bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology and Nomogram Development for Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL-NOS): Insights from the SEER Database
Authors: Wang Fan
Published: October 2023

Background

Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL-NOS), a rare and intricate hematological disorder characterized by uncontrolled eosinophilic proliferation, presents clinical challenges owing to its infrequency. This study aimed to investigate the epidemiology and develop a prognostic nomogram for CEL-NOS patients.

Methods

Utilizing the Surveillance, Epidemiology and End Results (SEER) database, CEL-NOS cases diagnosed between 2001 and 2020 were analyzed for incidence rates, clinical profiles, and survival outcomes. Patients were randomly divided into training and validation cohorts (7:3 ratio). LASSO regression analysis and Cox regression analysis were performed to screen the prognostic factors for overall survival. A nomogram was then constructed and validated to predict the 3- and 5-year overall survival probability of CEL-NOS patients by incorporating these factors.

Results

The incidence rate of CEL-NOS was very low, with an average of 0.033 per 100,000 person-years from 2001 to 2020. The incidence rate significantly increased with age and was higher in males than females. The mean age at diagnosis was 57 years. Prognostic analysis identified advanced age, specific marital statuses, and secondary CEL-NOS as independent and adverse predictors of overall survival (OS). To facilitate personalized prognostication, a nomogram was developed incorporating these factors, demonstrating good calibration and discrimination. Risk stratification using the nomogram effectively differentiated patients into low- and high-risk groups.

Conclusions

This study enhances our understanding of CEL-NOS, offering novel insights into its epidemiology, demographics, and prognostic determinants, while providing a possible prognostication tool for clinical use. However, further research is warranted to elucidate molecular mechanisms and optimize therapeutic strategies for CEL-NOS.
Prenatal exposure to THC vapor influences feeding, bodyweight and glucose metabolism under both basal conditions and following high fat diet
Authors: Hume Catherine , Baglot Samantha L. , Javorcikova Lucia , Lightfoot Savannah H.M. , Scheufen Jessica B.K. , Hill Matthew N.
Published: October 2023

4-20% of people report using cannabis during pregnancy, thereby it is essential to assess the associated risks. There is some evidence that prenatal cannabis exposure (PCE) may be associated with increased risk for development of obesity and diabetes later in life, however this has not been well explored under controlled conditions. The aim of this study was to use a translational THC vapor model in rodents to characterize the effects of PCE on adiposity, glucose metabolism, and feeding patterns in adulthood, with focus on potential sex differences. Pregnant Sprague Dawley rats were exposed to vaporized THC (100mg/ml) or control (polyethylene glycol vehicle) across the entire gestational period. Adult offspring from PCE or control litters were subjected to measures of adiposity, glucose metabolism and feeding behavior. Rats were then placed onto special diets (60% high-fat diet [HFD] or control 10% low fat diet [LFD]) for 4-months, then re-subjected to adiposity, glucose metabolism and feeding behavior measurements. PCE did not influence maternal weight or food consumption but was associated with transient decreased pup weight. PCE did not initially influence bodyweight or adiposity, but PCE did significantly reduce the rate of bodyweight gain when animals were maintained on special diets (HFD/LFD), regardless of which diet. Further, PCE had complex effects on glucose metabolism and feeding behavior that were both sex and diet dependent. No effects of PCE were found on plasma leptin or insulin, or white adipose tissue mass. Overall, this data enhances current understanding of the potential impacts of PCE.
Accurate Identification of Motoneuron Discharges from Ultrasound Images Across the Full Muscle Cross-Section
Authors: Lubel Emma , Rohlén Robin , Sgambato Bruno Grandi , Barsakcioglu Deren Y , Ibáñez Jaime , Tang Meng-Xing , Farina Dario
Published: October 2023

Objective

Non-invasive identification of motoneuron (MN) activity is commonly done using (EMG). However, surface EMG (sEMG) signals detect only superficial sources, at less than approximately 10-mm depth. Intramuscular EMG can detect deep sources, but it is limited to sources within a few mm of the detection site. Conversely, ultrasound (US) images have high spatial resolution across the whole muscle cross-section. The activity of MNs can be extracted from US images due to the movements that MN activation generates in the innervated muscle fibers. Current US-based decomposition methods can accurately identify the location and average twitch induced by MN activity. However, they cannot accurately detect MN discharge times.

Methods

Here, we present a method based on the convolutive blind source separation of US images to estimate MN discharge times with high accuracy. The method was validated across 10 participants using concomitant sEMG decomposition as the ground truth.

Results

140 unique MN spike trains were identified from US images, with a rate of agreement (RoA) with sEMG decomposition of 87.4 ± 10.3 %. Over 50% of these MN spike trains had a RoA greater than 90%. Furthermore, with US, we identified additional MUs well beyond the sEMG detection volume, at up to >30 mm below the skin.

Conclusion

The proposed method can identify discharges of MNs innervating muscle fibers in a large range of depths within the muscle from US images.

Significance

The proposed methodology can non-invasively interface with the outer layers of the central nervous system innervating muscles across the full cross-section.
A morphotype ofSaccolaimus saccolaimus(Chiroptera: Emballonuridae) from West Bengal, India with a comparative note of the species
Authors: Bhakat Somnath
Published: October 2023

An adultSaccolaimus saccolaimusTemminck, 1838 is described here with morphometric measurements in detail. The present species though showed morphological similarities with the species reported from India and abroad but it bears an exceptional character, a white oval pad at the base of the thumb. A comparative note of the species found in India and other countries are also presented here with a suggestion to rethink the IUCN status of the species “Least Concern” in India.
TreeArchTraits: an R package to analyse the architectural traits of trees using TLS data
Authors: Puletti Nicola , Innocenti Simone , Guasti Matteo , Alvites Cesar
Published: October 2023

1

The architecture of trees is significantly influenced by their interactions, directly affecting their functioning and structural development. Different tree architectural indicators (TAT) have evolved, including these interactions’ measurements.

Recent advances in Terrestrial Laser Scanning data collection make measuring the three-dimensional characteristics of trees more more efficient.

The R packageTreeArchTraitsfacilitates the processing of three-dimensional tree characteristics obtained through Terrestrial Laser Scanning, enabling the computation of various indices.

A set of trees belonging to different forest conditions was used to demonstrate theTreeArchTraitspotential for characterizing tree architectures.

Abstract Figure
HIV-DRIVES: HIV Drug Resistance Identification, Variant Evaluation, & Surveillance Pipeline
Authors: Kanyerezi Stephen , Sserwadda Ivan , Ssemaganda Aloysius , Seruyange Julius , Ayitewala Alisen , Oundo Hellen , Tenywa Wilson , Kagurusi Brian , Tusabe Godwin , Were Stacy , Ssewanyana Isaac , Nabadda Susan , Namaganda Maria Magdalene , Mboowa Gerald
Published: October 2023

The global prevalence of resistance to the Human Immunodeficiency Virus (HIV) combined antiretroviral therapy (cART) emphasizes the need to continuous monitoring to better understand the dynamics of drug-resistant mutations to guide treatment optimization and patient management as well as check the spread of resistant viral strains. We have recently, integrated next-generation sequencing (NGS) into routine HIV drug resistance (HIVDR) monitoring, with key challenges in the bioinformatic analysis and interpretation of the complex data generated while ensuring data security and privacy of patient information. To address these challenges, here, we present HIV-DRIVES (HIV Drug Resistance Identification, Variant Evaluation, and Surveillance), an NGS-HIVDR bioinformatics pipeline that has been developed and validated using Illumina short-reads, FASTA, and sanger ab1.seq files.

Availability and implementation

HIV-DRIVES source codes and operation manual freely available athttps://github.com/MicroBioGenoHub/HIV-DRIVES.
Default mode network shows distinct emotional and contextual responses yet common effects of retrieval demands across tasks
Authors: Souter Nicholas E. , de Freitas Antonia , Zhang Meichao , Shao Ximing , del Jesus Gonzalez Alam Tirso Rene , Engen Haakon , Smallwood Jonathan , Krieger-Redwood Katya , Jefferies Elizabeth
Published: October 2023

The default mode network (DMN) lies towards the heteromodal end of the principal gradient of intrinsic connectivity, maximally separated from sensory-motor cortex. It supports memory-based cognition, including the capacity to retrieve conceptual and evaluative information from sensory inputs, and to generate meaningful states internally; however, the functional organisation of DMN that can support these distinct modes of retrieval remains unclear. We used fMRI to examine whether activation within subsystems of DMN differed as a function of retrieval demands, or the type of information to be retrieved, or both. In a picture association task, participants retrieved two types of semantic features about contexts and emotions: in the generate phase, these associations were retrieved from a novel picture, while in a switch phase, participants retrieved a new association for the same image. Semantic context and emotion trials were associated with dissociable DMN subnetworks, indicating that a key dimension of DMN organisation relates to the type of information being accessed. The fronto-temporal and medial temporal DMN showed a preference for emotional and contextual associations, respectively. Relative to the generate phase, the switch phase recruited clusters closer to the heteromodal apex of the principal gradient – a cortical hierarchy separating unimodal and heteromodal regions. There were no differences in this effect between association types. Instead, memory switching was associated with a distinct subnetwork associated with controlled internal cognition. These findings delineatedistinctpatterns of DMN recruitment for different kinds of associations yetcommonresponses across tasks that reflect retrieval demands.

Key points

Retrieval of contextual and emotional features relies on distinct default mode subnetworks.

Novelty of visual input has an equivalent effect across default mode subnetworks.

Secondary associations retrieved from re-presented pictures activate heteromodal end of the principal gradient.
Antiepileptic medication strengthens excitatory neurotransmission in pyramidal neurons of the adult human neocortex
Authors: Lenz Maximilian , Kruse Pia , Eichler Amelie , Straehle Jakob , Hemeling Hanna , Stöhr Phyllis , Beck Jürgen , Vlachos Andreas
Published: October 2023

Homeostatic synaptic plasticity serves to maintain neuronal function within a dynamic range upon perturbations in network activity. While coordinated structural and functional changes at synaptic sites play a crucial role in adaptive processes, the specific regulatory mechanisms and biological relevance of homeostatic plasticity in the human brain warrant further investigation. In this study, we investigated the effects of neural network silencing, achieved through pharmacological inhibition of voltage-gated sodium channels or glutamatergic neurotransmission – common targets of antiepileptic medication – on functional and structural properties of murine and human cortical tissue. Using mouse entorhino-hippocampal tissue cultures, acute neocortical slices of adult mice, and human brain tissue, we characterize homeostatic synaptic plasticity across models, brain regions, and species. Our findings demonstrate local homeostatic synaptic plasticity in the adult human neocortex, highlighting the potential effects of antiepileptic medication in brain regions unaffected by the primary diseases, which might represent a mechanism for neuropsychiatric effects linked to these medications and increased seizure susceptibility upon discontinuation of antiepileptic medication.
A senescence-like state is beneficial for ovarian cancer treatment
Authors: Skulimowski Michael , Calvo Llilians , Cheng Shuofei , Clément Isabelle , Portelance Lise , Zhan Yu , Carmona Euridice , Lafontaine Julie , de Ladurantaye Manon , Rahimi Kurosh , Provencher Diane , Mes-Masson Anne-Marie , Rodier Francis
Published: October 2023

High-grade serous ovarian carcinoma (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that tissue-derived primary HGSOC epithelial cultures reflecting the original disease primarily undergo therapy-induced senescence in response to DNA damage and first-line carboplatin/paclitaxel chemotherapy. Unlike previous observations using cell lines, primary HGSOC cell TIS displays a stable senescence proliferation arrest and p16INK4A expression, and is accompanied by persistent DNA damage, an inflammatory secretome, and senolytic sensitivity, suggesting new avenues for selective pharmacological manipulation of these cells. Whether cell senescence induced by cancer therapy is beneficial or detrimental to clinical outcomes remains unknown. Single cell comparison of pre- and post-chemotherapy patient HGSOC tissue samples revealed changes in physio-pathological senescence biomarkers supporting a post-treatment senescence-like state. Importantly, patients with stronger senescence signatures post-chemotherapy displayed better 5-year survival suggesting that senescence accounts, at least in part, for beneficial cellular responses to treatment. Given that ovarian cancer epithelial cells almost universally retain the capacity to undergo senescence and that senescence appears beneficial in this context, HGSOC senescence-centric therapeutic avenues should be further explored.

Author Summary

Whether cancer therapy-induced cell fate decisions like senescence are good or bad for patient treatment outcome is unknown. We find that ovarian cancer cells almost universally retain senescence competence and that senescence in treated cancer tissues correlate with good clinical outcomes. This reveals that senescence is a relevant drug target in ovarian cancer.
Torpor energetics are related to the interaction between body mass and climate in bats of the family Vespertilionidae
Authors: Ayala-Berdon Jorge , Medina-Bello Kevin I.
Published: October 2023

Torpor is an adaptive strategy that allows animals to cope with energy limitations under adverse environmental conditions. In birds and mammals, intrinsic and extrinsic factors such as body mass (Mb) and ambient temperature (Ta) are well established triggers of torpor. Interestingly, the interplay betweenMband climate with differentTaon torpor traits in bats remains unexplored. Using open flow respirometry, we calculatedTaupon entering torpor (Tat), the reduction in torpid metabolic rate relative to the basal metabolic rate (TMRred), theTaat which torpor metabolic rate reached its minimum (Taadjust), and minimum torpid metabolic rate (TMRmin) in 11 bat species of the family Vespertilionidae that differ inMbfrom warm and cold climates. We also includedTMRmindata retrieved through a bibliography review. We tested the effects ofMband climate on torpor traits using mixed-effect phylogenetic models. All models showed a significant interaction betweenMband climate. This interaction was inversely related toTat,TMRred,Taadjust, and positively related toTMRmin. These results are likely explained by the differences inMband the metabolic rate of bats from different climates, which may allow individuals to express torpor in places with differentTa. Further studies to assess torpor use in bats of different climates are proposed.

Summary statement

The interaction between body mass and climate influences torpor energetics in bats of the family Vespertilionidae. As a result, torpid traits change based on body mass and climate.
ATF7IP2/MCAF2 directs H3K9 methylation and meiotic gene regulation in the male germline
Authors: Alavattam Kris G. , Esparza Jasmine M. , Hu Mengwen , Shimada Ryuki , Kohrs Anna R. , Abe Hironori , Munakata Yasuhisa , Otsuka Kai , Yoshimura Saori , Kitamura Yuka , Yeh Yu-Han , Hu Yueh-Chiang , Kim Jihye , Andreassen Paul R. , Ishiguro Kei-ichiro , Namekawa Satoshi H.
Published: October 2023

H3K9 tri-methylation (H3K9me3) plays emerging roles in gene regulation, beyond its accumulation on pericentric constitutive heterochromatin. It remains a mystery why and how H3K9me3 undergoes dynamic regulation in male meiosis. Here, we identify a novel, critical regulator of H3K9 methylation and spermatogenic heterochromatin organization: the germline-specific protein ATF7IP2 (MCAF2). We show that, in male meiosis, ATF7IP2 amasses on autosomal and X pericentric heterochromatin, spreads through the entirety of the sex chromosomes, and accumulates on thousands of autosomal promoters and retrotransposon loci. On the sex chromosomes, which undergo meiotic sex chromosome inactivation (MSCI), the DNA damage response pathway recruits ATF7IP2 to X pericentric heterochromatin, where it facilitates the recruitment of SETDB1, a histone methyltransferase that catalyzes H3K9me3. In the absence of ATF7IP2, male germ cells are arrested in meiotic prophase I. Analyses of ATF7IP2-deficient meiosis reveal the protein’s essential roles in the maintenance of MSCI, suppression of retrotransposons, and global upregulation of autosomal genes. We propose that ATF7IP2 is a downstream effector of the DDR pathway in meiosis that coordinates the organization of heterochromatin and gene regulation through the spatial regulation of SETDB1-mediated H3K9me3 deposition.
Influence of Monaural Auditory Stimulation Combined with Music on Brain Activity
Authors: Chang Ming , Tanaka Kenta , Naruse Yasushi , Imamura Yasuhiko , Fujii Shinya
Published: October 2023

Recently, the increasing attention to mental states and psychophysical health has fueled the research into methods that can aid in relaxation and recovery. Traditional methods like meditation and sauna, while effective, have their limitations; thus, the need for more accessible and convenient alternatives. Our innovative approach combines monaural beats with music, attempting to replicate the relaxing effects of a sauna in the auditory domain. In comparison to normal music and silent condition, the power of the theta active band significantly increased when listening to our modified music. Furthermore, after listening to modified music, there was a significant increase in mismatch negativity (MMN) amplitude in the oddball task. Additionally, participants’ subjective responses to a questionnaire indicated significant changes in body relaxation and other metrics after listening to the processed music. This state is considered similar to the “totonou” state previously reported for the sauna. Thus, the present research proposes a convenient method for achieving relaxation, opening an avenue for individuals to customize their “totonou” music based on personal preferences.
Arrested Agonist Paradigm For Selective Radiosensitization of Prostate Cancer
Authors: Coulter Jonathan B. , Haffner Michael C. , Zhang Yonggang , Zhou Haoming , Pham Minh-Tam , Chen Jiayu , Chikarmane Roshan , Mishra Alok , Mehl Maire S. , Kazibwe Stella , Choi Kirsten , Archey Ava , Valluri Sarayu , Lupold Shawn E. , Song Daniel , De Marzo Angelo , Nelson William G. , DeWeese Theodore L. , Yegnasubramanian Srinivasan
Published: October 2023

As a prototypical nuclear hormone receptor, the androgen receptor (AR) signals via a sequential cascade triggered by binding to androgenic ligands such as testosterone and dihydrotestosterone (DHT). This cascade includes dimerization of the ligand-receptor complex, nuclear translocation, chromatin binding to response elements, recruitment of TOP2B and co-activator complexes, and induction of an effector transcriptional program. In prostate cancers, this AR signaling cascade is an essential driver of growth and survival, yet its activity confers potential vulnerabilities through transient TOP2B-mediated DNA double strand breaks. We investigated the ability of non-steroidal AR ligands to activate initial steps of the AR signaling cascade up to the point of AR- and TOP2B-mediated double strand breaks, with subsequent arrest of the signaling cascade to prevent induction of pro-growth/survival transcriptional programs in prostate cancer cells. We identified hydroxyflutamide (FLU) as such an androgen receptor arrested agonist; in androgen-deprived conditions, FLU induced AR nuclear translocation, chromatin binding, and TOP2B-mediated double strand breaks, but failed to induce AR target gene expression and prostate cancer cell growth. The FLU-mediated arrest in the signaling cascade could be attributed to the inability of FLU to allow association of AR with SMARCD2, a critical component of the BAF chromatin remodeling complex required for androgen induced AR co-activation. Interestingly, the FLU-induced, AR- and TOP2B-mediated double strand breaks could be used to selectively sensitize AR-positive prostate cancer cells to ionizing radiationin vitroandin vivo. These findings support a novel arrested agonist paradigm for selective radiosensitization of prostate cancer cells without inducing AR-mediated pro-growth and survival transcriptional programs.
Puzzle cell shape emerges from the interaction of growth with mechanical constraints
Authors: Trozzi Nicola , Lane Brendan , Perruchoud Alice , Wang Yixuan , Hörmayer Lukas , Ansel Mylan , Mollier Corentin , Malivert Alice , Clark Frances , Reichgelt Tammo , Roeder Adrienne H.K. , Hamant Olivier , Boudaoud Arezki , Kwiatkowska Dorota , Runions Adam , Smith Richard S. , Majda Mateusz
Published: October 2023

The puzzle-shaped cells found in the shoot epidermis of many plant species are a fascinating example of complex cell shapes. Because biological form often follows function, the unique shape of these cells suggests that they must serve some adaptive purpose for the plant. We previously proposed that these intricate shapes provide an effective strategy for reducing mechanical stress on the cell wall when epidermal cells undergo growth in more than one direction. Here we analyze a large selection of living and paleo plant species and find that the ability to make puzzle cells is a shared feature across all plant species, although their presence can be hidden as it varies depending on the organ, developmental stage, and environmental conditions. Computational modeling ofArabidopsisand maize epidermal cells revealed that presence and patterning of lobes is a dynamic process that is intricately linked to the growth history and environmental context of the plant organ. Conversely, disrupted lobeyness in mutants or with drug treatments affects plant development and leads to compensatory strategies. We propose that the mechanism underlying the formation of puzzle-shaped cells is likely conserved among higher plants and is a response to a developmental constraint driven by growth and mechanical stress.
SaProt: Protein Language Modeling with Structure-aware Vocabulary
Authors: Su Jin , Han Chenchen , Zhou Yuyang , Shan Junjie , Zhou Xibin , Yuan Fajie
Published: October 2023

Abstract

Large-scale protein language models (PLMs), such as the ESM family, have achieved remarkable performance in various downstream tasks related to protein structure and function by undergoing unsupervised training on residue sequences. They have become essential tools for researchers and practitioners in biology. However, a limitation of vanilla PLMs is their lack ofexplicitconsideration for protein structure information, which suggests the potential for further improvement. Motivated by this, we introduce the concept of a “structure-aware vocabulary” that integrates residue tokens with structure tokens. The structure tokens are derived by encoding the 3D structure of proteins using Foldseek. We then propose SaProt, a large-scale general-purpose PLM trained on an extensive dataset comprising approximately 40 million protein sequences and structures. Through extensive evaluation, our SaProt model surpasses well-established and renowned baselines across 10 significant downstream tasks, demonstrating its exceptional capacity and broad applicability. We have made the code1, pre-trained model, and all relevant materials available athttps://github.com/westlake-repl/SaProt.
ProxyTyper: Generation of Proxy Panels for Privacy-aware Outsourcing of Genotype Imputation
Authors: Zhi Degui , Jiang Xiaoqian , Harmanci Arif
Published: October 2023

One of the major challenges in genomic data sharing is protecting the privacy of participants. Numerous studies demonstrated that genetic data and related summary statistics can be used for identifying individuals. These studies led to a strong chilling effect on researchers that hindered collaborative data sharing. Consequently, population-level genetic databases are often siloed in central repositories with complex and burdensome data usage agreements. While cryptographic methods that are provably secure have been developed, these methods require high-level expertise in security and depend on large computational resources.

To fill the methodological gap in this domain, we present ProxyTyper, a set of data protection mechanisms to generate “proxy-panels” from sensitive haplotype-level genetic datasets. ProxyTyper uses haplotype sampling, allele hashing, and anonymization to protect the genetic variant coordinates, genetic maps, and chromosome-wide haplotypes. These mechanisms can provide strong deterrence against honest-but-curious entities and well-known re-identification and linking attacks. The proxy panels can be used as input to existing tools without any modifications to the underlying algorithms. We focus on building proxy-panels for genotype imputation to protect typed and untyped variants. We demonstrate that proxy-based imputation provides protection against well-known attacks with a minor decrease of imputation accuracy for variants in wide range of allele frequencies.
A dicer-related helicase opposes the age-related pathology from SKN-1 activation in ASI neurons
Authors: Turner Chris D. , Stuhr Nicole L. , Ramos Carmen M. , Van Camp Bennett T. , Curran Sean P.
Published: October 2023

Coordination of cellular responses to stress are essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here we identify how SKN-1 activation in two ciliated ASI neurons inC. elegansresults in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of non-coding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a novel regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase,drh-1, in the intestine, can oppose the e2ffects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell non-autonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.

SIGNIFICANCE STATEMENT

Unlike activation, an understudied fundamental question across biological systems is how to deactivate a pathway, process, or enzyme after it has been turned on. The irony that the activation of a transcription factor that is meant to be protective can diminish health was first documented by us at the organismal level over a decade ago, but it has long been appreciated that chronic activation of the human ortholog of SKN-1, NRF2, could lead to chemo- and radiation resistance in cancer cells. A colloquial analogy to this biological idea is a sink faucet that has an on valve without a mechanism to shut the water off, which will cause the sink to overflow. Here, we define this off valve.
Implementing evidence ecosystems in the public health service: Development of a seven-step framework for designing tailored training programs
Authors: Arnold Laura , Bimczok Simon , Clemens Timo , Brand Helmut , Starke Dagmar
Published: October 2023

The COVID-19 pandemic has highlighted the importance of local evidence-ecosystems in which academia and practice in the Public Health Service (PHS) are interconnected. However, appropriate organizational structures and well-trained staff are lacking and evidence use in local public health decision-making has to be integrated into training programs in Germany. To address this issue, we developed a toolbox to conceptualize training programs designed to qualify public health professionals for working at the interface between academia and practice. We conducted a scoping review of training programs, key-informant interviews with public health experts, and a multi-professional stakeholder workshop and triangulated their output. The toolbox consists of four core elements, encompassing 15 parameters: (1) content-related aspects, (2) context-related aspects, (3) aspects relevant for determining the training format, and (4) aspects relevant for consolidation and further development. Guiding questions with examples supports the application of the toolbox. The developed seven-step frame-work aims to facilitate new training programs for knowledge-transfer at the academia-practice interface, equipping public health researchers and practitioners with relevant skills for needs-based PHS research. The joint development of training approaches can foster cross-institutional collaboration and enhance evidence utilization, resulting in long-term resource savings and a stronger evidence base for implementing complex public health measures on site. In this way, co-development of tailored solutions within the local evidence ecosystem has the potential to enhance both scientific and practical impact.
Assessment of brain-derived extracellular vesicle enrichment for blood biomarker analysis in age-related neurodegenerative diseases: An international overview
Authors: Badhwar AmanPreet , Hirschberg Yael , Tamayo Natalia Valle , Iulita M. Florencia , Udeh-Momoh Chinedu T. , Matton Anna , Tarawneh Rawan M. , Rissman Robert A. , Ledreux Aurélie , Winston Charisse N. , Haqqani Arsalan S. ,   Alzheimer’s Association International Society to Advance Alzheimer's Research and Treatment, BBB-EWG
Published: October 2023

INTRODUCTION

Brain-derived extracellular vesicles (BEVs) in blood allows for minimally- invasive investigations of CNS-specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV-enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS-specificity of proteins associated with these protocols.

METHODS

NDD articles investigating BEVs in blood using polymer-based and/or IP-based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV-enrichment and/or post-enrichment were assessed for CNS- and brain-cell-type- specificity; extracellular domains (ECD+); and presence in EV-databases.

RESULTS

82.1% of studies used polymer-based (ExoQuick) EV-enrichment, and 92.3% used L1CAM for IP-based BEV-enrichment. Centrifugation times differed across studies. 26.8% of 82 proteins systematically identified were CNS-specific: 50% ECD+, 77.3% were listed in EV- databases.

DISCUSSION

We identified protocol steps requiring standardization, and recommend additional CNS-specific proteins that can be used for BEV-enrichment or as BEV-biomarkers.
Next-Generation Breast Organoids Capture Human Organogenesis with High-Resolution Live Imaging
Authors: Rauner Gat , Traugh Nicole C. , Trepicchio Colin J. , Parrish Meadow E. , Mushayandebvu Kenan , Kuperwasser Charlotte
Published: October 2023

Organoids have emerged as a powerful tool for modeling tissue growth and diseases. In this study, we introduce a groundbreaking organotypic culture technique that replicates the morphology, scale, and heterogeneity of human breast tissue, and includes a mesenchymal-like stromal component. A standout feature of this approach is the use of long-term live imaging at high temporal resolution to directly observe stem cell dynamics during organogenesis, from single cells to mature organ tissue. The system is adaptable for high throughput applications and allows for genetic manipulation of the cells. Real-time imaging of ex-vivo tissue formation reveals a non-canonical process of ductal-lobular morphogenesis and branching, and de-novo generation of a supportive stroma. Incorporating patient-derived single cells from multiple donors offers an enhanced representation of the spectrum of individual responses and the impacts of distinct exposures. While developed for breast tissue, the principles of this technology can serve as a model for the development of similar systems in other tissues, where organoids do not merely reproduce the tissue, but where their regeneration can also be observed and studied. In addition, this model provides a quantitative experimental system to study mechanisms of embryogenesis, development, and tissue organization where biomechanics plays an important role.
Identification and structural characterization of small-molecule inhibitors of PINK1
Authors: Rasool Shafqat , Shomali Tara , Truong Luc , Croteau Nathalie , Veyron Simon , Trempe Jean-François
Published: October 2023

Mutations in PTEN-induced putative kinase 1 (PINK1) cause early-onset autosomal recessive Parkinson’s Disease (PD). PINK1 is a Ser/Thr protein kinase which functions as a mitochondrial damage sensor and initiates mitochondrial quality control by accumulating on the damaged organelle. There, it will autophosphorylate and then phosphorylate ubiquitin chains, which in turn will recruit and activate Parkin, and E3 ubiquitin ligase also implicated in PD. Ubiquitylation of mitochondrial proteins leads to the autophagic degradation of the damaged organelle. Pharmacological modulation of PINK1 constitutes an appealing avenue to study its physiological function and develop PD therapeutics. In this study, we used a thermal shift assay to identify small-molecule inhibitors of PINK1. In vitro kinase activity assays demonstrate that these molecules are ATP competitive inhibitors that block ubiquitin phosphorylation. PRT062607 (a SYK inhibitor) is the most potent inhibitor of PINK1 in our screen and has anIC50of 2 μM against insect PINK1 and 1 μM in HeLa cells expressing human PINK1. The crystal structures of PINK1 in complex with PRT062607 or CYC116 reveal how the compounds interact with the ATP-binding pocket. PRT062607 notably engages with the catalytic aspartate (type-1 inhibition) and causes a destabilization of insert-2 at the autophosphorylation dimer interface. Our findings provide a scaffold for the development of more selective and potent inhibitors of PINK1 that can be used as chemical probes.
Multiomics Analysis Revealed Anti-freezing Mechanism ofStaphylococcus aureusin Its Anti-freezing Strain
Authors: Youzhi Wu , Linjun Sun , Chunlei Shi , Xia Jiao Ling , Fuzhou Ye
Published: October 2023

Frozen food is currently a common food type. However, the presence ofStaphylococcus aureuscontamination caused serious challenge to frozen food safety. In this study, we explored the differences between sensitive strains and anti-freeze strains through multiomics analysis such as proteomics, phosphorylated proteomics, and metabolomics studies to understand the anti-freezing mechanism ofS. aureus. This study compared the proteomics, phosphorylated proteomics and metabolomic differences between anti-freeze strains and sensitive strains before and after freezing. Before and after freezing, the differential protein-enriched channels changed from fructose-6-phosphate pathway, arachidonic acid metabolism pathway, atrazine degradation pathway to atrazine degradation pathway, starch and sucrose metabolism pathway, cysteine and methionine metabolism pathway, nitrogen metabolism pathway. In addition, this study inferred thatpgigene,ureA (urease subunit γ),ureB (urease subunit α),ureC (urease subunit β) gene,mtlD gene,fruB gene andasdgene could be crucial genes for the anti-freezing mechanism ofS. aureus, which needs further investigation. Furthermore, the experimental results showed that PfkA, DeoC and Fda proteins fromS. aureuswere the key proteins for anti-freezing. They correspondingly involved in carbon fixation, fructose and mannose metabolism, and glycolysis/gluconeogenesis pathways in photosynthetic organisms. Finally, important metabolic pathways involved in the anti-freezing mechanism, mainly ABC transport pathway, amino acid metabolism pathway and secondary metabolite anabolic pathway.
Cochlear tuning characteristics arise from temporal prediction of natural sounds
Authors: Trinh Freddy , King Andrew J , Willmore Ben D B , Harper Nicol
Published: October 2023

The cochlea decomposes incoming sound waveforms into different frequency components along the length of its basilar membrane. The receptor hair cells at the apical end of this resonant membrane are tuned to the lowest sound frequencies, with the preferred sound frequency of hair cell tuning increasing near-exponentially along the length of the membrane towards its basal end. This frequency composition of the sound is then transmitted to the brain by the auditory nerve fibers that innervate the inner hair cells. Hair cells respond to a sound impulse with a temporally asymmetric envelope and the sharpness of their tuning changes as the frequency to which they are most sensitive varies with their position along the basilar membrane. We ask if there is a normative explanation for why the cochlea decomposes sounds in this manner. Inspired by findings in the retina, we propose that cochlear tuning properties may be optimized for temporal prediction. This principle states that the sensory features represented by neurons are optimized to predict immediate future input from recent past input. We show that an artificial neural network optimized for temporal prediction of the immediate future of raw waveforms of natural sounds from their recent past produces tuning properties that resemble those observed in the auditory nerve. Specifically, the model captures the temporally asymmetric impulse responses, the tonotopic distribution and variation in tuning sharpness along the cochlea, and the frequency glide polarity of the impulse responses. These characteristics are not captured by a similar model optimized for compression of the sound waveform, rather than prediction. Given its success in accounting for the tuning properties at various processing levels in the auditory and visual systems, this finding for the cochlea provides further evidence that temporal prediction may be a general principle of sensory processing.
Inversions and integrations using CRISPR/Cas9 and a module-based plasmid construction kit for fission yeast
Authors: Berenguer Millanes Cristina , Nieuwenhuis Bart P.S.
Published: October 2023

Structural variants (SV) are genetic alterations that involve large-scale changes in the structure of a genome. These variations can encompass deletions, duplications, inversions, translocations, or complex rearrangements. While smaller structural variants are relatively well studied, much is unknown about the prevalence and effect of larger SV. Genome sequencing methods that are able to find large reorganization in the genome, e.g. using mate pair or long-reads, have shown inversions and translocations are more common than was previously expected. Reduced recombination between regions with different structural organizations leads to the rise of variant specific alleles. Studying the effect of the SV in isolation is obscured by their independent evolutionary histories. Tools are needed to introduce SVs without introducing correlated alleles. Here we describe a method to introduce specific inversions and rearrangements in the fission yeastSchizosacchromyces pombeusing the modified CRISPR/Cas9 system SpEDIT to introduce multiple breakpoints with a single plasmid. Sequences for homologous recombination that guide repair resulting in the desired SVs are generated using an extended method for Golden Gate DNA shuffling forS. pombe. Our extension of the system from Kakui et al. is more efficient for integration, introduces more flexibility, and extends the system beyond single construct integrations. Additionally, we extend the set of promoters, tags, markers and terminators, specifically using DNA sequences from other fission yeast species, which avoid introduction of homologous sequences, thereby reducing the chance of non-allelic homologous recombination during sexual reproduction.
Old foe, new host: epidemiology, genetic diversity and pathogenic characterization of maize streak virus in rice fields from Burkina Faso
Authors: Fouad Noun Magdy Ibrahim , Barro Mariam , Bangratz Martine , Sérémé Drissa , Filloux Denis , Fernandez Emmanuel , Julian Charlotte , Saïbou Nignan , Kassankogno Abalo Itolou , Guigma Abdoul Kader , Roumagnac Philippe , Wonni Issa , Tollenaere Charlotte , Poulicard Nils
Published: October 2023

Rice is of critical significance regarding food security worldwide including in Africa. Only two viruses impacting rice production in Africa have been deeply investigated for decades: the rice yellow mottle virus (Solemoviridae) and the rice stripe necrosis virus (Benyviridae). Using viral metagenomics, we aimed at exploring the diversity of viruses circulating in Burkina Faso rice fields. We performed an epidemiological survey in this country between 2016 and 2019 involving 57 small farmer’s rice fields under two production systems (rainfed lowlands and irrigated areas). More than 2700 rice samples were collected withouta priori(not based on symptom observation) following a regular scheme. In addition, wild and cultivated (maize and sugarcane)Poaceaegrowing nearby rice fields were also collected. Unexpectedly, metagenomics detected maize streak virus (MSV,Geminiviridae) in analyzed rice samples. Further molecular analyses using RCA-PCR showed that MSV is widely distributed and highly prevalent in both rainfed lowlands and irrigated rice areas. MSV-A and MSV-G strains were identified. MSV-G, exclusively identified so far in wild grasses, was the most prevalent strain while MSV-A, known to cause severe symptoms in maize, was sporadically identified. No genetic differentiation was detected between MSV isolates either infecting wild or cultivated plant species. Using infectious clones in experimental conditions, we confirmed the pathogenicity of both MSV strains on rice. Thus, in addition to contribute to the epidemiological surveillance of rice production in Africa, our results illuminate new epidemiological and pathogenic aspects of one of the most studied plant viruses with significant economic consequences in Africa.

Funding

French National Research Agency «Investissements d’avenir» program (ANR-10-LABX-001-01), Agropolis Fondation (ANR-16-IDEX-006), French National Research Agency “young researchers” program (ANR-20-CE35-0008-01), CGIAR Research Program on Rice Agri-food Systems (RICE), Cooperation and cultural action department of the French Embassy (SCAC) in Burkina Faso.
Allosteric activation of VCP, a AAA unfoldase, by small molecule mimicry
Authors: Jones N.H. , Liu Q. , Urnavicius L. , Dahan N.E. , Vostal L.E. , Kapoor T.M.
Published: October 2023

The loss of function of AAA (ATPases associated with diverse cellular activities) mechanoenzymes has been linked to diseases, and small molecules that activate these proteins can be powerful tools to probe mechanisms and test therapeutic hypotheses. Unlike chemical inhibitors that can bind a single conformational state to block enzyme activity, activator binding must be permissive to different conformational states needed for enzyme function. However, we do not know how AAA proteins can be activated by small molecules. Here, we focus on valosin-containing protein (VCP)/p97, a AAA unfoldase whose loss of function has been linked to protein aggregation-based disorders, to identify druggable sites for chemical activators. We identified VCP Activator 1 (VA1), a compound that dose-dependently stimulates VCP ATPase activity up to ∼3-fold. Our cryo-EM studies resulted in structures (∼2.9-3.5 Å-resolution) of VCP in apo and ADP-bound states, and revealed VA1 binding an allosteric pocket near the C-terminus in both states. Engineered mutations in the VA1 binding site confer resistance to VA1, and furthermore, modulate VCP activity to a similar level as VA1-mediated activation. The VA1 binding site can alternatively be occupied by a phenylalanine residue in the VCP C-terminal tail, a motif that is post-translationally modified and interacts with cofactors. Together, our findings uncover a druggable allosteric site and a mechanism of enzyme regulation that can be tuned through small molecule mimicry.

Significance

The loss of function of valosin-containing protein (VCP/p97), a mechanoenzyme from the AAA superfamily that hydrolyzes ATP and uses the released energy to extract or unfold substrate proteins, is linked to protein aggregation-based disorders. However, druggable allosteric sites to activate VCP, or any AAA mechanoenzyme, have not been identified. Here, we report cryo-EM structures of VCP in two states in complex with VA1, a compound we identified that dose-dependently stimulates VCP’s ATP hydrolysis activity. The VA1 binding site can also be occupied by a phenylalanine residue in the VCP C-terminal tail, suggesting that VA1 acts through mimicry of this interaction. Our study reveals a druggable allosteric site and a mechanism of enzyme regulation.
Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses
Authors: Ma Cheng-Bao , Liu Chen , Park Young-Jun , Tang Jingjing , Chen Jing , Xiong Qing , Lee Jimin , Stewart Cameron , Asarnow Daniel , Brown Jack , Tortorici M. Alejandra , Yang Xiao , Sun Ye-Hui , Chen Yuan-Mei , Yu Xiao , Si Jun-Yu , Liu Peng , Tong Fei , Huang Mei-Ling , Li Jing , Shi Zheng-Li , Deng Zengqin , Veesler David , Yan Huan
Published: October 2023

The angiotensin-converting enzyme 2 (ACE2) receptor is shared by various coronaviruses with distinct receptor-binding domain (RBD) architectures, yet our understanding of these convergent acquisition events remains elusive. Here, we report that two European bat MERS-related coronaviruses (MERSr-CoVs) infectingPipistrellus nathusii(P.nat), MOW15-22 and PnNL2018B, use ACE2 as their receptor, with narrow ortholog specificity. Cryo-electron microscopy structures of the MOW15-22 RBD-ACE2 complex unveil an unexpected and entirely distinct binding mode, mapping 50Å away from that of any other known ACE2-using coronaviruses. Functional profiling of ACE2 orthologs from 105 mammalian species led to the identification of host tropism determinants, including an ACE2 N432-glycosylation restricting viral recognition, and the design of a soluble P.nat ACE2 mutant with potent viral neutralizing activity. Our findings reveal convergent acquisition of ACE2 usage for merbecoviruses found in European bats, underscoring the extraordinary diversity of ACE2 recognition modes among coronaviruses and the promiscuity of this receptor.

Graphic abstract