients were from the neighboring districts, and some were referred from other states.

Conclusion:

The most common hemoglobin disorders were heterozygous β-thalassemia in 73 cases (46.8%) and sickle hemoglobinopathy in 35 cases (22.4%). A heterogeneous group of hemoglobin disorders, including uncommon α-hemoglobinopathies, was found in the study population, likely due to the referral of patients from various regions.
Atypical Foot Swelling in Metastatic Endometrial Carcinoma: Role of FDG PET/CT
Authors: Chuang Tzyy-Ling , Wang Yuh-Feng
Published: October 2024

An 83-year-old woman with a history of endometrial carcinoma (EMC), treated with surgery and chemotherapy in August 2020, presented with a 1-year history of left foot swelling, tenderness, and heat. Despite multiple consultations, no diagnosis was made, and she developed painful swelling with a limping gait. A biopsy was done on July 14, 2023, confirmed metastatic EMC. FDG PET/CT revealed widespread metastases, including in the lungs, pleura, mediastinal, hilar, inguinal, right external iliac nodes, left labia majora, left iliac bone, left tibia, and left foot. Excision of left inguinal and vulvar tumors also confirmed metastatic EMC.
Exploring the genomic landscape of Chlamydiifrater species: Novel features include multiple truncated CDS of the major outer membrane porin (MOMP), more than 150 unique genes, and an ortholog of the chlamydial plasticity zone
Authors: Hölzer Martin , Reuschel Charlotte , Vorimore Fabien , Laroucau Karine , Sachse Konrad
Published: October 2024

Recently discovered obligate intracellular bacteria belonging to the genus Chlamydiifrater (Cf.) with the species of Cf. phoenicopteri and Cf. volucris were studied to explore the composition of their genomes and their relatedness to Chlamydia, the other genus of the family Chlamydiaceae. We investigated four isolates of Cf. volucris, two of them newly sequenced, and one of Cf. phoenicopteri alongside 12 representatives of the Chlamydia species. Using state-of-the-art bioinformatics techniques, including a hybrid sequencing approach and advanced annotation pipelines, our study reveals previously unrecognized genomic structures within Cf. and provides insights into species-specific adaptations and evolutionary dynamics. The integration of long-read sequencing data, comprehensive re-annotation strategies, and pan-genomics enabled localization of the unique plasticity zone and identification of novel gene clusters in Chlamydiifrater strains, which improves our understanding of chlamydial genome architecture and plasticity in the family Chlamydiaceae. Our analysis revealed that 761 CDS are shared among members of both genera (approx. 80%). We further identified 158 unique genes of Cf. species but their annotation remains challenging because of the absence of functionally annotated orthologs in public databases. A full-length ompA gene encoding the major outer membrane porin (MOMP) was seen in all Cf. strains. One of the most interesting findings is the presence in Cf. of multiple truncated CDS of members of the ompA family, whose localization and structure we describe here.
While genome analysis of Chlamydiifrater spp. confirmed numerous common features shared with representatives of the genus Chlamydia, many unique genomic elements were identified that underpin the distinct phenotype and separate genetic position of these new microorganisms.
Farm to Harm: Parasite Infection in an Elderly Farmer on Long-term Steroids
Authors: Malhotra Shikhir , Shrimali Twishi , Tak Vibhor , Lodha Mahendra
Published: October 2024

We present a rare case of Enterobius vermicularis and Helicobacter pylori coinfection in an 82-year-old male from a rural area of Jodhpur, India. The patient had a long history of rheumatoid arthritis and chronic corticosteroid use, rendering him immunosuppressed. He presented with non-specific gastrointestinal symptoms such as abdominal pain, weight loss, malaise, and heartburn. Laboratory and stool analyses revealed the presence of a small worm, which was later identified as Enterobius vermicularis. Additionally, the patient tested positive for H. pylori infection through various diagnostic modalities. The patient responded well to a combination of Albendazole and an H. pylori eradication kit. This case highlights the unusual presentation of E. vermicularis in an elderly patient and its coinfection with H. pylori, typically not associated with this demographic.
The neural correlates of shared and individual experience
Authors: Coppola Peter , Owen Adrian M , Menon David , Naci Lorina , Stamatakis Emmanuel A
Published: October 2024

Contemporary neuroscience research typically focuses on shared contents of experience and common neural states. Conversely, we set out to explore the neural correlates of individual-specific experiences that shape the distinct traits of each person. We propose an approach through which we compute individual-specific dynamics of functional connectivity states. These dynamics do not require estimation of common states across individuals and can be directly related to dynamic behavioural ratings of subjective experience. To this end, we leverage a unique functional magnetic resonance imaging dataset where subjects listened to an engaging naturalistic story while awake and under different levels of anaesthesia, altering or abolishing conscious experience. We find that this method can detect correspondences between neural and subjective dynamics. We then show that the dynamics of the default mode network underlie more personal experiences of the story as they are more dissimilar between participants during awareness compared to unconsciousness. On the other hand, the auditory and posterior dorsal attention networks show higher inter-subject similarity in consciousness compared to unconsciousness and suggest that the dynamics of these networks support more generalisable experiences of the story. We further characterise individual-specific brain dynamics by showing that they are associated with higher complexity in consciousness, whilst conversely, brain dynamics underlying shared experience become less complex during the conscious experience of the story.
BoundaryStats: An R package to calculate boundary overlap statistics
Authors: Luo Amy Rongyan
Published: October 2024

Ecologists and epidemiologists frequently rely on spatially distributed data. Studies in these fields may concern geographic boundaries, as environmental variation can determine the spatial distribution of organismal traits or diseases. In such cases, environmental boundaries produce coincident geographic boundaries in, for example, disease prevalence. Boundary analysis can be used to investigate the co-occurrence of organismal trait or disease boundaries and underlying environmental boundaries. Boundary and boundary overlap statistics test for the presence of significant geographic boundaries and spatial associations between the boundaries of two variables. There currently exists one implementation of boundary overlap statistics, though only on Windows and ESRI ArcView, limiting the availability of boundary overlap statistics to researchers. I have created BoundaryStats--an R package available on CRAN--that implements boundary and boundary overlap statistics. BoundaryStats is the first open-source, cross-platform implementation of these statistical methods making the statistics more widely accessible to researchers.
Adaptive optical correction forin vivotwo-photon fluorescence microscopy with neural fields
Authors: Kang Iksung , Kim Hyeonggeon , Natan Ryan , Zhang Qinrong , Yu Stella X. , Ji Na
Published: October 2024

Adaptive optics (AO) restore ideal imaging performance in complex samples by measuring and correcting optical aberrations, but often require custom-built microscopes with carefully aligned wavefront sensing/shaping devices and can be susceptible to sample motion. Here we describe NeAT, a computational framework using neural fields for AO two-photon fluorescence microscopy. NeAT estimates wavefront aberration and recovers sample structure from a 3D image stack without requiring external datasets for training. Incorporating motion correction in learning and correcting conjugation errors commonly found in commercial microscopes, NeAT is designed for deployment in biological laboratories forin vivoimaging. We validate NeAT’s performance using a custom-built microscope with a wavefront sensor under varying signal-to-noise ratios, aberration, and motion conditions. With a commercial microscope, we demonstrate real-time aberration correction forin vivomorphological and functional imaging in the living mouse brain, with NeAT improving signal and accuracy of glutamate and calcium imaging of synapses and neurons.
From single species to communities: microsatellite amplicon sequencing to monitor felids using Feliplex
Authors: Rana Divyashree , Boyer Frédéric , Barba Marta De , Taberlet Pierre , Ramakrishnan Uma
Published: October 2024

The current biodiversity crisis demands a shift from single-species to multispecies approaches in conservation, particularly for rare and endangered species. However, this transition requires tools optimised for multispecies research, which are currently limited.

Recent advances in high-throughput sequencing (HTS) technologies and bioinformatics have enabled efficient and robust acquisition of genetic data. Amplicon sequencing approaches, in particular, have demonstrated potential for enhancing non-invasive genetic studies of endangered species, but their application has been mostly limited to single species.

To enable multispecies genetic research, we introduce a cost-effective and robust HTS-based amplicon sequencing approach for genotyping multiple species simultaneously, designed for population monitoring, including individual identification and ascertaining patterns of population structure.

We developed Feliplex, a multiplex panel of 85 co-amplifying tetranucleotide microsatellite markers for cross-genotypingFelidaespecies, to demonstrate the utility of our approach. Feliplex was validated on known samples from nine Indian felid species across the generaPanthera, Prionailurus, andFelis. We applied it to invasive (blood and tissue) and non-invasive (hair and faeces) DNA extracts from 173 wild individuals obtaining respectively 70% and 56% multilocus genotyping success rates. The panel accurately identified known population clusters in tigers (Panthera tigris, n=19) and revealed hitherto unknown genetic structure in fishing cats (Prionailurus viverrinus, n=40).

Feliplex’s wide applicability acrossFelidaeallows reliable multispecies genotyping from low-quality/quantity samples, while supporting cost-effective genetic studies and conservation monitoring of lesser-known species like small cats. Our approach has a broad applicability and can be adapted to develop similar multispecies panels for closely related species groups.
Toden-E: Topology-Based and Density-Based Ensembled Clustering for the Development of Super-PAG in Functional Genomics using PAG Network and LLM
Authors: Li Qi , Nichols Cody , Welner Robert S , Chen Jake Y. , Ku Wei-Shinn , Yue Zongliang
Published: October 2024

The integrative analysis of gene sets, networks, and pathways is pivotal for deciphering omics data in translational biomedical research. To significantly increase gene coverage and enhance the utility of pathways, annotated gene lists, and gene signatures from diverse sources, we introduced pathways, annotated gene lists, and gene signatures (PAGs) enriched with metadata to represent biological functions. Furthermore, we established PAG-PAG networks by leveraging gene member similarity and gene regulations. However, in practice, high similarity in functional descriptions or gene membership often leads to redundant PAGs, hindering the interpretation from a fuzzy enriched PAG list. In this study, we developed todenE (topology-based and density-based ensemble) clustering, pioneering in integrating topology-based and density-based clustering methods to detect PAG communities leveraging the PAG network and Large Language Models (LLM). In computational genomics annotation, the genes can be grouped/clustered through the gene relationships and gene functions via guilt by association. Similarly, PAGs can be grouped into higher-level clusters, forming concise functional representations called Super-PAGs. TodenE captures PAG-PAG similarity and encapsulates functional information through LLM, in characterizing network-based functional Super-PAGs. In synthetic data, we introduced a metric called the Disparity Index (DI), measuring the connectivity of gene neighbors to gauge clusterability. We compared multiple clustering algorithms to identify the best method for generating performance-driven clusters. In non-simulated data (Gene Ontology), by leveraging transfer learning and LLM, we formed a language-based similarity embedding. TodenE utilizes this embedding together with the topology-based embedding to generate putative Super-PAGs with superior performance in semantic and gene member inclusiveness.
Investigating curvature sensing by the Nt17 domain of Huntingtin protein
Authors: Nanajkar Neha , Sahoo Abhilash , Frey Shelli L. , Matysiak Silvina
Published: October 2024

Abstract

Nt17, the N-terminal domain of the huntingtin protein (htt), has garnered significant attention for its role in htt’s membrane binding and aggregation processes. Previous studies have identified a nuclear export sequence within the Nt17 domain and demonstrated its localization at various cellular organelles. Recent evidence suggests that, like other amphipathic helices, Nt17 can sense and preferentially bind to curved membranes. Gaining deeper insight into this behavior is essential to fully understand the function of this domain.

In this study, we combine coarse-grained molecular dynamics simulations with circular dichroism (CD) spectroscopy to investigate the mechanism behind Nt17’s curvature sensing. We generated a unique hemispherical-planar membrane model, where 36% of the upper leaflet surface is curved, allowing us to evaluate Nt17’s binding preferences. Our findings show that Nt17 exhibits a strong preference for curved regions, with approximately 78 ± 7 % of peptides binding to these areas. This interaction is primarily mediated by the terminal Phe residues, indicating that Nt17’s curvature sensing is driven by its ability to detect lipid packing defects. Furthermore, Nt17 not only senses these defects but also amplifies them by coalescing smaller pockets. Mutating the Phe residues to methionine, a smaller hydrophobic residue, significantly reduces Nt17’s curvature sensitivity, resulting in equal binding to both curved and planar regions. CD spectroscopy corroborates these results, showing that Nt17 binds more strongly to highly curved small unilamellar vesicles (SUVs) compared to larger, less curved large unilamellar vesicles (LUVs).
Local postural changes elicit extensive and diverse skin stretch around joints, on the trunk, and the face
Authors: Rupani Mia , Cleland Luke D , Saal Hannes P
Published: October 2024

Skin stretch, induced by bodily movements, offers a potential source of information about the conformation of the body that can be transmitted to the brain via stretch-sensitive mechanoreceptive neurons. While previous studies have primarily focused on skin stretch directly at joints, here we investigate the extent and complexity of natural skin stretch across various body regions, including the face and trunk. We used a quad-camera setup to image large ink-based speckle patterns stamped on participants’ skin and calculated the resulting stretch patterns on a millimeter scale during a range of natural poses. We observed that skin stretch associated with joint movement extends far beyond the joint itself, with knee flexion inducing stretch on the upper thigh. Large and uniform stretch patterns were found across the trunk, covering considerable portions of the skin. The face exhibited highly complex and non-uniform stretch patterns, potentially contributing to our capacity to control fine facial movements in the absence of traditional proprioceptors. Importantly, all regions demonstrated skin stretch in excess of mechanoreceptive thresholds, suggesting that behaviorally relevant skin stretch can occur anywhere on the body. These signals might provide the brain with valuable information about body state and conformation, potentially supplementing or even surpassing the capabilities of traditional proprioception.
Functional and causal neural mechanisms of human voice perception in noisy situations
Authors: Ceravolo Leonardo , Jaussi Elisa Scariati , Frühholz Sascha , Van De Ville Dimitri , Grandjean Didier
Published: October 2024

Human communication entails an efficient way of simultaneously processing voice and reducing the impact of environmental noise. By manipulating background noise, we aimed at clarifying the neural mechanisms allowing voice comprehension in noisy situations. Our results point to spatial and temporal coexistence of lateral and medial temporal cortex networks when voice is easily detected in highly noisy conditions, revealing the necessary neural underpinnings of human communication in realistic situations.
Connectome-based Predictive Models of General and Specific Executive Functions
Authors: Qu Shijie , Qu Yueyue Lydia , Yoo Kwangsun , Chun Marvin M.
Published: October 2024

Executive functions, the set of cognitive control processes that facilitate adaptive thoughts and actions, are composed primarily of three distinct yet interrelated cognitive components: Inhibition, Shifting, and Updating. While prior research has examined the nature of different components as well as their inter-relationships, fewer studies examined whole-brain connectivity to predict individual differences for the three cognitive components and associated tasks. Here, using the Connectome-based Predictive Modelling (CPM) approach and open-access data from the Human Connectome Project, we built brain network models to successfully predict individual performance differences on the Flanker task, the Dimensional Change Card Sort task, and the 2-back task, each putatively corresponding to Inhibition, Shifting, and Updating. We focused on grayordinate fMRI data collected during the 2-back tasks after confirming superior predictive performance over resting-state and volumetric data. High cross-task prediction accuracy as well as joint recruitment of canonical networks, such as the frontoparietal and default-mode networks, suggest the existence of a common executive function factor. To investigate the relationships among the three executive function components, we developed new measures to disentangle their shared and unique aspects. Our analysis confirmed that a shared executive function component can be predicted from functional connectivity patterns densely located around the frontoparietal, default-mode and dorsal attention networks. The Updating-specific component showed significant cross-prediction with the general executive function factor, suggesting a relatively stronger role than the other components. In contrast, the Shifting-specific and Inhibition-specific components exhibited lower cross-prediction performance, indicating more distinct and specialized roles. Given the limitation that individual behavioral measures do not purely reflect the intended cognitive constructs, our study demonstrates a novel approach to infer common and specific components of executive function.
Deletion of Zyxin Reduces Endothelial Inflammation and Mitigates Atherosclerosis
Authors: Huang Haozhong , Wang Yingzi , Gao Zhenyu , Feng Yi , Yang Tan , Liu Zihao , Li Lei , Weng Huimin , Tang Yuquan , Liu Linlu , Li Yuhao , Li Zhixin , Xie Yucheng , Liao Bin , Yu Fengxu , Nie Yongmei
Published: October 2024

BACKGROUND

Oscillatory shear stress (OSS)-induced endothelial inflammation plays a critical role in the pathogenesis of atherosclerosis. However, the involvement of endothelial zyxin, a mechanosensor, in OSS-associated atherosclerosis and its underlying mechanisms remains unclear.

METHODS

To investigate the role of zyxin in vivo, ZyxiniECKOApoE−/−mice were utilized in atherosclerosis model induced by carotid artery ligation; in vitro, endothelial cells were subjected to disturbed flow in Ibidi systerm.

RESULTS

Zyxin was significantly upregulated in the OSS regions of both human and mouse arteries. The specific deletion of zyxin in endothelial cells (ECs) in ApoE−/−(ZyxiniECKOApoE−/−) mice reversed the ECs activation and atherosclerosis induced by OSS. In vitro studies indicated that the absence of zyxin reduced the induction of adhesion molecules and pro-inflammatory cytokines stimulated by OSS. Mechanistic investigations demonstrated that 14-3-3β facilitated yes-associated protein (YAP) phosphorylation at Serine 127, which played a critical role in retaining YAP within the cytoplasm. Under OSS stimulation, zyxin inhibited the phosphorylation of YAP at Serine 127 through its interaction with 14-3-3β, rather than direct regulation of YAP. This inhibition enhanced YAP’s nuclear translocation and promoted endothelial inflammation. Furthermore, it was shown that rosuvastatin inhibited zyxin expression in human umbilical vein endothelial cells and the vascular endothelium of ApoE−/−mice. This inhibition led to decreased levels of inflammatory markers and adhesion molecules associated with atherosclerotic lesions observed in the partially ligated left common carotid arteries of ApoE−/−mice.

CONCLUSIONS

This study further confirms that zyxin is a mechanoreceptor in endothelial cells and elucidates the indispensable role of the zyxin-14-3-3β-YAP axis in endothelial inflammation and atherogenesis. This indicates that Zyxin plays a crucial role in protecting against atherosclerosis.
Transcriptional Signatures of the Right Ventricle in End-Stage Heart Failure
Authors: Garry Jonah D. , Davogustto Giovanni E. , Agrawal Vineet , Ye Fei , Tomasek Kelsey , Su Yan Ru , Absi Tarek , West James D. , Hemnes Anna , Brittain Evan L.
Published: October 2024

The molecular mechanisms of right ventricular (RV) adaptation to stress and failure in end stage heart failure (HF) are largely unknown. In this study, we performed transcriptomic analysis on paired RV and left ventricular (LV) myocardial samples from 33 subjects with AHA stage D HF referred for transplantation, and 8 controls who provided donor hearts not ultimately used for transplantation. We categorized patients by RV function - defining failure by Pulmonary Artery Pulsatility Index <1.85 - into control (n=8), compensated (n=25), and failing groupings (n=8). Our analysis found dysregulation of extracellular matrix remodeling, fatty acid metabolism, mitochondrial function, and inflammation in the stressed RV (comparing compensated and failing RVs to controls), implicating similar molecular mechanisms to those identified from studies of pre-capillary pulmonary hypertension (PH) associated RV dysfunction. The compensated and failing RVs were differentiated by protein production/processing and inflammation. PPAR signaling and fatty acid metabolism were consistently enriched in the RV compared to the LV. We also examined 16 previously proposed transcriptional biomarkers of RV failure, finding that none effectively differentiated between RV compensation and failure, and only 4 were RV-specific (changing in RV-failure but not LV-failure). Our findings suggest that the molecular mechanisms of pre-capillary PH and HF-associated RV dysfunction exhibit significant overlap. Furthermore, fatty acid metabolism and related signaling may be constitutively different between the RV and LV in both normal function and failure.
Age-Dependent Maturation and Rejuvenation of the Neural 3D Chromatin Interactome in Enriched Environments
Authors: Gancedo-Verdejo Javier , Urdinguio Rocío G. , Tejedor Juan Ramón , Pérez Raúl F. , Peñarroya Alfonso , Santamarina-Ojeda Pablo , Roberti Annalisa , Kefauver Jennifer M. , Álvarez-Díaz Carlota , Rodríguez-Santamaría Mar , Trejo José Luis , Tomás-Daza Laureano , Rovirosa Llorenç , Javierre Biola M. , Fernández Agustín F. , Fraga Mario F.
Published: October 2024

Aging is a multifactorial biological process resulting in physiological and cellular decline. However, our understanding of age-related changes in 3D genome organization and the effect of external interventions on this process, remains limited. Here we describe alterations in the landscape of the 3D chromatin interactome upon aging, utilizing the low input Promoter Capture Hi-C (liCHi-C) technique with hippocampal neurons. We integrated liCHi-C data with RNA-seq data to identify functional implications. Furthermore, we assessed the effect of exposure to environmental enrichment (EE). Remarkably, our results demonstrated an age- dependent modulation of promoter interactions and expression with EE, with aging-like changes induced in young mice upon EE, likely associated with early brain maturation; while age-related alterations were reverted in old mice, leading to a partial rejuvenation of aged mouse hippocampi. These findings revealed a dynamic behaviour of the neuronal 3D chromatin structure over time, which can be modulated by external interventions.
Novel bacteriophages targeting wheat phyllosphere bacteria carry DNA modifications and single-strand breaks
Authors: Dougherty Peter Erdmann , Pedersen Maja Schmidt , Forero-Junco Laura Milena , Carstens Alexander Byth , Raaijmakers Jos M. , Riber Leise , Hansen Lars Hestbjerg
Published: October 2024

The phyllosphere microbiome can positively or negatively impact plant health and growth, but we currently lack the tools to control microbiome composition. Contributing to a growing collection of bacteriophages (phages) targeting bacteria living in the wheat phyllosphere, we here isolate and sequence eight novel phages targeting common phyllosphereErwiniaandPseudomonasstrains, including two jumbo phages. We characterize genomic, phylogenetic, and morphological traits from these phages and argue for establishing four novel viral genera. We also search the genomes for anti-defense systems and investigate DNA modifications using Nanopore sequencing. In Pseudomonas phage Rembedalsseter we find evidence of 13 motif-associated single-stranded DNA breaks. A bioinformatics search revealed that 60 relatedPseudomonasphages are enriched in the same motif, suggesting these single-stranded nicks may be widely distributed in this family of phages. Finally, we also search the Sequence Read Archive for similar phages in public metagenomes. We find close hits to theErwiniajumbo-phage Kaldavass in a wide variety of plant, food, and wastewater metagenomes including a near-perfect hit from a Spanish spinach sample, illustrating how interconnected geographically distant phages can be.
The transfer of antibiotic resistance genes between evolutionary distant bacteria
Authors: Parras-Moltó Marcos , Lund David , Ebmeyer Stefan , Larsson DG Joakim , Johnning Anna , Kristiansson Erik
Published: October 2024

Infections from antibiotic-resistant bacteria threaten human health globally. Resistance is often caused by mobile antibiotic resistance genes (ARGs) shared horizontally between bacterial genomes. Many ARGs originate from environmental and commensal bacteria and are transferred between divergent bacterial hosts before they reach pathogens. This process remains, however, poorly understood, which complicates the development of countermeasures that reduce the spread of ARGs. In this study, we aimed to systematically analyze the ARGs transferred between the most evolutionary distant bacteria, here defined based on their phylum. We implemented an algorithm that identified inter-phyla transfers (IPTs) by combining ARG-specific phylogenetic trees with the taxonomy of the bacterial hosts. From the analysis of almost 1 million resistance genes identified in >400,000 bacterial genomes, we identified 661 IPTs, which included transfers between all major bacterial phyla. The frequency of IPTs varies substantially between ARG classes and was highest for the aminoglycoside resistance gene AAC(3) while the levels for beta-lactamases were, generally, lower. ARGs involved in IPTs also differed between phyla where, for example, tetracycline resistance genes were commonly transferred between Firmicutes and Proteobacteria, but rarely between Actinobacteria and Proteobacteria. The results, furthermore, show that conjugative systems are seldom shared between bacterial phyla, suggesting that other mechanisms drive the dissemination of ARGs between divergent hosts. We also show that bacterial genomes involved in IPTs of ARGs are either over- or under-represented in specific environments. These IPTs were also found to be more recent compared to transfers associated with bacteria isolated from water, soil, and sediment. While macrolide and tetracycline resistance genes involved in ITPs almost always were +95% identical between phyla, corresponding β-lactamases showed a median identity of < 60%. We conclude that inter-phyla transfer is recurrent and our results offer new insights into how resistance genes are disseminated between evolutionary distant bacteria.
NIPBL and STAG1 enable loop extrusion by providing differential DNA-cohesin affinity
Authors: van Wee Raman , Asor Roi , Li Yiwen , Drechsel David , Popova Maria , Litos Gabriele , Davidson Iain , Peters Jan-Michael , Kukura Philipp
Published: October 2024

DNA loop extrusion by cohesin has emerged as a critical pathway for chromosome organization. In vitro single-molecule experiments indicate that loop extrusion requires the assembly of an heteropentameric complex consisting of the SMC1/SMC3 heterodimer, STAG1, NIPBL and the kleisin SCC1. The multimeric nature of this complex and regulatoin of its dynamic DNA interactions that are modulated by ATP binding-hydrolysis cycles make it challenging to reveal the molecular mechanism of loop extrusion. Here, we use mass photometry to quantify the key interactions responsible for cohesin assembly, DNA binding, and their modulation by ATP binding and hydrolysis. We find that STAG1 binds tightly to the trimeric complex formed by the SMC1/SMC3 heterodimer and SCC1, creating a DNA binding site whose strength is modulated by the presence of ATP. NIPBL binds strongly to both DNA and the STAG1-tetramer, enabling assembly of the holoenzyme in the absence of DNA or ATP. Taken together, these results suggest that NIPBL acts as a DNA anchor, while a dynamic STAG1-Trimer binding site drives DNA loop formation.
Rejuvenating aged osteoprogenitors for bone repair
Authors: Reeves Joshua , Tournier Pierre , Becquart Pierre , Carton Robert , Tang Yin , Vigilante Alessandra , Fang Dong , Habib Shukry J
Published: October 2024

Aging is marked by a decline in tissue regeneration, posing significant challenges to an increasingly older population. Here, we investigate age-related impairments in calvarial bone healing and introduce a novel two-part rejuvenation strategy to restore youthful repair. We demonstrate that aging negatively impacts the calvarial bone structure and its osteogenic tissues, diminishing osteoprogenitor number and function and severely impairing bone formation. Notably, increasing osteogenic cell numbers locally fails to rescue repair in aged mice, identifying the presence of intrinsic cellular deficits. Our strategy combines Wnt-mediated osteoprogenitor expansion with intermittent fasting, which leads to a striking restoration of youthful levels of bone healing. We find that intermittent fasting improves osteoprogenitor function, benefits that can be recapitulated by modulating NAD+dependent pathways or the gut microbiota, underscoring the multifaceted nature of this intervention. Mechanistically, we identify mitochondrial dysfunction as a key component in age-related decline in osteoprogenitor function and show that both cyclical nutrient deprivation and Nicotinamide mononucleotide rejuvenate mitochondrial health, enhancing osteogenesis. These findings offer a promising therapeutic avenue for restoring youthful bone repair in aged individuals, with potential implications for rejuvenating other tissues.
A rational approach for the targeted discovery and characterisation of microbiome-derived therapeutics
Authors: Krause Lutz , Boyd Joel , Vivian Charlotte , Krueger Annika , Jimenez Loayza Jeimy , Ljungberg Johanna K. , Zhou Joyce , Rabellino Andrea , Nyeverecz Bozica , Nissen Michael , Tousignant Kaylyn , Bongers Mareike , Cooper Martha M. , Parks Donovan H. , Alsheikh Areej , Vera-Wolf Patricia , Sullivan Mitchell , Newell Rhys , Masterman Kelly-Anne , Evans Peter , Fang Liang , MacDonald Samantha , Chuvochina Maria , Bessette Darrell , Zimmermann Kate , Pribyl Alena , Chipperfield Hiram , Caban Shandelle , McCarthy Huw , Soh Joanne , Reid Luke , Frazer Ian H. , Angel Nicola , Kenna Tony , Wood David L.A. , Wills Blake , Begun Jakob , Keely Simon , Munro Trent , Tyson Gene W. , Hugenholtz Philip , Cuív Páraic Ó
Published: October 2024

The human gut microbiome is intrinsically involved in health and disease, representing a wealth of untapped therapeutic potential. Here, we demonstrate the utility and potential of a metagenome guided, large cohort-based approach for the rational selection of live biotherapeutics from the human gut. We applied this approach to Inflammatory Bowel Disease (IBD), identifying several lead candidates that were significantly depleted in individuals with IBD compared to healthy controls. Their therapeutic potential was assessed in preclinical models of IBD where they improved markers of disease pathology by reducing inflammation and promoting mucosal healing and wound repair. All leads had excellent safety profilesin silicoandin vitro, and several additionally presented favourable manufacturing properties, supporting their progression into clinical trials. We believe that this rational approach will be generalisable to any disease state with underlying microbiome aetiology and will expedite the development of novel microbiome-derived therapeutics to improve human health.
An end-to-end model of active electrosensation
Authors: Turcu Denis , Zadina Abigail , Abbott L.F. , Sawtell Nathaniel B.
Published: October 2024

1

Weakly electric fish localize and identify objects by sensing distortions in a self-generated electric field. Fish can determine the resistance and capacitance of an object, for example, even though the field distortions being sensed are small and highly-dependent on object distance and size. Here we construct a model of the responses of the fish’s electroreceptors on the basis of experimental data, and we develop a model of the electric fields generated by the fish and the distortions due to objects of different resistances and capacitances. This provides us with an accurate and efficient method for generating large artificial data sets simulating fish interacting with a wide variety of objects. Using these sets, we train an artificial neural network (ANN), representing brain areas downstream of electroreceptors, to extract the 3D location, size, and electrical properties of objects. The model performs best if the ANN operates in two stages: first estimating object distance and size and then using this information to extract electrical properties. This suggests a specific form of modularity in the electrosensory system that can be tested experimentally and highlights the potential of end-to-end modeling for studies of sensory processing.
Sociodemographic, clinical, and genetic factors associated with self-reported antidepressant response outcomes in the UK Biobank
Authors: Kamp Michelle , Lo Chris Wai Hang , Kokkinidis Grigorios , Chauhan Mimansa , Gillett Alexandra C. ,   AMBER Research Team, McIntosh Andrew M. , Pain Oliver , Lewis Cathryn M.
Published: October 2024

Background

In major depressive disorder (MDD), only ∼35% achieve remission after first-line antidepressant therapy. Using UK Biobank data, we identify sociodemographic, clinical, and genetic predictors of antidepressant response through self-reported outcomes, aiming to inform personalized treatment strategies.

Methods

In UK Biobank Mental Health Questionnaire 2, participants with MDD reported whether specific antidepressants helped them. We tested whether retrospective lifetime response to four selective serotonin reuptake inhibitors (SSRIs) (N=19,516)-citalopram (N=8,335), fluoxetine (N=8,476), paroxetine (N=2,297) and sertraline (N=5,883)-was associated with sociodemographic (e.g., age, gender) and clinical factors (e.g., episode duration). Genetic analyses evaluated the association between CYP2C19 variation and self-reported response, while polygenic score (PGS) analysis assessed whether genetic predisposition to psychiatric disorders and antidepressant response predicted self-reported SSRI outcomes.

Results

71%-77% of participants reported positive responses to an SSRI. Non-response was significantly associated with self-medication (OR=1.56, p=2.08×10−19), younger age (OR=0.87, p=2.49×10−11), male gender (OR=1.26, p=3.18×10−08), and lower income (OR=1.34, p=6.17×10−07). A worst episode lasting over two years (OR=1.97, p=1.25×10−16) and no mood improvement from positive events (OR=1.33, p=1.35×10−06) were also associated with non-response. CYP2C19 poor metabolizers had higher non-response rates (OR=1.31, p=1.77×10−02). Additionally, higher PGS for depression (OR=1.08, p=3.37×10−05), ADHD (OR=1.06, p=1.06×10−03), and schizophrenia (OR =1.06, p=1.53×10−03) predicted negative SSRI outcomes.

Conclusion

Self-reported antidepressant response in the UK Biobank is influenced by sociodemographic, clinical, and genetic factors, mirroring clinical response measures. While positive outcomes are more frequent than remission reported in clinical trials, these self-reports replicate known treatment associations, suggesting they capture meaningful aspects of antidepressant effectiveness from the patient’s perspective.
Transverse spin asymmetries and the electron Yukawa coupling at an FCC-ee
Authors: Boughezal Radja , Petriello Frank , Şimşek Kağan
Published: October 2024

We show that measurements of single transverse-spin asymmetries at an e+e− collider can enhance the sensitivity to the electron Yukawa coupling, possibly enabling observation of the Standard Model value for this quantity. We demonstrate that the significance in both the bb¯ and semileptonic WW final states can be enhanced by factors of up to 3 compared to inclusive cross-section determinations of this coupling for transversely polarized electrons. If the positrons can be simultaneously longitudinally polarized, even at the level of 30%, the significance can be enhanced by a factor of 5 or more. The method utilizes quantum interference between the Higgs signal and the continuum background and is also applicable in other WW and ZZ final states.

Published by the American Physical Society
2024
Covariant and manifestly projective invariant formulation of Thomas-Whitehead gravity
Authors: Grover Tyler , Stiffler Kory , Vecera Patrick
Published: October 2024

Thomas-Whitehead (TW) gravity is a recently formulated projectively invariant extension of Einstein-Hilbert gravity. Projective geometry was used long ago by Thomas to succinctly package equivalent paths encoded by the geodesic equation. Projective invariance in gravity has further origins in string theory through a geometric action constructed from the method of coadjoint orbits using the Virasoro algebra. A projectively invariant connection arises from this construction, a part of which is known as the diffeomorphism field. TW gravity exploits projective Gauss-Bonnet terms in the action functional to endow the diffeomorphism field with dynamics, while allowing the theory to collapse to general relativity in the limit that the diffeomorphism field vanishes and the connection becomes Levi-Civita. In the original formulation of TW gravity, the diffeomorphism field is projectively invariant but not tensorial and the connection is projectively invariant but not affine. In this paper we reformulate TW gravity in terms of projectively invariant tensor fields and a projectively invariant covariant derivative, derive field equations respecting these symmetries, and show that the field equations obtained are classically equivalent across formulations. This provides a “Rosetta Stone” between this newly constructed covariant and projective invariant formulation of TW gravity and the original formulation that was manifestly projective invariant, but not covariant.

Published by the American Physical Society
2024
Analysis of crystallographic phase retrieval using iterative projection algorithms
Authors: Barnett Michael J. , Millane Rick P. , Kingston Richard L.
Published: October 2024

For protein crystals in which more than two thirds of the volume is occupied by solvent, the featureless nature of the solvent region often generates a constraint that is powerful enough to allow direct phasing of X-ray diffraction data. Practical implementation relies on the use of iterative projection algorithms with good global convergence properties to solve the difficult nonconvex phase-retrieval problem. In this paper, some aspects of phase retrieval using iterative projection algorithms are systematically explored, where the diffraction data and density-value distributions in the protein and solvent regions provide the sole constraints. The analysis is based on the addition of random error to the phases of previously determined protein crystal structures, followed by evaluation of the ability to recover the correct phase set as the distance from the solution increases. The properties of the difference-map (DM), relaxed–reflect–reflect (RRR) and relaxed averaged alternating reflectors (RAAR) algorithms are compared. All of these algorithms prove to be effective for crystallographic phase retrieval, and the useful ranges of the adjustable parameter which controls their behavior are established. When these algorithms converge to the solution, the algorithm trajectory becomes stationary; however, the density function continues to fluctuate significantly around its mean position. It is shown that averaging over the algorithm trajectory in the stationary region, following convergence, improves the density estimate, with this procedure outperforming previous approaches for phase or density refinement.