bluuebunny/crossref_metadata_2025 huggingface dataset:
Levator Ani Avulsion in Ultrasound Increases Recurrence in Sacrospinous Fixation
Authors: Maluenda Andrea , Santis-Moya Fernanda , Arévalo Diego , Pohlhammer Dominga , Blumel Bernardita , Guzmán-Rojas Rodrigo , Pizarro-Berdichevsky Javier
Published: November 2023

Importance

Pelvic floor translabial ultrasound (TLUS) can identify levator ani muscle (LAM) avulsion and ballooning, which some studies have shown to be possible risk factors for prolapse recurrence. Our group uses TLUS to counsel patients preoperatively. If any of these risk factors exist, we offer sacrocolpopexy over vaginal repair. However, some patients, even though they have these possible risk factors, prefer to undergo vaginal surgery.

Objective

The objective of this study was to determine if TLUS LAM avulsion and/or ballooning are risk factors for composite outcome recurrence in patients undergoing sacrospinous ligament fixation for pelvic organ prolapse.

Study design

This was a retrospective observational study. All patients with vaginal apical repair with sacrospinous ligament fixation with preoperative TLUS were included. Demographics, clinical characteristics, and follow-up were analyzed. Multivariable logistic regression analysis was performed for composite outcome that included TLUS risk factors, age, Pelvic Organ Prolapse Quantification System measurements and stage, and variables with P < 0.1 in the univariate analysis.

Results

Eighty-two patients were included. All patients had symptomatic vaginal bulge; 65.4% had stage III prolapse. Concomitant hysterectomy was performed in 54.3%. Median follow-up was 20 months (interquartile range, 8–35 months); 19.8% had LAM avulsion, and 43.2% had ballooning. Anatomic recurrence rate was 23.5%, symptomatic was 22.2%, and reoperation was 1.2%. The composite recurrence rate was 29.6%. In the multivariable logistic regression analysis, unilateral/bilateral avulsion in TLUS was found to be a significant risk factor for composite outcome with an odds ratio of 4.33 (confidence interval, 1.219–15.398; P = 0.023).

Conclusions

Composite outcome of recurrence in our study was 29.6%. Avulsion on TLUS increased the risk of recurrence of pelvic organ prolapse by fourfold.
Maternal 15q11.2-q13.1 duplication syndrome-associated psychosis and mania: a new case and review of the literature
Authors: Colijn Mark Ainsley , Smith Christopher S. , Thomas Mary Ann
Published: November 2023

Maternal 15q11.2-q13.1 duplication syndrome is associated with a variety of developmental and neuropsychiatric abnormalities. Although schizophrenia-like presentations have been reported, details pertaining to the nature of the corresponding psychotic symptoms and their response to treatment have only been described in a few cases, and no reviews summarizing the literature currently exist. As such, we describe a new case of 15q11.2-q13.1 duplication syndrome-associated schizoaffective disorder and also performed a systematic review of the literature. Our patient’s presentation is somewhat unique as she experienced visual hallucinations in the absence of auditory hallucinations. This is also the first report to describe full symptomatic remission in response to relatively low-dose atypical antipsychotic therapy.
Brain size predicts bees' tolerance to urban environments
Authors: Lanuza Jose B. , Collado Miguel Á. , Sayol Ferran , Sol Daniel , Bartomeus Ignasi
Published: November 2023

The rapid conversion of natural habitats to anthropogenic landscapes is threatening insect pollinators worldwide, raising concern regarding the negative consequences on their fundamental role as plant pollinators. However, not all pollinators are negatively affected by habitat conversion, as certain species find appropriate resources in anthropogenic landscapes to persist and proliferate. The reason why some species tolerate anthropogenic environments while most find them inhospitable remains poorly understood. The cognitive buffer hypothesis, widely supported in vertebrates but untested in insects, offers a potential explanation. This theory suggests that species with larger brains have enhanced behavioural plasticity, enabling them to confront and adapt to novel challenges. To investigate this hypothesis in insects, we measured brain size for 89 bee species, and evaluated their association with the degree of habitat occupancy. Our analyses revealed that bee species mainly found in urban habitats had larger brains relative to their body size than those that tend to occur in forested or agricultural habitats. Additionally, urban bees exhibited larger body sizes and, consequently, larger absolute brain sizes. Our results provide the first empirical support for the cognitive buffer hypothesis in invertebrates, suggesting that a large brain in bees could confer behavioural advantages to tolerate urban environments.
Michael James Stowell. 10 July 1935—27 February 2022
Authors: Brown FRS L. M.
Published: November 2023

Mike Stowell was a Bristol physicist turned metallurgist who led the development of practical aluminium-based superplastic alloys by showing how to retain grains small enough, at temperatures high enough, to allow almost unlimited shape changes in forming operations. He can be regarded as the father of SUPRAL alloys, as these are now called. At the Tube Investment laboratory in Hinxton Hall, Essex, he led teams that made effective use of the novel electron-optical equipment invented there to solve numerous fascinating problems of technical importance, among them the sequence of growth by evaporation of thin metallic films and the mechanisms controlling the precipitation of graphite in cast iron. He was dedicated to science at the heart of industrial metallurgy, so that when the laboratory closed, rather than retire, he became research director at Alcan, interacting with a laboratory in Italy as well as managing disparate laboratories in England and Canada to develop coatings for the electrodes used in aluminium production. He was a founder member of what we now know as the ‘Cambridge Phenomenon’, the close interaction between innovative, high-tech industry and the university. In connection with these activities, he made long-lasting fundamental contributions to the understanding of precipitation both of two-dimensional islands in the growth of thin films and in three dimensions in the bulk solid state.
The Immediate Impact of App-Based Psychotherapeutic Exercises on Anxiety: An RCT
Authors: Kahl Fabian , Sandkühler Julia Fabienne , Sadurska Magda Zena , Brietbart Peter , Greenberg Spencer , Brauner Jan
Published: November 2023

Background

Despite the growing integrative trend in psychotherapy, few studies have examined the potential for immediate anxiety relief of many different psychotherapeutic exercises side by side under the same conditions. This information might be important to enhance engagement and self-efficacy, stop negative feedback loops, and prevent avoidant or destructive behaviour during crises. Technology-based psychotherapeutic exercises are of particular interest because they are accessible and scalable.

Methods

This parallel, double-blind, randomised trial (N=1092) compared twelve psychotherapeutic exercises of the Mind Ease app against a reading control and a measurement-only control. Efficacy was measured with a custom scale validated against the state subscale of the State-Trait Anxiety Inventory.

Results

Each of the twelve exercises significantly reduced anxiety more than controls (p = 0.018 to <.001, η2P= .06 to .37, d = 0.5 to 1.5, d [95% CI] for all exercises together vs reading control = 0.8 [0.6; 1.0], and vs measurement-only control = 0.8 [0.6; 1.0]). Exercises employing cognitive restructuring had effect sizes d [95% CI] of 0.5 [0.2; 0.8], 0.7 [0.3; 1.0], and 0.9 [0.6; 1.2], diaphragmatic breathing of 0.6 [0.3; 0.9], gratitude practice of 0.8 [0.5; 1.1], positive expressive writing of 1.1 [0.7; 1.4], progressive muscle relaxation of 1.3 [0.9; 1.6], guided imagery of 1.3 [1.0; 1.6], and mindfulness of 0.9 [0.6; 1.2], 1.0 [0.7; 1.3], 1.2 [0.9; 1.5], and 1.5 [1.2; 1.9]. Twenty-eight comparisons between exercises (42%) had p < .05, nine met the Bonferroni-adjusted threshold of p < .0008.

Conclusions

The twelve psychotherapeutic exercises proved effective at immediately mitigating anxiety. Differences between exercises were substantial even within categories. Mindfulness tended to have a larger effect than cognitive restructuring.

Trial registration

The trial was prospectively registered (clinicaltrials.govidentifier:NCT05850975,https://osf.io/36ukh).
Influence of amino acid substitutions in capsid proteins of coxsackievirus B5 on free chlorine and thermal inactivation
Authors: Torii Shotaro , Gouttenoire Jérôme , Kumar Kiruthika , Antanasijevic Aleksandar , Kohn Tamar
Published: November 2023

The sensitivity of enteroviruses to disinfectants varies among genetically similar variants and coincides with amino acid changes in capsid proteins, though the effect of individual substitutions remains unknown. Here, we employed reverse genetics to investigate how amino acid substitutions in coxsackievirus B5 (CVB5) capsid proteins affect its sensitivity to free chlorine and heat treatment. Of ten amino acid changes hypothesized to coincide with free chlorine resistance, none significantly reduced the chlorine-sensitivity, indicating a minor role of the capsid composition in chlorine sensitivity of CVB5. Conversely, we observed reduced heat sensitivity in mutants with substitutions at the C-terminal region of the viral protein 1. Cryo-electron microscopy revealed that these changes affect the assembly of intermediate viral states (particle A and E), suggesting that the mechanism for reduced heat sensitivity could be related to improved molecular packing of CVB5, resulting in greater stability and/or altered dynamics of virus uncoating during infection.
Microencapsulation of mesenchymal stromal cells in covalent alginate hydrogels for cell therapy
Authors: Ambrosino Mathilde , Nativel Fabien , Boyer Cécile , Lagneau Nathan , Loll François , Halgand Boris , Djouad Farida , Renard Denis , Tessier Arnaud , Guicheux Jérôme , Delplace Vianney , Le Visage Catherine
Published: November 2023

Osteoarthritis (OA) is the most common inflammatory joint disease and currently lacks an effective curative treatment. Intra-articular injection of mesenchymal stromal cells (MSCs) has gained attention as a relevant therapeutic approach for OA treatment due to the MSC’s ability to secrete anti-inflammatory and immunomodulatory factors. Given their limited viability post-intraarticular injection and the potential leakage of cells out of the injection site, encapsulating MSCs in hydrogels is considered a promising strategy to protect them and provide a suitable 3D microenvironment to support their biological activities. Calcium-cross-linked alginate hydrogels are commonly used for MSC encapsulation, but their long-term in vivo stability remains uncertain. On the other hand, alginate cross-linking by the strain-promoted azide-alkyne cycloaddition (SPAAC) reaction would create a network unaffected by an ionic environment. Hence, this study aimed to develop an alginate-based hydrogel cross-linked via stable and cytocompatible covalent bonds for cell encapsulation. We established for the first time the formation of covalent alginate hydrogels between two SPAAC precursors, namely alginate-BCN and alginate-N3. These hydrogels exhibited in vitro stability and enabled the diffusion of molecules of interest. We then generated alginate-based SPAAC microgels of 170 μm in mean diameter, suitable for intra-articular injection. We next encapsulated human adipose MSCs (hASCs) in these alginate-based SPAAC microgels and confirmed their cytocompatibility, with over 90 % of cells remaining viable after 14 days in culture. Finally, the microencapsulated hASCs maintained their biological properties and were able to secrete anti-inflammatory factors (IDO, PGE2, and HGF) when exposed to pro-inflammatory cytokines (TNF-α and IFN-γ). In the end, human activated lymphocytes were cultured in contact with microencapsulated hASCs, and CD3+ T cell proliferation was quantified by flow cytometry. We demonstrated that the encapsulation process did not impair the hASC immunomodulatory activity. Overall, our findings show the potential of alginate-based SPAAC hydrogels for microencapsulating hASCs for cell therapy.
A simple agent-based hybrid model to simulate the biophysics of glioblastoma multiforme cells and the concomitant evolution of the oxygen field
Authors: Saucedo-Mora Luis , Sanz Miguel Ángel , Montáns Francisco Javier , Benítez José María
Published: November 2023

Background and objectives: Glioblastoma multiforme (GBM) is one of the most aggressive cancers of the central nervous system. It is characterized by a high mitotic activity and an infiltrative ability of the glioma cells, neovascularization and necrosis. GBM evolution entails the continuous interplay between heterogeneous cell populations, chemotaxis, and physical cues through different scales. In this work, an agent-based hybrid model is proposed to simulate the coupling of the multiscale biological events involved in the GBM invasion, specifically the individual and collective migration of GBM cells and the concurrent evolution of the oxygen field and phenotypic plasticity. An asset of the formulation is that it is conceptually and computationally simple but allows to reproduce the complexity and the progression of the GBM micro-environment at cell and tissue scales simultaneously. Methods: The migration is reproduced as the result of the interaction between every single cell and its micro-environment. The behavior of each individual cell is formulated through genotypic variables whereas the cell micro-environment is modeled in terms of the oxygen concentration and the cell density surrounding each cell. The collective behavior is formulated at a cellular scale through a flocking model. The phenotypic plasticity of the cells is induced by the micro-environment conditions, considering five phenotypes. Results: The model has been contrasted by benchmark problems and experimental tests showing the ability to reproduce different scenarios of glioma cell migration. In all cases, the individual and collective cell migration and the coupled evolution of both the oxygen field and phenotypic plasticity have been properly simulated. This simple formulation allows to mimic the formation of relevant hallmarks of glioblastoma multiforme, such as the necrotic cores, and to reproduce experimental evidences related to the mitotic activity in pseudopalisades. Conclusions: In the collective migration, the survival of the clusters prevails at the expense of cell mitosis, regardless of the size of the groups, which delays the formation of necrotic foci and reduces the rate of oxygen consumption.
CRISPR-GRIT: Guide-RNAs with Integrated Repair Templates Enable Precise Multiplexed Genome Editing in the Diploid Fungal PathogenCandida albicans
Authors: Cotter Christopher J. , Trinh Cong T.
Published: November 2023

Candida albicansis an opportunistic fungal pathogen that causes severe infections in immunocompromised individuals. Overuse of antifungals coupled with climate change has led to the rapid emergence of antifungal resistance. Thus, there is an urgent need to understand fungal pathogen genetics to develop new antifungal strategies. Genetic manipulation ofC. albicansis encumbered by its diploid chromosomes which require editing both alleles for elucidating gene function. Even though recent development of CRISPR-Cas systems has facilitated genome editing inC. albicans, large-scale functional genomic studies are still hindered by the necessity of co-transforming repair templates for homozygous knockouts. Here, we present CRISPR-GRIT, a repair template-integrated guide RNA design for expedited gene knockouts inC. albicans,and demonstrate its utility for multiplexed editing. We envision that this method can be employed for high-throughput library screens and identification of synthetic lethal pairs in bothC. albicansand other diploid organisms with strong homologous recombination machinery.
Mathematical model of a cell membrane
Authors: Gorkavyi Nick
Published: November 2023

Bimolecular cell membranes play a crucial role in many biological processes and possess a unique set of physical properties. Bimolecular membranes and monomolecular films can be considered as a “two-dimensional fluid” because the diffusion of molecules along the membrane or film is a hydrodynamic process. On the other hand, the bending of the cell membrane is controlled by its stiffness and elastic tension. The aim of this work is to adapt the Navier-Stokes hydrodynamic equations, obtained using the classical Chapman-Enskog method, to the case of two-dimensional membranes. The hydrodynamic equation system is complemented by an elasticity equation for the bending oscillations of the membrane. The obtained system of equations for the dynamics of the cell membrane is linearized for the case of disturbances with small amplitude. Dispersion equations for stable and unstable linear oscillations of cell membranes are investigated, and conditions for the onset of instabilities are derived.
Digital twinning of cardiac electrophysiology for congenital heart disease
Authors: Salvador Matteo , Kong Fanwei , Peirlinck Mathias , Parker David W. , Chubb Henry , Dubin Anne M. , Marsden Alison Lesley
Published: November 2023

In recent years, blending mechanistic knowledge with machine learning has had a major impact in digital healthcare. In this work, we introduce a computational pipeline to build certified digital replicas of cardiac electrophysiology in pediatric patients with congenital heart disease. We construct the patient-specific geometry by means of semi-automatic segmentation and meshing tools. We generate a dataset of electrophysiology simulations covering cell-to-organ level model parameters and utilizing rigorous mathematical models based on differential equations. We previously proposed Branched Latent Neural Maps (BLNMs) as an accurate and efficient means to recapitulate complex physical processes in a neural network. Here, we employ BLNMs to encode the parametrized temporal dynamics of in silico 12-lead electrocardiograms (ECGs). BLNMs act as a geometry-specific surrogate model of cardiac function for fast and robust parameter estimation to match clinical ECGs in pediatric patients. Identifiability and trustworthiness of calibrated model parameters are assessed by sensitivity analysis and uncertainty quantification.
Microfluidic device for simple diagnosis of plant growth condition by detecting miRNAs from filtered plant extracts
Authors: Kawakatsu Yaichi , Okada Ryo , Hara Mitsuo , Tsutsui Hiroki , Yanagisawa Naoki , Higashiyama Tetsuya , Arima Akihide , Baba Yoshinobu , Kurotani Ken-ichi , Notaguchi Michitaka
Published: November 2023

Plants are exposed to a variety of environmental stress and starvation of inorganic phosphorus can be a major constraint in crop production. In plants, in response to phosphate deficiency in soil, miR399, a type of microRNA (miRNA), is upregulated. By detecting miR399, the early diagnosis of phosphorus deficiency stress in plants can be accomplished. However, general miRNA detection methods require complicated experimental manipulations. Therefore, simple and rapid miRNA detection methods are required for early plant nutritional diagnosis. For the simple detection of miR399, microfluidic technology is suitable for point-of-care applications because of its ability to detect target molecules in small amounts in a short time and with simple manipulation. In this study, we developed a microfluidic device to detect miRNAs from filtered plant extracts for the easy diagnosis of plant growth conditions. To fabricate the microfluidic device, verification of the amine-terminated glass as the basis of the device and the DNA probe immobilization method on the glass was conducted. In this device, the target miRNAs were detected by fluorescence of sandwich hybridization in a microfluidic channel. For plant stress diagnostics using a microfluidic device, we developed a protocol for miRNA detection by validating the sample preparation buffer, filtering, and signal amplification. Using this system, endogenous sly-miR399 in tomatoes, which is expressed in response to phosphorus deficiency, was detected before the appearance of stress symptoms. This early diagnosis system of plant growth conditions has a potential to improve food production and sustainability through cultivation management.
The clinician-AI interface: intended use and explainability in FDA-cleared AI devices for medical image interpretation
Authors: McNamara Stephanie L. , Yi Paul H. , Lotter William
Published: November 2023

As applications of AI in medicine continue to expand, there is an increasing focus on integration into clinical practice. An underappreciated aspect of clinical translation is where the AI fits into the clinical workflow, and in turn, the outputs generated by the AI to facilitate clinician interaction in this workflow. For instance, in the canonical use case of AI for medical image interpretation, the AI could prioritize cases before clinician review or even autonomously interpret the images without clinician review. A related aspect is explainability – does the AI generate outputs to help explain its predictions to clinicians? While many clinical AI workflows and explainability techniques have been proposed, a summative assessment of the current scope in clinical practice is lacking. Here, we evaluate the current state of FDA-cleared AI devices for medical image interpretation assistance in terms of intended clinical use, outputs generated, and types of explainability offered. We create a curated database focused on these aspects of the clinician-AI interface, where we find a high frequency of “triage” devices, notable variability in output characteristics across products, and often limited explainability of AI predictions. Altogether, we aim to increase transparency of the current landscape of the clinician-AI interface and highlight the need to rigorously assess which strategies ultimately lead to the best clinical outcomes.
The pleiotropic architecture of human impulsivity across biological scales
Authors: Mallard Travis T. , Tubbs Justin D. , Jennings Mariela , Zhang Yingzhe , Gustavson Daniel E. , Grotzinger Andrew D. , Westwater Margaret L. , Williams Camille M. , Fortgang Rebecca G. ,   23andMe Research Team, Elson Sarah L. , Fontanillas Pierre , Davis Lea K. , Raznahan Armin , Tucker-Drob Elliot M. , Choi Karmel W. , Ge Tian , Smoller Jordan W. , Palmer Abraham A. , Sanchez-Roige Sandra
Published: November 2023

Impulsivity is a complex psychological construct that represents a core feature of many psychiatric and neurological conditions. Here, we used multivariate methods to formally model the genetic architecture of impulsivity in humans, advancing genomic discovery and revealing pervasive pleiotropy that largely counters theories of impulsivity as a unitary construct. We identified 18 loci and 93 genes with diverse effects in GWAS and TWAS analyses, respectively, including a hotspot at 17q21.31 that harbors genes involved in neurodevelopmental and neurodegenerative disorders. Downstream analyses revealed that heterogeneous signals were localized to specific biological correlates, including expression in brain tissue during fetal development and cortical alterations in the inferior frontal gyrus. Polygenic score analyses suggested that liability for different forms of impulsivity may differentiate across development, operating via broad pathways early in life but affecting diverse outcomes by adulthood. Collectively, our study generates new insights into the pleiotropic architecture of impulsivity, which provides a more comprehensive understanding of its multi-faceted biology.
Comparative Transcriptome Analysis of Acne vulgaris, Rosacea, and Hidradenitis Suppurativa Supports High Dose Dietary Zinc as a Therapeutic Agent
Authors: Li Li , Hajam Irshad , McGee Jean S. , Tang Zhengkuan , Zhang Ye , Badey Nikil , Mintzer Esther , Zhang Zhenrui , Liu George Y. , Church George M. , Wang Yu
Published: November 2023

Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. We also identified high dose dietary zinc as a potential therapeutic agent and validated its efficacy in an acne mouse model.
Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca2+channel modulate its β-adrenergic regulation
Authors: Oz Shimrit , Sharon Tom , Subramaniam Suraj , Pallien Tamara , Katz Moshe , Tsemakhovich Vladimir , Tripathy Debi Ranjan , Sasson Giorgia , Chomsky-Hecht Orna , Vysochek Leonid , Schulz Maike , Fecher-Trost Claudia , Zühlke Kerstin , Bertinetti Daniela , Herberg Friedrich W. , Keren-Raifman Tal , Flockerzi Veit , Hirsch Joel A. , Klussmann Enno , Weiss Sharon , Dascal Nathan
Published: November 2023

The adrenergic nervous system augments cardiac contraction by increasing the activity of L-type voltage-gated CaV1.2 channels. Dysregulation of this process is linked to severe cardiac dysfunctions. The signaling cascade involves activation of β-adrenergic receptors, elevation of cAMP levels, separation of protein kinase A (PKA) regulatory subunit (PKAR) from catalytic subunit (PKAC), and phosphorylation of the inhibitory protein Rad leading to increased Ca2+influx. In cardiomyocytes, the core subunit of CaV1.2 (α1C) exists in two forms: full-length (FL) or proteolytically processed (truncated), lacking the distal C-terminus (dCT). Specificity and efficiency in the cascade are believed to emanate from unique protein-protein interactions, such as anchoring PKA (via PKAR) to α1Cby A-kinase anchoring proteins (AKAPs). However, most AKAPs do not interact with the truncated α1C, and their role in βAR regulation of cardiac CaV1.2 remains unclear. Here we show that PKAC, independently of PKAR or AKAPs, directly interacts with α1Cat two domains in α1C-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Furthermore, we find that DCRD competes with PCRD and reduces its interaction with PKAC. The physiological consequences of these complex interactions are incompletely understood; our data suggest that they may fine-tune the βAR regulation of CaV1.2. We propose that the newly discovered interactions take part in governing colocalization of regulatory proteins within the βAR-CaV1.2 multimolecular signaling complexes in cardiomyocytes.
Translation variation across genetic backgrounds reveals a post-transcriptional buffering signature in yeast
Authors: Teyssonniere Elie M. , Shichino Yuichi , Friedrich Anne , Iwasaki Shintaro , Schacherer Joseph
Published: November 2023

Gene expression is known to vary among individuals, and this variability can impact the phenotypic diversity observed in natural populations. While the transcriptome and proteome have been extensively studied, little is known about the translation process itself. Here, we therefore performed ribosome and transcriptomic profiling on a genetically and ecologically diverse set of natural isolates of theSaccharomyces cerevisiaeyeast. Interestingly, we found that the Euclidean distances between each profile and the expression fold changes in each pairwise isolate comparison were higher at the transcriptomic level. This observation clearly indicates that the transcriptional variation observed in the different isolates is buffered through a phenomenon known as post-transcriptional buffering at the translation level. Furthermore, this phenomenon seemed to have a specific signature by preferentially affecting essential genes as well as genes involved in complex-forming proteins, and low transcribed genes. We also explored the translation of theS. cerevisiaepangenome and found that the accessory genes related to introgression events displayed similar transcription and translation levels as the core genome. By contrast, genes acquired through horizontal gene transfer events tended to be less efficiently translated. Together, our results highlight both the extent and signature of the post-transcriptional buffering.
Ventral hippocampal interneurons govern extinction and relapse of contextual associations
Authors: Lacagnina Anthony F. , Dong Tri N. , Iyer Rasika R. , Khan Saqib , Mohamed Mazen K , Clem Roger L.
Published: November 2023

ABSTRACT/SUMMARY

Contextual associations are critical for survival but must be extinguished when new conditions render them nonproductive. By most accounts, extinction forms a new memory that competes with the original association for control over behavior, but the mechanisms underlying this competition remain largely enigmatic. Here we find the retrieval of contextual fear conditioning and extinction yield contrasting patterns of activity in prefrontal cortex and ventral hippocampus. Within ventral CA1, activation of somatostatin-expressing interneurons (SST-INs) occurs preferentially during extinction retrieval and correlates with differences in input synaptic transmission. Optogenetic manipulation of these cells but not parvalbumin interneurons (PV-INs) elicits bidirectional changes in fear expression following extinction, and the ability of SST-INs to gate fear is specific to the context in which extinction was acquired. A similar pattern of results was obtained following reward-based extinction. These data show that ventral hippocampal SST-INs are critical for extinguishing prior associations and thereby gate relapse of both aversive and appetitive responses.
Interpretable Inflammation Landscape of Circulating Immune cells
Authors: Jiménez-Gracia Laura , Maspero Davide , Aguilar-Fernández Sergio , Craighero Francesco , Ruiz Sara , Marchese Domenica , Caratù Ginevra , Elosua-Bayes Marc , Abdalfatah Mohamed , Sanzo-Machuca Angela , Corraliza Ana M. , Massoni-Badosa Ramon , Tran Hoang A. , Normand Rachelly , Nestor Jacquelyn , Hong Yourae , Kole Tessa , van der Velde Petra , Alleblas Frederique , Pedretti Flaminia , Aterido Adrià , Banchero Martin , Soriano German , Román Eva , van den Berge Maarten , Salas Azucena , Carrascosa Jose Manuel , Nebro Antonio Fernández , Domènech Eugeni , Cañete Juan , Tornero Jesús , Pérez-Gisbert Javier , Choy Ernest , Girolomoni Giampiero , Siegmund Britta , Julià Antonio , Serra Violeta , Elosua Roberto , Tejpar Sabine , Vidal Silvia , Nawijn Martijn C. , Marsal Sara , Vandergheynst Pierre , Villani Alexandra-Chloé , Nieto Juan C. , Heyn Holger
Published: November 2023

Inflammation is a biological phenomenon involved in a wide variety of physiological and pathological processes. Although a controlled inflammatory response is beneficial for restoring homeostasis, it can become unfavorable if dysregulated. In recent years, major progress has been made in characterizing acute and chronic inflammation in specific diseases. However, a global, holistic understanding of inflammation is still elusive. This is particularly intriguing, considering the crucial function of inflammation for human health and its potential for modern medicine if fully deciphered. Here, we leverage advances in the field of single-cell genomics to delineate the full spectrum of circulating immune cell activation underlying inflammatory processes during infection, immune-mediated inflammatory diseases and cancer. Our single-cell atlas of >2 million peripheral blood mononuclear cells from 356 patients and 18 diseases allowed us to learn a foundation model of inflammation in circulating immune cells. The atlas expanded our current knowledge of the biology of inflammation of acute (e.g. inflammatory bowel disease, sepsis) and chronic (e.g. cirrhosis, asthma, and chronic obstructive pulmonary disease) disease processes and laid the foundation to develop a precision medicine framework using unsupervised as well as explainable machine learning. Beyond a disease-centered classification, we charted altered activity of inflammatory molecules in peripheral blood cells, depicting functional biomarkers to further understand mechanisms of inflammation. Finally, we have laid the groundwork for developing precision medicine diagnostic tools for patients experiencing severe acute or chronic inflammation by learning a classifier for inflammatory diseases, presenting cells in circulation as a powerful resource for patient stratification.
Adolescent stress-induced behavioral deficits, ventral hippocampus redox dysregulation and excitatory/inhibitory imbalance related to schizophrenia
Authors: Santos-Silva Thamyris , Lopes Caio Fábio Baeta , Ülgen Doğukan Hazar , Guimarães Danielle Aparecida , Guimarães Francisco S. , Alberici Luciane Carla , Sandi Carmen , Gomes Felipe V.
Published: November 2023

Redox dysregulation has been proposed as a convergent point of childhood trauma and the emergence of psychiatric disorders, such as schizophrenia (SCZ). However, the impact of severe stressors during adolescence on the ventral hippocampus (vHip) redox states and their functional consequences, including behavioral and electrophysiological changes related to SCZ, are not entirely understood. After exposing adolescent animals to physical stress (postnatal day, PND31–40), we explored social and cognitive behaviors (PND47–49) and the activity of pyramidal glutamate neurons, the number of parvalbumin (PV) interneurons, and the transcriptomic signature of the vHip (PND51). We also evaluated the impact of stress on the redox system one and ten days after stress, while glutathione levels were measured in the vHip and serum following the behavioral test. Adolescent-stressed animals exhibited loss of sociability, cognitive impairment, and vHip excitatory/inhibitory (E/I) imbalance. Genome-wide transcriptional profiling unveiled the impact of stress on synaptic and redox system-related genes. Stress impacted mitochondrial respiratory function, leading to changes in reactive oxygen species levels in the vHip. Glutathione (GSH) and glutathione disulfide (GSSG) levels were elevated in the serum of stressed animals, while GSSG was also increased in the vHip and negatively correlated with sociability. Additionally, PV interneuron deficits in the vHip caused by adolescent stress were associated with oxidative stress. Our results highlight the negative impact of adolescent stress on vHip redox regulation and mitochondrial function, which are partially associated with E/I imbalance and behavioral abnormalities related to SCZ.
Expression and fusogenic activity of SARS CoV-2 Spike protein displayed in the HSV-1 Virion
Authors: Desai Prashant J.
Published: November 2023

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a zoonotic pathogen that can cause severe respiratory disease in humans. The new SARS-CoV-2 is the cause of the current global pandemic termed coronavirus disease 2019 (COVID-19) that has resulted in many millions of deaths world-wide. The virus is a member of the Betacoronavirus family, its genome is a positive strand RNA molecule that encodes for many genes which are required for virus genome replication as well as for structural proteins that are required for virion assembly and maturation. A key determinant of this virus is the Spike (S) protein embedded in the virion membrane and mediates attachment of the virus to the receptor (ACE2). This protein also is required for cell-cell fusion (syncytia) that is an important pathogenic determinant. We have developed a pseudotyped herpes simplex virus type 1 (HSV-1) recombinant virus expressing S protein in the virion envelop. This virus has also been modified to express a Venus fluorescent protein fusion to VP16, a virion protein of HSV-1. The virus expressing Spike can enter cells and generates large multi-nucleated syncytia which are evident by the Venus fluorescence. The HSV-1 recombinant virus is genetically stable and virus amplification can be easily done by infecting cells. This recombinant virus provides a reproducible platform for Spike function analysis and thusaddsto the repertoire of pseudotyped viruses expressing Spike.

Impact Statement

The isolation of a pseudotyped herpes simplex virus type 1 (HSV-1) virus using the Spike protein is new and innovative. This virus can be used to study entry and fusion events mediated by the S protein as well as test antibodies for their ability to neutralize this particle. In addition, these virions can be used for screening antibody specificity using the S protein displayed in its natural membrane bound conformation.
Structure and dynamics of human cardiac fibroblast nanotubes
Authors: Schmid-Herbstritt S.C. , Stief G. , Greiner J. , Felekary A. , Madl J. , Zeidler V. , Heer J. , Iaconianni P. , Koch M. , Kollmar K. , Walz C. , Nübling S. , Kok T. , Pronto J.R. , Kutschka I. , Voigt N. , Morgan G. , Dienert J. , Brox T. , Briquez P. , Peyronnet R. , Rohrbach A. , Kohl P. , Rog-Zielinska E.A.
Published: November 2023

Efficient and dynamic interactions between cardiac fibroblasts and their environment are essential for the maintenance of tissue homeostasis in healthy hearts and play an important role during pathological remodelling. Here, we investigate a relatively obscure mechanism through which human atrial fibroblasts communicate with each other, with other cells, and with the extracellular matrix (ECM) – nanotubes (NT). We investigated NT structure and dynamics in primary right atrial fibroblasts isolated from patients in sinus rhythm (SR) and atrial fibrillation (AF), in an immortalised human atrial fibroblasts cell line, and in intact human tissue, using a wide range of imaging approaches (including confocal microscopy, label-free reflection microscopy, rotating coherent scattering microscopy, and cryo-electron tomography). We show that fibroblasts maintain continuous NT activityin vitro, with numerous protrusions constantly probing the surrounding environment. NT structure and activity change during AF and following pharmacological (transforming growth factor-β, latrunculin B) and environmental (hypoxia) interventions. We also show that cardiac fibroblast NT mediate intercellular organelle exchange and dynamically interact with ECM. Finally, we present evidence for the presence of fibroblast-borne NT in human atrial tissue. Our results advance our understanding of how cardiac fibroblasts interact with their environment. NT are versatile structures capable of both sensory and actuating functions, and offer a dynamic and rapid communication conduit that facilitates cell–cell and cell–extracellular matrix interactions.
Protein Design by Directed Evolution Guided by Large Language Models
Authors: Tran Trong Thanh , Hy Truong Son
Published: November 2023

Directed evolution, a strategy for protein engineering, optimizes protein properties (i.e., fitness) by a rigorous and resource-intensive process of screening or selecting among a vast range of mutations. By conducting an in silico screening of sequence properties, machine learning-guided directed evolution (MLDE) can expedite the optimization process and alleviate the experimental workload. In this work, we propose a general MLDE framework in which we apply recent advancements of Deep Learning in protein representation learning and protein property prediction to accelerate the searching and optimization processes. In particular, we introduce an optimization pipeline that utilizes Large Language Models (LLMs) to pinpoint the mutation hotspots in the sequence and then suggest replacements to improve the overall fitness. Our experiments have shown the superior efficiency and efficacy of our proposed framework in the conditional protein generation, in comparision with other state-of-the-art baseline algorithms. We expect this work will shed a new light on not only protein engineering but also on solving combinatorial problems using data-driven methods. Our implementation is publicly available at https://github.com/HySonLab/Directed_Evolution
Performance of Chrysanthemum Cultivars under Agro-climatic condition of Chhattisgarh plains
Authors: Bhoi Madhusmita , Tirkey Tarsiyus
Published: November 2023

Chrysanthemum is the second largest flower after rose in the global ornamental plants market; It is third in terms of cut flower and ranks fifth in global floriculture trading. Therefore, floricultural study of chrysanthemum has gained widespread attention recently. As the state of Chhattisgarh is rising as a floral hub, we are propelled to determine suitable cultivars of chrysanthemum for different characters in Chhattisgarh plains. To this end, we conducted an experiment based on Randomized Block Design (under field condition) during the year 2016-2017, with seven cultivars of Chrysanthemum namely Pusa Sona, Pusa Arunodaya, Pusa Kesari, Pusa Chitraksha, Pusa Aditya, Mother Teresa, and White Prolific. Our results indicate that Pusa Sona exhibits the early bud appearance (32.80 days), early flowering (60.27 days), maximum number of flowers per plant (137.80), and maximum number of branches per plant (19.73). Further, maximum plant height (49.47 cm) and plant spread (32.63 cm) were observed in Pusa Chitraksha. While Pusa Kesari recorded maximum flower diameter (7.00 cm) and maximum weight of flowers per plant (177.50 g), the maximum flowering duration (59.40 days) was noted under Pusa Aditya. We are certain that these novel findings would help floriculturists’ decision making significantly regarding chrysanthemum plantation.
Enhanced detection of RNA modifications and mappability with high-accuracy nanopore RNA basecalling models
Authors: Diensthuber Gregor , Pryszcz Leszek , Llovera Laia , Lucas Morghan C , Delgado-Tejedor Anna , Cruciani Sonia , Roignant Jean-Yves , Begik Oguzhan , Novoa Eva Maria
Published: November 2023

In recent years, nanopore direct RNA sequencing (DRS) has established itself as a valuable tool for studying the epitranscriptome, due to its ability to detect multiple modifications within the same full-length native RNA molecules. While RNA modifications can be identified in the form of systematic basecalling ‘errors’ in DRS datasets,N6-methyladenosine (m6A) modifications produce relatively low ‘errors’ compared to other RNA modifications, limiting the applicability of this approach to m6A sites that are modified at high stoichiometries. Here, we demonstrate that the use of alternative RNA basecalling models, trained with fully unmodified sequences, increases the ‘error’ signal of m6A, leading to enhanced detection and improved sensitivity even at low stoichiometries. Moreover, we find that high-accuracy alternative RNA basecalling models can show up to 97% median basecalling accuracy, outperforming currently available RNA basecalling models, which show 91% median basecalling accuracy. Notably, the use of high-accuracy basecalling models is accompanied by a significant increase in the number of mapped reads –especially in shorter RNA fractions– and increased basecalling error signatures at pseudouridine (Ψ) and N1-methylpseudouridine (m1Ψ) modified sites. Overall, our work demonstrates that alternative RNA basecalling models can be used to improve the detection of RNA modifications, read mappability and basecalling accuracy in nanopore DRS datasets.
Eco-evolutionary dynamics of partially migratory metapopulations in spatially and seasonally varying environments
Authors: Haaland Thomas R. , Payo-Payo Ana , Acker Paul , Fortuna Rita , Burthe Sarah J. , Ratikainen Irja I. , Daunt Francis , Reid Jane M.
Published: November 2023

Predicting population responses to environmental changes requires understanding interactions among environmentally induced phenotypic variation, selection, demography and genetic variation, and thereby predicting eco-evolutionary dynamics emerging across diverse temporal and spatial scales. Partially migratory metapopulations (PMMPs), featuring seasonal coexistence of resident and migrant individuals across multiple spatially distinct subpopulations, have clear potential for complex spatio-seasonal eco-evolutionary dynamics through impacts of selection on migration on spatial population dynamics, and feedbacks resulting from ongoing micro-evolution. However, the key genetic and environmental conditions that maintain migratory polymorphisms, and eco-evolutionary dynamics of PMMPs under stochastic environmental variation and strong seasonal perturbations, have not yet been resolved. Accordingly, we present a general individual-based model that tracks eco-evolutionary dynamics in PMMPs inhabiting spatially structured, seasonally varying landscapes, with migration formulated as a quantitative genetic threshold trait. Our simulations show that such genetic and landscape structures, which commonly occur in nature, can readily produce a variety of stable partially migratory systems given diverse regimes of spatio-seasonal environmental variation. Typically, partial migration is maintained whenever sites differ in non-breeding season suitability resulting from variation in density-dependence, causing ‘ideal free’ non-breeding distributions where residents and migrants occur with frequencies that generate similar survival probabilities. Yet, stable partial migration can also arise without any fixed differences in non-breeding season density-dependence among sites, and even without density-dependence at all, through risk-spreading given sufficiently large stochastic environmental fluctuations among sites and years. Finally, we show that local non-breeding season mortality events, as could result from extreme climatic events, can generate eco-evolutionary dynamics that ripple out to affect breeding and non-breeding season space use of subpopulations throughout the PMMP, on both short and longer timeframes. Such effects result from spatially divergent selection on both the occurrence and destinations of migration. Our model thus shows how facultative seasonal migration can act as a key mediator of eco-evolutionary dynamics in spatially and seasonally structured environments, providing key steps towards predicting responses of natural partially migratory populations to ongoing changes in spatio-seasonal patterns of environmental variation.