bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Brain Aging is Associated with Dysregulation of Cell-Type Epigenetic Identity
Authors: Jeong Hyeonsoo , Mendizabal Isabel , Yi Soojin V.
Published: June 2024

Significant links between aging and DNA methylation are emerging from recent studies. On the one hand, DNA methylation undergoes changes with age, a process termed as epigenetic drift. On the other hand, DNA methylation serves as a readily accessible and accurate biomarker for aging. A key missing piece of information, however, is the molecular mechanisms underlying these processes, and how they are related, if any. Addressing the limitations of previous research due to the limited number of investigated CpGs and the heterogeneous nature of tissue samples, here we have examined DNA methylation of over 20 million CpGs across a broad age span in neurons and non-neuronal cells, primarily oligodendrocytes. We show that aging is a primary predictor of DNA methylation variation, surpassing the influence of factors such as sex and schizophrenia diagnosis, among others. On the genome-wide scale, epigenetic drift manifests as significant yet subtle trends that are influenced by the methylation level of individual CpGs. We reveal that CpGs that are highly differentiated between cell types are especially prone to age-associated DNA methylation alterations, leading to the divergence of epigenetic cell type identities as individuals age. On the other hand, CpGs that are included in commonly used epigenetic clocks tend to be those sites that are not highly cell type differentiated. Therefore, dysregulation of epigenetic cell-type identities and current DNA epigenetic clocks represent distinct features of age-associated DNA methylation alterations.
Comprehensive profiling of genomic invertons in defined gut microbial community reveals associations with intestinal colonization and surface adhesion
Authors: Jin Xiaofan , Cheng Alice G. , Chanin Rachael , Yu Feiqiao B. , Dimas Alejandra , Jasper Marissa , Weakley Allison , Yan Jia , Bhatt Ami S. , Pollard Katherine S.
Published: June 2024

Bacteria use invertible genetic elements known as invertons to generate heterogeneity amongst a population and adapt to new and changing environments. In human gut bacteria, invertons are often found near genes associated with cell surface modifications, suggesting key roles in modulating dynamic processes such as surface adhesion and intestinal colonization. However, comprehensive testing of this hypothesis across complex bacterial communities like the human gut microbiome remains challenging. Metagenomic sequencing holds promising for detecting inversions without isolation and culturing, but ambiguity in read alignment limits the accuracy of the result-ing inverton predictions. Here, we developed a customized bioinformatic workflow – PhaseFinderDC – to identify and track invertons in metagenomic data. Applying this method to a defined yet complex gut community (hCom2) across different growth environments over time using bothin vitroandin vivometagenomic samples, we detected invertons in most hCom2 strains. These include invertons whose orientation probabilities change over time and are statistically associated with environmental conditions. We used motif enrichment to identify putative inverton promoters and predict genes regulated by inverton flipping during intestinal colonization and surface adhesion. Analysis of inverton-proximal genes also revealed candidate invertases that may regulate flipping of specific invertons. Collectively, these findings suggest that surface adhesion and intestinal colonization in complex gut communities directly modulate inverton dynamics, offering new insights into the genetic mechanisms underlying these processes.
Discovery of Potent Degraders of the Dengue Virus Envelope Protein
Authors: Li Zhengnian , Liu Han-Yuan , He Zhixiang , Chakravarty Antara , Golden Ryan P. , Jiang Zixuan , You Inchul , Yue Hong , Donovan Katherine A. , Du Guangyan , Che Jianwei , Tse Jason , Che Isaac , Lu Wenchao , Fischer Eric S. , Zhang Tinghu , Gray Nathanael S. , Yang Priscilla L.
Published: June 2024

Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here we report the development of small molecule degraders of the envelope (E) protein of dengue virus. We developed two classes of bivalent E-degraders, linking two previously reported E-binding small molecules, GNF-2 and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBNligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E degrader with ABL inhibition while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof-of-concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class antiviral drugs.
Assessing the efficiency and heritability of blocked tree breeding trials
Authors: Piepho Hans-Peter , Williams Emlyn , Prus Maryna
Published: June 2024

Progeny trials in tree breeding are often laid out using blocked experimental designs, in which families are randomly assigned to plots and several trees are planted per plot. Such designs are optimized for the assessment of family effects. However, tree breeders are primarily interested in assessing breeding values of individual trees. This paper considers the assessment of heritability at both the family and tree levels. We assess heritability based on pairwise comparisons among individual trees. The approach shows that there is considerable heterogeneity in pairwise heritabilities, primarily due to the differences in both genetic as well as error variances among within- and between-family comparisons. Our results further show that efficient blocking positively affects all types of comparison except those among trees within the same plot.
Estimating the historical impact of outbreak response immunization programs across 210 outbreaks in LMICs
Authors: Delport D. , Muellenmeister A.M. , MacKechnie G. , Vaccher S. , Mengistu T. , Hogan D. , Abeysuriya R.G. , Scott N.
Published: June 2024

Background

Outbreaks of vaccine-preventable diseases continue to occur in low- and middle-income countries (LMICs), requiring outbreak response immunization (ORI) programs for containment. To inform future investment decisions, this study aimed to estimate the cases, deaths, disability-adjusted life years (DALYs), and societal economic costs averted by past ORI programs. Outbreaks of measles, Ebola, yellow fever, cholera, and meningococcal meningitis in LMICs between 2000-2023 were considered.

Methods

210 outbreaks (51 measles, 40 cholera, 88 yellow fever, 24 meningitis, 7 Ebola) were identified with sufficient data for analysis. Agent-based models were calibrated for each disease such that after controlling for baseline vaccine coverage, ORI initiation time, speed of vaccine delivery, environmental variables, or endemic prevalence of the disease, observed outbreaks were within the distribution of simulated outbreaks. A status-quo and no ORI scenario were compared for each outbreak.

Findings

Across 210 outbreaks, ORI programs are estimated to have averted 5·81M [95% uncertainty interval 5·75M–5·87M] cases (4·01M measles, 283K cholera, 1·50M yellow fever, 21·3K meningitis, 820 Ebola), 327K [317K–338K] deaths (20.0K measles, 5215 cholera, 300K yellow fever, 1599 meningitis, 381 Ebola), 14·6M [14·1M–15·1M] DALYs (1·27M measles, 220K cholera, 13·0M yellow fever, 113K meningitis, 16·6K Ebola), and US$31·7B [29·0B–34·9B] (US$710M measles, US$156M cholera, US$30·7B yellow fever, US$97·6M meningitis, US$6·72M Ebola) in societal economic costs. In general, the more rapidly the ORI was initiated the greater the impact.

Interpretation

ORI programs are critical for reducing the health and economic impacts of outbreaks of vaccine-preventable diseases.

Funding

Gavi,the Vaccine Alliance.
Ethnoracial Disparities in Breast Cancer Treatment Time and Survival: A Systematic Review With a DAG-based Causal Model
Authors: Hesari Parisa M. , James Drexler , Lizotte Daniel J. , Bauer Greta R.
Published: June 2024

For interventions aimed at redressing health disparities in breast cancer to be effective, a clear understanding of the nature and causes of these disparities is required. Our question is: what is the current evidence for ethnoracial disparities in time-to-treatment initiation and survival in breast cancer, and how are the causal mechanisms of these disparities conceptualized in the literature? A comprehensive systematic search of studies on cohorts of female breast cancer patients diagnosed with stage I-III was performed. Directed acyclic graphs were used to describe implicit causal relationships between ethnoracial group membership and time-to-treatment initiation and survival outcomes. This review revealed strong evidence for ethnoracial disparities in both time to treatment and survival among breast cancer patients. Unmeasured factors identified by the authors highlighted gaps in data sources and opportunities for causal reasoning. While the existing literature describes ethnoracial disparities, there is very limited discussion of causal mechanisms, and no discussion of system-level rather than individual-level effects. In response, a biosocioecological model of breast cancer disparity was developed to integrate system-level considerations into future research. Addressing established ethnoracial disparities in breast cancer requires new research that explicitly considers the causal mechanisms of potential interventions, incorporating unmeasured factors contributing to these disparities.
Vaccine beliefs, adverse effects, and quality of life in patients with cancer undergoing routine COVID-19 vaccination
Authors: Body Amy , Donoghoe Mark , Lal Luxi , Wakefield Claire , Ahern Elizabeth Stephanie , Anazodo Antoinette , Fuentes Bolanos Noemi Auxiliadora , Padhye Bhavna , Downie Peter , Opat Stephen , Hamad Nada , Leahy Michael Francis , Milch Vivienne , Segelov Eva
Published: June 2024

Background

Concerns about side effects and treatment interactions and delays may contribute to COVID-19 vaccine hesitancy amongst cancer patients. In the large prospective SerOzNET study of COVID-19 vaccine response in children and adults with cancer, vaccine beliefs, physician- and participant-reported adverse events (AE), treatment interruptions and quality of life (QoL) were studied.

Methods

The Australian experience with COVID-19 gave a unique opportunity to study vaccination response in an infection- and vaccine-naïve cancer population. Patients with current or recent solid or hematological malignancy, aged five and over, had serial assessments prior to and following multiple SARS-CoV-2 vaccinations. Electronic surveys were administered at baseline and after first, second and third doses to collect vaccine beliefs (Oxford Confidence and Complacency Scale), patient-reported toxicity and QoL (QLQC30 or PedsQL). Detailed toxicity data were collected at clinic visits and from medical records.

Results

A total of 1385 vaccination doses were administered (93% BNT162b2), with at least 1 dose received by 499 patients, of whom only seven had known prior COVID-19 infection. Vaccine related beliefs were generally positive. There were no vaccine-related interruptions to cancer therapy. AE occurred in 95% of recipients, with the highest ranked severity being mild in 36% and moderate, severe or serious in 31%, 19% and 6% respectively. QoL showed no significant deterioration post-vaccination.

Conclusion

This robust dataset provides evidence regarding safety and tolerance of SARS-CoV-2 vaccination in adults and children with cancer. Patients and families can be reassured that rates of AEs are comparable to the general population and do not impact delivery of cancer therapy or QoL.
A myelinic channel system for motor-driven organelle transport
Authors: Chapple Katie J. , Green Tabitha R.F. , Wirth Sarah , Chen Yi-Hsin , Gerwig Ulrike , Aicher Marie Louise , Kim Yeonsu , Komarek Lina , Brown Angus , Crawford Colin L. , Smith Rebecca Sherrard , Lee Jeff , Pardo-Fernandez Luis , McHugh Rebecca E , Kassmann Celia M. , Werner Hauke B. , Davis Ilan , Kneussel Matthias , Brown Euan R , Goebbels Sandra , Nave Klaus-Armin , Edgar Julia M.
Published: June 2024

Myelin sheaths comprise compacted layers of oligodendroglial membrane wrapped spirally around axons. Each sheath, if imagined unwrapped, has a cytoplasm-filled space at its perimeter, linking it to the oligodendrocyte soma via a short process. By electron microscopy (EM), this space, which we term the ‘myelinic channel system’ contains microtubules and membranous organelles, but whether these are remnants of development or serve a function is unknown. Performing live imaging of myelinating oligodendrocytes expressing fluorescent reporters, we found that the myelinic channel system serves microtubule-dependent organelle transport. Further, the intra-myelinic movement of peroxisomes was modulated by neuronal electrical activity in these mixed neural cell cultures. Loss of oligodendroglial Kif21b or CNPin vivoled to apparent stasis of myelin organelles and secondary axon pathology. This suggests that oligodendrocytes require motor transport in myelin to maintain axonal integrity.
AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation
Authors: Biddinger Jessica E. , Elson Amanda E.T. , Fathi Payam A. , Sweet Serena R. , Nishimori Katsuhiko , Ayala Julio E. , Simerly Richard B.
Published: June 2024

During postnatal life, the adipocyte-derived hormone leptin is required for proper targeting of neural inputs to the paraventricular nucleus of the hypothalamus (PVH) and impacts the activity of neurons containing agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms are known to play a defining role during postnatal organization of neural circuits, but whether leptin-mediated postnatal neuronal activity specifies neural projections to the PVH or impacts downstream connectivity is largely unexplored. Here, we blocked neuronal activity of AgRP neurons during a discrete postnatal period and evaluated development of AgRP inputs to defined regions in the PVH, as well as descending projections from PVH oxytocin neurons to the dorsal vagal complex (DVC) and assessed their dependence on leptin or postnatal AgRP neuronal activity. In leptin-deficient mice, AgRP inputs to PVH neurons were significantly reduced, as well as oxytocin-specific neuronal targeting by AgRP. Moreover, downstream oxytocin projections from the PVH to the DVC were also impaired, despite the lack of leptin receptors found on PVH oxytocin neurons. Blocking AgRP neuron activity specifically during early postnatal life reduced the density of AgRP inputs to the PVH, as well as the density of projections from PVH oxytocin neurons to the DVC, and these innervation deficits were associated with dysregulated autonomic function. These findings suggest that postnatal targeting of descending PVH oxytocin projections to the DVC requires leptin-mediated AgRP neuronal activity, and represents a novel activity-dependent mechanism for hypothalamic specification of metabolic circuitry, with consequences for autonomic regulation.

Significance statement

Hypothalamic neural circuits maintain homeostasis by coordinating endocrine signals with autonomic responses and behavioral outputs to ensure that physiological responses remain in tune with environmental demands. The paraventricular nucleus of the hypothalamus (PVH) plays a central role in metabolic regulation, and the architecture of its neural inputs and axonal projections is a defining feature of how it receives and conveys neuroendocrine information. In adults, leptin regulates multiple aspects of metabolic physiology, but it also functions during development to direct formation of circuits controlling homeostatic functions. Here we demonstrate that leptin acts to specify the input-output architecture of PVH circuits through an activity-dependent, transsynaptic mechanism, which represents a novel means of sculpting neuroendocrine circuitry, with lasting effects on how the brain controls energy balance.
Prophages are Infrequently Associated With Antibiotic Resistance inPseudomonas aeruginosaClinical Isolates
Authors: Chang Tony H. , Pourtois Julie D. , Haddock Naomi L. , Furkuawa Daisuke , Kelly Kate E. , Amanatullah Derek F. , Burgener Elizabeth , Milla Carlos , Banaei Niaz , Bollyky Paul L.
Published: June 2024

Lysogenic bacteriophages can integrate their genome into the bacterial chromosome in the form of a prophage and can promote genetic transfer between bacterial strainsin vitro. However, the contribution of lysogenic phages to the incidence of antimicrobial resistance (AMR) in clinical settings is poorly understood. Here, in a set of 186 clinical isolates ofPseudomonas aeruginosacollected from respiratory cultures from 82 patients with cystic fibrosis (CF), we evaluate the links between prophage counts and both genomic and phenotypic resistance to six anti-pseudomonal antibiotics: tobramycin, colistin, ciprofloxacin, meropenem, aztreonam, and piperacillin-tazobactam. We identified 239 different prophages in total. We find thatP. aeruginosaisolates contain on average 3.06 +/- 1.84 (SD) predicted prophages. We find no significant association between the number of prophages per isolate and the minimum inhibitory concentration (MIC) for any of these antibiotics. We then investigate the relationship between particular prophages and AMR. We identify a single lysogenic phage associated with phenotypic resistance to the antibiotic tobramycin and, consistent with this association, we observe that AMR genes associated with resistance to tobramycin are more likely to be found when this prophage is present. However we find that they are not encoded directly on prophage sequences. Additionally, we identify a single prophage statistically associated with ciprofloxacin resistance but do not identify any genes associated with ciprofloxacin phenotypic resistance. These findings suggest that prophages are only infrequently associated with the AMR genes in clinical isolates ofP. aeruginosa.

Importance

Antibiotic-resistant infections ofPseudomonas aeruginosa, a leading pathogen in patients with Cystic Fibrosis (CF) are a global health threat. While lysogenic bacteriophages are known to facilitate horizontal gene transfer, their role in promoting antibiotic resistance in clinical settings remains poorly understood. In our analysis of 186 clinical isolates ofP. aeruginosafrom CF patients, we find that prophage abundance does not predict phenotypic resistance to key antibiotics but that specific prophages are infrequently associated with tobramycin resistance genes. In addition, we do not find antimicrobial resistance (AMR) genes encoded directly on prophages. These results highlight that while phages can be associated with AMR, phage-mediated AMR transfer may be rare in clinical isolates and difficult to identify. This work is important for future efforts on mitigating AMR in Cystic Fibrosis and other vulnerable populations affected byPseudomonas aeruginosainfections and advances our understanding of bacterial-phage dynamics in clinical infections.
Inhibition of the HSP90 homodimerization and HSP90-HIF1α interactions by employing small molecules at C-terminal ATP binding site of HSP90
Authors: Poyya Jagadeesha , Joshi Chandrashekhar G
Published: June 2024

The Heat shock protein HSP 90-alpha (HSP90AA1) is a major chaperone that stabilizes the hypoxia-inducible factor 1α under hypoxic stress and develops solid tumors. Recent studies revealed that in addition to N-terminal ATP binding site, HSP90 has an additional ATP binding site at the C-terminal end. So, disruption of HSP90 and HIF 1 α interaction is an innovative method to control cancer progression. This can be achieved by employing small molecules at C-terminal ATP-binding that do not affect the overall functioning of the HSP90. But there is a lack of structural basis for HIF-1α and HSP90AA1 interactions. This study screened natural products and their derivatives against HSP90AA1 and HIF-1α interaction disruption. Virtual screening was carried out using Glide. We found that compounds with indole rings bind to the C-terminal ATP binding site of HSP90 and prevent its interaction with HIF-1α. Tryptamine derivatives with indole rings showed a greater binding affinity than other molecules. Thus, Tryptamine hydrochloride compounds can be used as a drug repurposing approach to treat hypoxic tumors.

Abstract Figure
Ecological fNIRS in mobile children: Using short separation channels to correct for systemic contamination during naturalistic neuroimaging
Authors: Pinti P. , Dina L.M , Smith T
Published: June 2024

Abstract

Significance

The advances and the miniaturization in functional Near Infrared Spectroscopy (fNIRS) instrumentation offers the potential to move the classical laboratory-based cognitive neuroscience investigations into more naturalistic settings. Wearable and mobile fNIRS devices also provide a novel child-friendly means to image functional brain activity in freely moving toddlers and preschoolers. Measuring brain activity in more ecologically valid settings with fNIRS presents additional challenges, such as the increased impact of physiological interferences. One of the most popular methods to minimize such interferences is to regress out short separation channels from the long separation channels (i.e., superficial signal regression or SSR). Whilst this has been extensively investigated in adults, little is known about the impact of systemic changes on the fNIRS signals recorded in children in either classical or novel naturalistic experiments.

Aim

We aim to investigate if extracerebral physiological changes occur in toddlers and preschoolers, and whether SSR can help minimize these interferences.

Approach

We collected fNIRS data from 3-to-7 years olds during a conventional computerized static task and in a dynamic naturalistic task in an immersive virtual reality (VR) continuous automatic virtual environment (CAVE).

Results

Our results show that superficial signal contamination data is present in both young children as in adults. Importantly, we find that SSR helps in improving the localization of functional brain activity, both in the computerized task and, to a larger extent, in the dynamic VR task.

Conclusions

Following from these results, we formulate suggestions to advance the field of developmental neuroimaging with fNIRS, particularly in ecological settings.
Diverse intrinsic properties shape transcript stability and stabilization inMycolicibacterium smegmatis
Authors: Sun Huaming , Vargas-Blanco Diego A. , Zhou Ying , Masiello Catherine S. , Kelly Jessica M. , Moy Justin K. , Korkin Dmitry , Shell Scarlet S.
Published: June 2024

In mycobacteria, regulation of transcript degradation is known to occur in response to environmental stress and to facilitate adaptation. However, the mechanisms underlying this regulation are unknown. Here we sought to gain an understanding of the mechanisms controlling mRNA stability by investigating the transcript properties associated with variance in transcript stability and stress-induced transcript stabilization. We performed transcriptome-wide mRNA degradation profiling ofMycolicibacterium smegmatisin both log phase growth and hypoxia-induced growth arrest. The transcriptome was globally stabilized in response to hypoxia, with all transcripts having longer half-lives, but some having greater degrees of stabilization than others. The transcripts of essential genes were generally stabilized more than those of non-essential genes. We then developed machine learning models that utilized a compendium of transcript properties and enabled us to identify the non-linear collective effect of diverse properties on transcript stability and stabilization. The comparisons of these properties confirmed the association of 5’ UTRs with transcript stability, along with other differences between leadered and leaderless transcripts. Our analysis highlighted the protective effect of translation in log phase but not in hypoxia-induced growth arrest. Steady-state transcript abundance had a weak negative association with transcript half-life that was stronger in hypoxia, while coding sequence length showed an unexpected correlation with half-life in hypoxia only. In summary, we found that transcript properties are differentially associated with transcript stability depending on both the transcript type and the growth condition. Our results reveal the complex interplay between transcript features and microenvironment that shapes transcript stability in mycobacteria.
Diptera-specific Daedalus controls Zucchini endonucleolysis in piRNA biogenesis independent of exonucleases
Authors: Koga Yuica , Hirakata Shigeki , Negishi Mayu , Yamazaki Hiroya , Siomi Mikiko C.
Published: June 2024

piRNAs protect germline genomes and maintain fertility by repressing transposons. Daedalus and Gasz act together as a mitochondrial scaffold for Armitage, a necessary factor for Zucchini-dependent piRNA processing. However, the mechanism underlying this function remains unclear. Here, we find that the roles of Daedalus and Gasz in this process are distinct, although both are necessary: Daedalus physically interacts with Armitage, whereas Gasz supports Daedalus to maintain its function. Daedalus binds to Armitage through two distinct regions, an extended coiled-coil identified in this study, and a SAM. The former tethers Armitage to mitochondria, while the latter controls Zucchini endonucleolysis to define the length of piRNAs in an exonuclease-independent manner. piRNAs produced in the absence of Daedalus SAM do not exhibit full transposon silencing functionality. Daedalus is Diptera specific. UnlikeDrosophilaand mosquitoes, evolutionarily more complex species, such as mice, rely on exonucleases after Zucchini processing to specify the length of piRNAs.
A chromosome-level reference-quality genome ofPunica granatumL
Authors: Yan Ming
Published: June 2024

Pomegranate (Punica granatumL.) is one of the most ancient edible fruit tree species. Here we reported a new chromosome-level genome assembly and annotation of sour pomegranate. We assembled the genome with a size of 331.47 Mb and used BUSCO to estimate the completeness of the assembly as 98.8%. More than 97.40% of sequences in the final assembly were anchored to 8 pseudochromosomes, higher than the corresponding percentages for the existing reference genomes ‘Tunisia’ (92.62%). Using a combination of de novo prediction, protein homology and RNA-seq annotation, 29,326 protein-coding genes were predicted. We re-annotated the protein-coding genes of five other published pomegranate genomes using the same annotation method. We constructed the pan-genome of pomegranate using protein-coding genes, integrating data from our newly assembled genome and five other published genomes. The pan-genome was composed of 28,314 gene families, of which 68.96% were core genes, 30.00% were dispensable genes, and 1.04% were private genes. The chromosome-level reference genome of sour pomegranate would be valuable resource for research and molecular breeding of pomegranate.
Ultrasonic cerebrospinal fluid clearance improves outcomes in hemorrhagic brain injury models
Authors: Azadian Matine M. , Macedo Nicholas , Yu Brenda J. , Fame Ryann M. , Airan Raag D.
Published: June 2024

Introduction (Abstract)

Impaired clearance of the byproducts of aging and neurologic disease from the brain exacerbates disease progression and severity. We have developed a noninvasive, low intensity transcranial focused ultrasound protocol that facilitates the removal of pathogenic substances from the cerebrospinal fluid (CSF) and the brain interstitium. This protocol clears neurofilament light chain (NfL) – an aging byproduct – in aged mice and clears red blood cells (RBCs) from the central nervous system in two mouse models of hemorrhagic brain injury. Cleared RBCs accumulate in the cervical lymph nodes from both the CSF and interstitial compartments, indicating clearance through meningeal lymphatics. Treating these hemorrhagic brain injury models with this ultrasound protocol reduced neuroinflammatory and neurocytotoxic profiles, improved behavioral outcomes, decreased morbidity and, importantly, increased survival. RBC clearance efficacy was blocked by mechanosensitive channel antagonism and was effective when applied in anesthetized subjects, indicating a mechanosensitive channel mediated mechanism that does not depend on sensory stimulation or a specific neural activity pattern. Notably, this protocol qualifies for an FDA non-significant risk designation given its low intensity, making it readily clinically translatable. Overall, our results demonstrate that this low-intensity transcranial focused ultrasound protocol clears hemorrhage and other harmful substances from the brain via the meningeal lymphatic system, potentially offering a novel therapeutic tool for varied neurologic disorders.
BaseNet: A Transformer-Based Toolkit for Nanopore Sequencing Signal Decoding
Authors: Li Qingwen , Sun Chen , Wang Daqian , Lou Jizhong
Published: June 2024

Nanopore sequencing provides a rapid, convenient and high-throughput solution for nucleic acid sequencing. Accurate basecalling in nanopore sequencing is crucial for downstream analysis. Traditional approaches such as Hidden Markov Models (HMM), Recurrent Neural Networks (RNN), and Convolutional Neural Networks (CNN) have improved basecalling accuracy but there is a continuous need for higher accuracy and reliability. In this study, we introduce BaseNet, an open-source toolkit that utilizes transformer models for advanced signal decoding in nanopore sequencing. BaseNet incorporates both autoregressive and non-autoregressive transformer-based decoding mechanisms, offering state-of-the-art algorithms freely accessible for future improvement. Our research indicates that cross-attention weights effectively map the relationship between current signals and base sequences, joint loss training through adding a pair of forward and reverse decoder facilitate model converge, and large-scale pre-trained models achieve superior decoding accuracy. This study helps to advance the field of nanopore sequencing signal decoding, contributes to technological advancements, and provides novel concepts and tools for researchers and practitioners.
Unveiling the guardians: IL-26-expressing MAIT cells protect epithelial barrier function and are dysregulated in Crohn’s disease
Authors: Bosáková Veronika , Ke Bo-Jun , Kohoutková Marcela Hortová , Papatheodorou Ioanna , Kafka Filip , Zuani Marco De , Santhosh Sneha , Biscu Francesca , Abdurahiman Saeed , Greef Ine De , Verstockt Sare , Verstockt Bram , Vermeire Séverine , Argüello Rafael J , Matteoli Gianluca , Frič Jan
Published: June 2024

BACKGROUND & AIMS

Inflammatory bowel disease (IBD) is characterized by a dysregulated immune response against the host’s microbiome. Mucosal-associated invariant T (MAIT) cells recognize microbiota-derived riboflavin metabolites and play a crucial role in mucosal homeostasis. However, their specific role in IBD remains enigmatic. MAIT cells express IL-26, a novel IL-10 family cytokine with a controversial role in IBD. We investigated the functions of MAIT cells and IL-26 in IBD using a unique combination of state-of-the-art 3D human intestinal tissue models and clinical samples.

METHODS

We analyzed MAIT cells from the peripheral blood and intestinal tissue of Crohn’s disease (CD) patients, using immunofluorescence staining and flow cytometry to describe the phenotype and IL-26 expression of MAIT cells. We used 3D iPSC-derived intestinal organoids as a complexin vitromodel of human tissue and RNA sequencing and functional assays such as wound healing assay to study the role of IL-26 in mucosal homeostasis and inflammation.

RESULTS

We observed a reduction of MAIT cells in the peripheral blood of CD patients compared to healthy donors (1.5 ± 0.4%; 4.1 ± 1.1%; p < .0065) and a significant decrease of MAIT cells in inflamed compared to non-inflamed ileum of CD patients (0.1 ± 0.03%; 0.17 ± 0.05%; p < .042). MAIT cells were found pathologically activated in inflamed tissue, exhibiting differences in CD8 and CD4 expression and dysregulation of IL-26 expression. Furthermore, we demonstrated a protective role of IL-26 in mucosal homeostasis and inflammation in the iPSC-derived organoid model.

CONCLUSION

Our results show a crucial role for IL-26 and MAIT cells in the homeostasis of intestinal tissue and in the pathogenesis of IBD. These cells may therefore represent new therapeutic targets for CD patients.
Gene PointNet for Tumor Classification
Authors: Lu Hao , Rezapour Mostafa , Baha Haseebullah , Niazi Muhammad Khalid Khan , Narayanan Aarthi , Gurcan Metin Nafi
Published: June 2024

The rising incidence of cancer underscores the imperative for innovative diagnostic and prognostic methodologies. This study delves into the potential of RNA-Seq gene expression data to enhance cancer classification accuracy. Introducing a pioneering approach, we model gene expression data as point clouds, capitalizing on the data’s intrinsic properties to bolster classification performance. Utilizing PointNet, a typical technique for processing point cloud data, as our framework’s cornerstone, we incorporate inductive biases pertinent to gene expression and pathways. This integration markedly elevates model efficacy, culminating in developing an end-to-end deep learning classifier with an accuracy rate surpassing 99%. Our findings not only illuminate the capabilities of AI-driven models in the realm of oncology but also highlight the criticality of acknowledging biological dataset nuances in model design. This research provides insights into application of deep learning in medical science, setting the stage for further innovation in cancer classification through sophisticated biological data analysis. The source code for our study is accessible at:https://github.com/cialab/GPNet.
The divergent responses of salinity generalists to hyposaline stress provide insights into the colonization of freshwaters by diatoms
Authors: Judy Kathryn J. , Pinseel Eveline , Downey Kala M. , Lewis Jeffrey A. , Alverson Andrew J.
Published: June 2024

Environmental transitions, such as the salinity divide separating marine and fresh waters, shape biodiversity over both shallow and deep timescales, opening up new niches and creating opportunities for accelerated speciation and adaptive radiation. Understanding the evolutionary genetic underpinnings behind habitat transitions is therefore a central question in evolutionary biology. We used time-resolved transcriptomics to contrast the hyposalinity stress responses of two ecologically important diatoms:Skeletonema marinoihas a deep marine ancestry but recently invaded brackish waters, whereasCyclotella crypticahas deep freshwater ancestry and can withstand a much broader salinity range.S. marinoiis less adept at mitigating even mild salinity stress compared toC. cryptica, which has distinct mechanisms for rapid mitigation of hyposaline stress and long-term growth in low salinity. We show that the cellular mechanisms underlying low salinity tolerance, which has allowed diversification across freshwater habitats worldwide, includes elements that are both conserved and variable across the diatom lineage. The balance between ancestral and lineage-specific environmental responses in phytoplankton have likely shaped marine–freshwater transitions on evolutionary timescales and, on contemporary timescales, will likely determine which lineages survive and adapt to changing ocean conditions.
A semidwarf and late-flowering isogenic Kosihihikari d60Hd16: development, productivity, and regional suitability revealed by correlation-based network analysis
Authors: Tomita Motonori , Honda Hiroshi
Published: June 2024

Breeding rice varieties that are tolerant to weather variability and optimizing cultivation methods for each developed variety are challenging issues for global food problems. In this study, the late-flowering geneHd16of Koganebare was introduced into Koshihikari through backcrossing to create ’Koshihikari Hd16’. It was then crossed with ’Koshihikari d60’ to develop an isogenic Koshihikari containing bothHd16andd60. Productivity tests were conducted in nine prefectures in Japan for two homogeneous rice genotypes,Hd16(late flowering) andd60Hd16(short culm and late flowering). By analyzing the relationship between genotype, traits, and accumulation temperature, we reexamined the characteristics of each genotype and inferred the optimal growing areas. Correlation-based network analysis among yield, grain quality, and value of taste and traits showed that quality was positively correlated with panicle length and 1000-grain weight, and yield was strongly positively correlated with 1000-grain weight. d60 genotype was negatively correlated with culm length and lodging degree. These correlations were supported by partial correlation analysis and significant differences compared to the wildtype was identified. Principal component analysis ofd60Hd16revealed that Yamanashi and Ehime, which have longer panicle length and culm length, were suitable in terms of yield and quality, while Shimane, which is warmer and has shorter panicle length and culm length, was suitable in terms of eating quality. Moreover, Koshihikari d60Hd16 could express traits that are less prone to lodging degree while maintaining the same quality and yield as the wild type in cultivation of late-flowering strains. Thus, thed60andH16genotypes express stable traits adapted to a wide range of Japanese climatic conditions and growing environments. This study provides fundamental information for promoting new smart agriculture, in which improved varieties are deployed in different regions with different climatic conditions.
Interplay of EGFR, JNK and ROS signalling in soma-germline communication in theDrosophilatestis
Authors: Alvarez Maria , Papagiannouli Fani
Published: June 2024

Cell communication via signalling exchange plays a pivotal role in multicellular development for building functional tissues and organs. In theDrosophilatestis, a pair of somatic cyst cells (CCs) encapsulate the germline that differentiates through close-range EGFR signalling activation. The conserved Dlg/Scrib/Lgl cortical polarity complex and clathrin-mediated endocytosis attenuate EGFR signalling in CCs and loss of their function leads to EGFR overactivation and non-autonomous death of the neighbouring germ cells. Here we show that EGFR overactivation results in upregulation of JNK and p38 signalling in CCs and ROS levels in the germ cells that are destined to die. Our data uncover a bidirectional feedback between JNK signalling and ROS who regulate each other within the CC-germline microenvironment, while reducing the levels of either JNK or ROS restores germ cell survival. This study provides a framework of how polarity and cellular trafficking regulate the output of multiple signalling responses cell-intrinsically and in adjacent cells, to coordinate tissue-specific responses and maintain homeostasis.
Frameshifts in Tandem Repeats: Consequences on Protein Physicochemical Properties and Function
Authors: Osmanli Zarifa , Aldrian Gudrun , Leclercq Jeremy , Falgarone Theo , Gomez Bergna Santiago M. , Gori Denis N. Prada , Oleinikov Andrew V. , Shahmuradov Ilham , Kajava Andrey V.
Published: June 2024

The genetic code uses three-nucleotide units to encode each amino acid in proteins. Insertions or deletions of nucleotides not divisible by three shift the reading frames, resulting in significantly different protein sequences. These events are disruptive but can also create variability important for evolution. Previous studies suggest that genetic code and gene sequences evolve to minimize frameshift effects, maintaining similar physicochemical properties to their reference proteins. Here, we focused on tandem repeat sequences, known as frameshift hotspots. Using cutting-edge bioinformatics tools, we compared reference and frameshifted protein sequences within tandem repeats across 50 prokaryotic and eukaryotic proteomes. Our analysis revealed several intriguing sequence-structure-function correlations. We showed that in contrast to the general tendency, frameshifts within these regions, especially with short repeats, lead to significant changes: increased hydrophobicity and arginine content, new aggregation-prone and transmembrane regions. Overall, frameshifts have stronger effects on tandem repeat regions compared to non-repetitive sequences, and therefore can be a primary cause of altered functions, cellular localization, and the development of various pathologies.
Genomic alterations and transcriptional phenotypes in circulating tumor DNA and matched metastatic tumor
Authors: Takahashi Nobuyuki , Pongor Lorinc , Agrawal Shivam P. , Shtumpf Mariya , Rajapakse Vinodh N. , Shafiei Ahmad , Schultz Christopher W. , Kim Sehyun , Roame Diana , Carter Paula , Vilimas Rasa , Nichols Samantha , Desai Parth , Figg William Douglas , Bagheri Mohammad , Teif Vladimir B. , Thomas Anish
Published: June 2024

Background

Profiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features has not been systematically compared to standard single-lesion tumor biopsies in prospective cohorts of patients. The use of plasma instead of tissue to guide therapy is particularly attractive for patients with small cell lung cancer (SCLC), a cancer whose aggressive clinical course making it exceedingly challenging to obtain tumor biopsies.

Methods

Here, a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent SCLC, we study cfDNA low pass whole genome (0.1X coverage) and exome (130X) sequencing in comparison with time-point matched tumor, characterized using exome and transcriptome sequencing.

Results

Direct comparison of cfDNA versus tumor biopsy reveals that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor but also identifies clinically relevant resistance mechanisms and cancer driver alterations not found in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Genomic sequencing coverage of plasma DNA fragments around transcription start sites shows distinct treatment-related changes and captures the expression of key transcription factors such as NEUROD1 and REST in the corresponding SCLC tumors, allowing prediction of SCLC neuroendocrine phenotypes and treatment responses.ConclusionsThese findings have important implications for non-invasive stratification and subtype-specific therapies for patients with SCLC, now treated as a single disease.
Electrochemically controlled switching of dyes for enhanced super-resolution optical fluctuation imaging (SOFI)
Authors: Yang Ying , Ma Yuanqing , Tilley Richard D. , Gooding J. Justin
Published: June 2024

In super-resolution optical fluctuation imaging (SOFI), the locations of molecules spaced closer than the diffraction limit of light can be identified through spatial and temporal correlation analysis of the fluorescence intensity fluctuation. Using organic dyes as fluorophore probes, the fast but stochastic switching of the individual dyes is favourable for improving SOFI imaging resolution and speed, especially in the case of high-order cumulant analysis. While in practice, fluorophore switching can be non-uniform, with some fluorophores remaining in ON or OFF state for extended periods. Furthermore, in some cases the overall rate of switching of the fluorophores can be too slow, presenting practical limitations for high-resolution and fast SOFI imaging. In this work, we demonstrate how to overcome these challenges using electrochemical controlled fluorophore switching. The oscillating electrochemical potential setting with high frequency increases the switching rate and reduces the switching heterogeneity of fluorophores. The dye Alexa Fluor 647, applied here as an example, exhibits over 3-fold decrease in average ON time and over 2-fold decrease in switching variance, resulting in significantly improved SOFI image resolution with fewer frames. We demonstrated that this new electrochemically controlled SOFI imaging modality can achieve a SOFI image with ∼130 nm resolution in 2 seconds of acquisition time, and 80 nm resolution in 6 seconds. This advancement enables fast, large area tile-scan super-resolution imaging, which opens the full potential of SOFI imaging.
BIT: Bayesian Identification of Transcriptional Regulators from Epigenomics-Based Query Region Sets
Authors: Lu Zeyu , Xu Lin , Wang Xinlei
Published: June 2024

Transcriptional regulators (TRs) are master controllers of gene expression and play a critical role in both normal tissue development and disease progression. However, existing computational methods for identification of TRs regulating specific biological processes have significant limitations, such as relying on distance on a linear chromosome or binding motifs that have low specificity. Many also use statistical tests in ways that lack interpretability and rigorous confidence measures. We introduce BIT, a novel Bayesian hierarchical model forin-silicoTR identification. Leveraging a comprehensive library of TR ChIP-seq data, BIT offers a fully integrated Bayesian approach to assess genome-wide consistency between user-provided epigenomic profiling data and the TR binding library, enabling the identification of critical TRs while quantifying uncertainty. It avoids estimation and inference in a sequential manner or numerous isolated statistical tests, thereby enhancing accuracy and interpretability. BIT successfully identified critical TRs in perturbation experiments, functionally essential TRs in various cancer types, and cell-type-specific TRs within heterogeneous cell populations, offering deeper biological insights into transcriptional regulation.
Skeletal Muscle Specific PolG Dysfunction Activates the Integrated Stress Response and Promotes a Cachexia like Phenotype
Authors: Bond Simon T , King Emily J , Walker Shannen M , Yang Christine , Liu Yingying , Liu Kevin H , Zhuang Aowen , Jurrjens Aaron W , Fang Haoyun A , Formosa Luke E , Nath Artika P , Carmona Sergio Ruiz , Inouye Michael , Huynh Kevin , Meikle Peter J , Doomun Nadeem Elahee , de Souza David P , Rudler Danielle L , Calkin Anna C , Filipovska Aleksandra , Greening David W , Henstridge Darren C , Drew Brian G
Published: June 2024

During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is specifically activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for this activation remain elusive. A gene often associated with mtDNA mutations/deletions isPolg1, which encodes the mitochondrial DNA Polymerase γ (PolG). Here, we describe what is to our knowledge the first conditional muscle specific model of PolG mutation, and demonstrate a rapid development of mitochondrial dysfunction and cachexia in these animals from ∼5 months of age. Detailed molecular profiling of muscles demonstrated robust activation of the mtISR, likely mediated upstream by the HRI/DELE1 stress pathway. This was accompanied by striking alterations to the mitochondrial folate cycle and its metabolites, strongly implying imbalanced folate intermediates as a previously unrecognised pathology driving the mtISR in mitochondrial disease.