bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemispheric analysis of the magnetic flux in regular and irregular solar active regions
Authors: Zhukova A
Published: June 2024

Studying the hemispheric distribution of active regions (ARs) with different magnetic morphologies may clarify the features of the dynamo process that is hidden under the photospheric level. The magnetic flux data for 3047 ARs from the CrAO catalogue (https://sun.crao.ru/databases/catalog-mmc-ars), between May 1996 and December 2021 (cycles 23 and 24) were used to study ARs cyclic variations and perform correlation analysis. According to the magneto-morphological classification (MMC) of ARs proposed earlier, subsets of the regular (obeying empirical rules for sunspots) and irregular (violating these rules) ARs were considered separately. Our analysis shows the following: For ARs of each MMC type, in each of the hemispheres, time profiles demonstrate a multipeak structure. The double-peak structure of a cycle is formed by ARs of both MMC types in both hemispheres. For the irregular ARs, the pronounced peaks occur in the second maxima (close to the polar field reversal). Their significant hemispheric imbalance might be caused by a weakening of the toroidal field in one of the hemispheres due to the interaction between the dipolar and quadrupolar components of the global field, which facilitates the manifestation of the turbulent component of the dynamo. The similarity of the irregular ARs activity that was found in adjacent cycles in different hemispheres also hints at realization of the mix-parity dynamo solution. For the quadrupolar-like component of the flux (compiled in the simple axisymmetric approximation), signs of oscillations with a period of about 15 years are found, and they are pronounced specifically for the irregular groups. This MMC type ARs might also contribute in $\alpha$-quenching.
Lyα emission as a sensitive probe of feedback-regulated LyC escape from dwarf galaxies
Authors: Yuan Yuxuan , Martin-Alvarez Sergio , Haehnelt Martin G , Garel Thibault , Sijacki Debora
Published: June 2024

Lyα emission is an exceptionally informative tracer of the life cycle of evolving galaxies and the escape of ionizing photons. However, theoretical studies of Lyα emission are often limited by insufficient numerical resolution, incomplete sets of physical models, and poor line-of-sight (LOS) statistics. To overcome such limitations, we utilize here the novel pandora suite of high-resolution dwarf galaxy simulations that include a comprehensive set of state-of-the-art physical models for ionizing radiation, magnetic fields, supernova feedback, and cosmic rays. We post-process the simulations with the radiative transfer code rascas to generate synthetic observations and compare to the observed properties of Lyα emitters. Our simulated Lyα haloes are more extended than the spatial region from which the intrinsic emission emanates, and our spatially resolved maps of spectral parameters of the Lyα emission are very sensitive to the underlying spatial distribution and kinematics of neutral hydrogen. Lyα and LyC emissions display strongly varying signatures along different LOS depending on how each LOS intersects low-density channels generated by stellar feedback. Comparing galaxies simulated with different physics, we find the Lyα signatures to exhibit systematic offsets determined by the different levels of feedback strength and the clumpiness of the neutral gas. Despite this variance, and regardless of the different physics included in each model, we find universal correlations between Lyα observables and LyC escape fraction, demonstrating a robust connection between Lyα and LyC emission. Lyα observations from a large sample of dwarf galaxies should thus give strong constraints on their stellar feedback-regulated LyC escape and confirm their important role for the re-ionization of the Universe.
Gas conditions of a star-formation selected sample in the first billion years
Authors: Bakx Tom J L C , Algera Hiddo S B , Venemans Bram , Sommovigo Laura , Fujimoto Seiji , Carniani Stefano , Hagimoto Masato , Hashimoto Takuya , Inoue Akio K , Salak Dragan , Serjeant Stephen , Vallini Livia , Eales Stephen , Ferrara Andrea , Fudamoto Yoshinobu , Imamura Chihiro , Inoue Shigeki , Knudsen Kirsten K , Matsuo Hiroshi , Sugahara Yuma , Tamura Yoichi , Taniguchi Akio , Yamanaka Satoshi
Published: June 2024

We present Atacama Large Millimetre/submillimetre Array (ALMA) observations of the [O iii] 88 $\mu {\rm m}$ emission of a sample of thirteen galaxies at $z = 6$ to 7.6 selected as [C ii]-emitting companion sources of quasars. To disentangle the origins of the luminous Oxygen line in the $z\, \gt\, 6$ Universe, we looked at emission-line galaxies that are selected through an excellent star-formation tracer [C ii] with star-formation rates between 9 and 162 $\rm {\rm M}_{\odot }\,yr^{-1}$. Direct observations reveal [O iii] emission in just a single galaxy ($L_\mathrm{[O\, {\small III}]}/L_\mathrm{[C\, {\small II}]}$$\, = 2.3$), and a stacked image shows no [O iii] detection, providing deep upper limits on the $L_\mathrm{[O\, {\small III}]}/L_\mathrm{[C\, {\small II}]}$ ratios in the $z \gt 6$ Universe ($L_\mathrm{[O\, {\small III}]}/L_\mathrm{[C\, {\small II}]}$$\, \lt 1.2$ at $3 \sigma$). While the fidelity of this sample is high, no obvious optical/near-infrared counterpart is seen in the JWST imaging available for four galaxies. Additionally accounting for low-z CO emitters, line stacking shows that our sample-wide result remains robust: The enhanced $L_\mathrm{[O\, {\small III}]}/L_\mathrm{[C\, {\small II}]}$ reported in the first billion years of the Universe is likely due to the selection towards bright, blue Lyman-break galaxies with high surface star-formation rates or young stellar populations. The deep upper limit on the rest-frame 90 μm continuum emission ($\lt 141 \mu$Jy at $3 \sigma$), implies a low average dust temperature ($T_\mathrm{dust} \lesssim 30\,$ K) and high-dust mass ($M_\mathrm{dust} \sim 10^8\, \mathrm{M}_\odot$). As more normal galaxies are explored in the early Universe, synergy between JWST and ALMA is fundamental to further investigate the ISM properties of the a broad range of samples of high-z galaxies.
Insights into the performance of PREDICT tool in a large Mainland Chinese breast cancer cohort: a comparative analysis of versions 3.0 and 2.2
Authors: Chen Endong , Chen Chen , Chen Yingying , You Jie , Jin Chun , Huang Zhenxuan , Zhang Jiayi , Wang Qingxuan , Cai Yefeng , Hu Xiaoqu , Li Quan
Published: June 2024

Background

PREDICT is a web-based tool for forecasting breast cancer outcomes. PREDICT version 3.0 was recently released. This study aimed to validate this tool for a large population in mainland China and compare v3.0 with v2.2.

Methods

Women who underwent surgery for nonmetastatic primary invasive breast cancer between 2010 and 2020 from the First Affiliated Hospital of Wenzhou Medical University were selected. Predicted and observed 5-year overall survival (OS) for both v3.0 and v2.2 were compared. Discrimination was compared using receiver-operator curves and DeLong test. Calibration was evaluated using calibration plots and chi-squared test. A difference greater than 5% was deemed clinically relevant.

Results

A total of 5424 patients were included, with median follow-up time of 58 months (IQR 38-89 months). Compared to v2.2, v3.0 did not show improved discriminatory accuracy for 5-year OS (AUC: 0.756 vs 0.771), same as ER-positive and ER-negative patients. However, calibration was significantly improved in v3.0, with predicted 5-year OS deviated from observed by −2.0% for the entire cohort, −2.9% for ER-positive and −0.0% for ER-negative patients, compared to −7.3%, −4.7% and −13.7% in v2.2. In v3.0, 5-year OS was underestimated by 9.0% for patients older than 75 years, and 5.8% for patients with micrometastases. Patients with distant metastases postdiagnosis was overestimated by 10.6%.

Conclusions

PREDICT v3.0 reliably predicts 5-year OS for the majority of Chinese patients with breast cancer. PREDICT v3.0 significantly improved the predictive accuracy for ER-negative groups. Furthermore, caution is advised when interpreting 5-year OS for patients aged over 70, those with micrometastases or metastases postdiagnosis.
The transcription factor MhZAT10 enhances antioxidant capacity by directly activating the antioxidant genes MhMSD1, MhAPX3a and MhCAT1 in apple rootstock SH6 (Malus honanensis × M. domestica)
Authors: Yang Qian , Liu Yan , Zhou Jia , Li Min-Ji , Yang Yu-Zhang , Wei Qin-Ping , Zhang Jun-Ke , Li Xing-Liang
Published: June 2024

Stress tolerance in apple (Malus domestica) can be improved by grafting to a stress-tolerant rootstock, such as ‘SH6’ (Malus honanensis × M. domestica ‘Ralls Genet’). However, the mechanisms of stress tolerance in this rootstock are unclear. In Arabidopsis (Arabidopsis thaliana), the transcription factor ZINC FINGER OF ARABIDOPSIS THALIANA 10 is a key component of plant tolerance to multiple abiotic stresses and positively regulates antioxidant enzymes. However, how reactive oxygen species are eliminated upon activation of ZINC FINGER OF ARABIDOPSIS THALIANA 10 in response to abiotic stress remains elusive. Here, we report that MhZAT10 in the rootstock SH6 directly activates the transcription of three genes encoding the antioxidant enzymes MANGANESE SUPEROXIDE DISMUTASE 1 (MhMSD1), ASCORBATE PEROXIDASE 3A (MhAPX3a) and CATALASE 1 (MhCAT1) by binding to their promoters. Heterologous expression in Arabidopsis protoplasts showed that MhMSD1, MhAPX3a and MhCAT1 localize in multiple subcellular compartments. Overexpressing MhMSD1, MhAPX3a or MhCAT1 in SH6 fruit calli resulted in higher superoxide dismutase, ascorbate peroxidase and catalase enzyme activities in their respective overexpressing calli than in those overexpressing MhZAT10. Notably, the calli overexpressing MhZAT10 exhibited better growth and lower reactive oxygen species levels under simulated osmotic stress. Apple SH6 plants overexpressing MhZAT10 in their roots via Agrobacterium rhizogenes–mediated transformation also showed enhanced tolerance to osmotic stress, with higher leaf photosynthetic capacity, relative water content in roots and antioxidant enzyme activity, as well as less reactive oxygen species accumulation. Overall, our study demonstrates that the transcription factor MhZAT10 synergistically regulates the transcription of multiple antioxidant-related genes and elevates reactive oxygen species detoxification.
Discrimination in the Workplace Linked to Psychological Distress
Authors: Keller Elizabeth , Guardiano Megan , Li Jian
Published: June 2024

Objective

This study aimed to explore the relationship between workplace discrimination and psychological distress across 9 years using data from the Midlife in the Unites States study.

Methods

Workplace discrimination was measured with a validated six-item scale at baseline with three categories (low, intermediate, and high), and psychological distress was measured with the Kessler 6 scale at baseline and follow-up. In total, 1,546 workers were analyzed by linear regression.

Results

High levels of workplace discrimination were significantly associated with increased psychological distress at follow-up (crude β = 0.633; 95% CI, 0.307–0.959). After adjusting for demographic factors, socioeconomic status, and health-related behaviors, associations were slightly attenuated (fully adjusted β = 0.447; 95% CI, 0.115–0.780).

Conclusions

High workplace discrimination was longitudinally associated with higher levels of psychological distress. Organizations should actively prevent discrimination, which may improve workers' mental health consequently.
The Emerging Future of Mobile Audiometry: A Prospective Validation Study of the Mimi Hearing Test Application
Authors: Moazzami Chloé , Gagnon Carolanne , Bertrand Léo , Saliba Issam , Saliba Joe
Published: June 2024

Objective

The objective of this study is to assess the accuracy of the Mimi Hearing Test (MHT) mobile application in the detection of air conduction (AC) thresholds and in screening for moderate hearing loss.

Study Design

Prospective clinical study.

Setting

Tertiary care center.

Patients

Participants with or without a varying degree of hearing loss, aged 18 years and over, without cognitive impairment and without active otorrhea or earwax impaction at the time of the hearing assessment were included.

Intervention

Subjects with a ranging severity of hearing loss underwent a conventional in-booth audiogram as well as mobile-based screening with MHT in a quiet room (45.5 dB background noise) on the same day. Both regular over-the-ear and noise-canceling headphones were tested with MHT.

Main Outcome Measures

Comparisons of AC thresholds between conventional audiometry and mobile-based audiometry at discrete frequencies and with pure-tone averages (PTA) were performed.

Results

A total of 75 adults (mean age: 56.2 yr, 54.7% male) were recruited and 63 used for analysis. Of the thresholds measured with MHT using regular headphones, 44.0% were within 10 dB of the conventional audiogram, compared to 39.3% using noise-canceling headphones. MHT demonstrated best accuracy at high frequencies (4–8 kHz). When screening for moderate hearing loss (PTA >40 dB HL), MHT demonstrated a sensitivity and specificity of 100.0% and 80.2%, respectively.

Conclusions

MHT is reliable for identifying moderate hearing loss but lacks precision in detecting thresholds at low frequencies. Noise canceling headphones seem to improve its precision at 4,000 Hz only.
The pathogenicity ofPSEN2variants is tied to Aβ production and homology toPSEN1
Authors: Liu Lei , Schultz Stephanie A. , Saba Adriana , Yang Hyun-Sik , Li Amy , Selkoe Dennis J. , Chhatwal Jasmeer P.
Published: June 2024

INTRODUCTION

Though recognized as a potential cause of Autosomal Dominant Alzheimer’s Disease, the pathogenicity of manyPSEN2variants remains uncertain. We compared Aβ production across all missensePSEN2variants in the Alzforum database and, when possible, to correspondingPSEN1variants.

METHODS

We expressed 74PSEN2variants, 21 of which had homologousPSEN1variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. Aβ production was compared to age at symptom onset (AAO) and between homologousPSEN1/2variants.

RESULTS

Aβ42/40 and Aβ37/42 ratios were associated with AAO acrossPSEN2variants, strongly driven byPSEN2variants withPSEN1homologs.PSEN2AAO was 18.3 years later compared toPSEN1homologs. Aβ ratios fromPSEN1/2homologs were highly correlated, suggesting a similar mechanism of γ-secretase dysfunction.

DISCUSSION

The existence of aPSEN1homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously-reported and newPSEN2variants.
Targeting Metabolic Dependencies in Acute Myeloid Leukemia: A Dual Strategy using Arsenic Trioxide and Artesunate
Authors: Balasundaram Nithya , Venkatraman Arvind , Augustin Yolanda , Palani Hamenth Kumar , Regnault Clement , Korula Anu , Kulkarni Uday Prakash , Edison Eunice Sindhuvi , Balasubramanian Poonkuzhali , George Biju , Abraham Aby , Krishna Sanjeev , Mathews Vikram
Published: June 2024

Acute myeloid leukemia (AML) remains a difficult disease to cure despite recent advances. Off-target side effects of therapy, especially prolonged cytopenia, lead to significant morbidity and mortality. There is an increased recognition that in AML, there is a potentially vulnerable dependence on OXPHOS metabolism, more so in the leukemia stem cell compartment (AML-LSC) that could be exploited. Drug re-purposing screens have suggested the possible role of artesunate (ART) in inhibiting mitochondrial respiration and arsenic trioxide (ATO) in inhibiting glycolysis. Here, we explore the potential of using a combination of ART and ATO to treat AML. Through in-vitro and in-vivo studies, we demonstrate the potential of this combination along with hypo-methylating agents and other mitocans, such as BCL-2 inhibitor venetoclax, to be used in the treatment of AML with minimal off-target effect on normal hematopoietic stem cells (HSC). These observations warrant further exploration of such novel combinations in clinical trials.
Improved BioCyc Operon Prediction: Revisiting the Operon Prediction Problem
Authors: Midford Peter E. , Cadigan John , Karp Peter D.
Published: June 2024

Introduction

Operon prediction is a valuable component of microbial-genome annotation because operon organization can yield inferences about gene function, and because knowledge of operon structure can aid the interpretation of gene expression data.

Methods

We present a number of improvements to the existing Pathway Tools operon predictor based mostly on 7 new features that we hypothesized would increase its performance. The new features include shared Gene Ontology biological process terms, similarity of codon usage and GC content, correlated gene expression, and shared protein complex.

Results

We evaluated the proposed 7 new features and found that the addition of 6 of them improved the performance of the operon predictor from 79.55% to 83.49%, a decrease in error rate of 19.3%. When gene expression data was not included, the accuracy decreased to 82.547, still an improvement of 14.7%. One of the proposed features as well as a previously used feature had no effect and were removed.

Discussion

Although some of the new features had strong predictive value individually, when combined with the other features they did not have a large impact on predictive accuracy, suggesting that they were not independent from the other features.
Deuterium Metabolic Imaging Phenotypes Mouse Glioblastoma Heterogeneity Through Glucose Turnover Kinetics
Authors: Simões Rui V. , Henriques Rafael N. , Olesen Jonas L , Cardoso Beatriz M. , Fernandes Francisca F. , Monteiro Mariana A.V. , Jespersen Sune N , Carvalho Tânia , Shemesh Noam
Published: June 2024

Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.
Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis
Authors: Zhuang Xueqian , Wang Qing , Joost Simon , Ferrena Alexander , Humphreys David T. , Li Zhuxuan , Blum Melissa , Bastl Klavdija , Ding Selena , Landais Yuna , Zhan Yingqian , Zhao Yang , Chaligne Ronan , Lee Joo-Hyeon , Carrasco Sebastian E. , Bhanot Umeshkumar K. , Koche Richard P. , Bott Matthew J. , Katajisto Pekka , Soto-Feliciano Yadira M. , Pisanic Thomas , Thomas Tiffany , Zheng Deyou , Wong Emily S. , Tammela Tuomas
Published: June 2024

Aging is associated with a decline in the number and fitness of adult stem cells1–4. Aging-associated loss of stemness is posited to suppress tumorigenesis5,6, but this hypothesis has not been testedin vivo. Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells7,8, we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1—lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1— lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.
MICROBIOME-MODIFIED METABOLITES PREDICT ACUTE BRAIN INJURY OUTCOME
Authors: DeLeon Orlando , Ceccato Hugo D , Sidebottom Ashley , Babtain Nada , Roy Sara , Koval Jason , Roth William H , Beiser David G. , Mansour Ali , Goldenberg Fernando D , Chang Eugene B , Lazaridis Christos
Published: June 2024

BACKGROUND

Acute brain injury (ABI)-mediated disruption of the microbiome may potentiate inflammation and secondary brain injury (SBI). However, microbial-specific mediators and mechanisms remain unclear.

METHODS

Thirty-five consecutive patients with ABI admitted to the neuroscience critical care unit at the University of Chicago were prospectively studied. Injury severity at hospital admission was assessed using the Injury Severity Score (ISS) and the Glasgow Coma Scale (GCS). Final neurologic function was assessed via the Glasgow Outcome Score extended (GOSe). Serum, plasma, and stool targeted metabolomics, as well as stool shotgun metagenomics, were performed on longitudinal samples collected during hospitalization.

RESULTS

Multivariate analysis identified microbiome-modified metabolites that were positively and negatively associated with functional outcomes after ABI. Novel identification of conjugated bile acid (BA) species and vitamin B12 precursors indicative of outcome were detected in the first collected samples (within 48 hours). Network analysis revealed greater integration of negatively associated metabolites across tissues and identified tauro-α/μ-muricholic acid (TMCA) as central to the cross-tissue metabolomes.

CONCLUSIONS

Microbiome metabolites may be useful in assessing brain injury outcomes to inform treatment. Bile acid species transformed by the gut microbiome are predictive of ABI outcome.
A machine learning and drug repurposing approach to target ferroptosis in colorectal cancer stratified by sex and KRAS
Authors: Yan Hong , Shen Xinyi , Yao Yisha , Khan Sajid A. , Ma Shuangge , Johnson Caroline H.
Published: June 2024

The landscape of sex differences in Colorectal Cancer (CRC) has not been well characterized with respect to the mechanisms of action for oncogenes such as KRAS. However, our recent study showed that tumors from male patients with KRAS mutations have decreased iron-dependent cell death called ferroptosis. Building on these findings, we further examined ferroptosis in CRC, considering both sex of the patient and KRAS mutations, using public databases and our in-house CRC tumor cohort.

Through subsampling inference and variable importance analysis (VIMP), we identified significant differences in gene expression between KRAS mutant and wild type tumors from male patients. These genes suppress (e.g.,SLC7A11) or drive (e.g.,SLC1A5) ferroptosis, and these findings were further validated with Gaussian mixed models. Furthermore, we explored the prognostic value of ferroptosis regulating genes and discovered sex- and KRAS-specific differences at both the transcriptional and metabolic levels by random survival forest with backward elimination algorithm (RSF-BE). Of note, genes and metabolites involved in arginine synthesis and glutathione metabolism were uniquely associated with prognosis in tumors from males with KRAS mutations.

Additionally, drug repurposing is becoming popular due to the high costs, attrition rates, and slow pace of new drug development, offering a way to treat common and rare diseases more efficiently. Furthermore, increasing evidence has shown that ferroptosis inhibition or induction can improve drug sensitivity or overcome chemotherapy drug resistance. Therefore, we investigated the correlation between gene expression, metabolite levels, and drug sensitivity across all CRC primary tumor cell lines using data from the Genomics of Drug Sensitivity in Cancer (GDSC) resource. We observed that ferroptosis suppressor genes such asDHODH,GCH1, andAIFM2in KRAS mutant CRC cell lines were resistant to cisplatin and paclitaxel, underscoring why these drugs are not effective for these patients. The comprehensive map generated here provides valuable biological insights for future investigations, and the findings are supported by rigorous analysis of large-scale publicly available data and our in-house cohort. The study also emphasizes the potential application of VIMP, Gaussian mixed models, and RSF-BE models in the multi-omics research community. In conclusion, this comprehensive approach opens doors for leveraging precision molecular feature analysis and drug repurposing possibilities in KRAS mutant CRC.
scCancerExplorer: a comprehensive database for interactively exploring single-cell multi-omics data of human pan-cancer
Authors: Huang Changzhi , Liu Zekai , Guo Yunlei , Wang Wanchu , Yuan Zhen , Guan Yusheng , Pan Deng , Hu Zhibin , Sun Linhua , Fu Zan , Bian Shuhui
Published: June 2024

Genomic, epigenomic, and transcriptomic alterations are hallmarks of cancer cells, and are closely connected. Especially, epigenetic regulation plays a critical role in tumorigenesis and progression. The growing single-cell epigenome data in cancer research provide new opportunities for data mining from a more comprehensive perspective. However, there is still a lack of databases designed for interactively exploring the single-cell multi-omics data of human pan-cancer, especially for the single-cell epigenome data. To fill in the gap, we developed scCancerExplorer, a comprehensive and user-friendly database to facilitate the exploration of the single-cell genome, epigenome (chromatin accessibility and DNA methylation), and transcriptome data of 50 cancer types. Five major modules were provided to explore those data interactively, including “integrated multi-omics analysis”, “single-cell transcriptome”, “single-cell epigenome”, “single-cell genome”, and “TCGA analysis”. By simple clicking, users can easily investigate gene expression features, chromatin accessibility patterns, transcription factor activities, DNA methylation states, copy number variations, and TCGA survival analysis results. Taken together, scCancerExplorer is distinguished from previous databases with rich and interactive functions for exploring the single-cell multi-omics data of human pan-cancer. It bridges the gap between single-cell multi-omics data and the end-users, and will facilitate progress in the field of cancer research. scCancerExplorer is freely accessible viahttps://bianlab.cn/scCancerExplorer.
N2 Sleep Inspires Insight
Authors: Löwe Anika T. , Petzka Marit , Tzegka Maria , Schuck Nicolas W.
Published: June 2024

Humans sometimes have an insight that leads to a sudden and drastic performance im-provement on the task they are working on. The precise origins of such insights are unknown. Some evidence has shown that sleep facilitates insights, while other work has not found such a relationship. One recent suggestion that could explain this mixed evidence is that different sleep stages have differential effects on insight. In addition, computational work has suggested that neural variability and regularisation play a role in increasing the likelihood of insight. To investigate the link between insight and different sleep stages as well as regularisation, we conducted a preregistered study in which N=90 participants performed a perceptual insight task before and after a 20 minute daytime. Sleep EEG data showed that N2 sleep, but not N1 sleep, increases the likelihood of insight after a nap, suggesting a specific role of deeper sleep. Exploratory analyses of EEG power spectra showed that spectral slopes could predict insight beyond sleep stages, which is broadly in line with theoretical suggestions of a link between insight and regularisation. In combination, our findings point towards a role of N2 sleep and aperiodic, but not oscillatory, neural activity for insight.
Dust storm-driven dispersal of potential pathogens and antibiotic resistance genes in the Eastern Mediterranean
Authors: Erkorkmaz Burak Adnan , Zeevi David , Rudich Yinon
Published: June 2024

The atmosphere hosts a microbiome that connects distant ecosystems yet remains relatively unexplored. In this study, we tested the hypothesis that dust storms enhance the spread of pathogenic microorganisms and whether these microorganisms carry antibiotic resistance and virulence-related genes in the Eastern Mediterranean. We collected air samples during a seasonal transition period, capturing data from 13 dusty days originating from Middle Eastern sources and 32 clear days, with temperatures ranging from 16.5 to 27.1 °C. Using metagenomic analysis, we identified several facultative pathogens likeKlebsiella pneumoniae,Stenotrophomonas maltophilia, andAspergillus fumigatus, which are linked to human respiratory diseases, and others likeZymoseptoria tritici,Fusarium poae, andPuccinia striiformis, which are harmful to wheat. The abundance of these pathogens increased during dust storms and with rising temperatures. Although we did not find strong evidence that these species harbored antibiotic resistance or virulence-related genes, which could be linked to their pathogenic potential, dust storms transported up to 125 times more total antibiotic resistance genes, as measured by RPKM abundance, compared to clear conditions. These levels during dust storms far exceeded those found in other ecosystems. While further research is needed to determine whether dust storms and temperature variations pose an immediate threat to public health and the environment, our findings underscore the importance of continuous monitoring of atmospheric microbiomes. This surveillance is crucial for assessing potential risks to human health and ecosystem stability, particularly in the face of accelerating global climate change.
Role of Stem-Like Cells in Chemotherapy Resistance and Relapse in pediatric T Cell Acute Lymphoblastic Leukemia
Authors: Costea Julia , Rauwolf Kerstin K. , Zafferani Pietro , Rausch Tobias , Mathioudaki Anna , Zaugg Judith , Schrappe Martin , Eckert Cornelia , Escherich Gabriele , Bourquin Jean P. , Bornhauser Beat , Kulozik Andreas E. , Korbel Jan O.
Published: June 2024

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia predominantly affecting adolescents and young adults. T-ALL relapses are characterized by chemotherapy resistance, cellular heterogeneity and dismal outcome. To gain a deeper understanding of the cellular heterogeneity and mechanisms driving relapse, we conducted single-cell full-length RNA sequencing of 13 matched pediatric T-ALL patient-derived xenografts (PDX) samples obtained at initial diagnosis and relapse, generating the to date most comprehensive longitudinal single cell study in paired T-ALL samples, along with 5 non-relapsing PDX samples collected at initial diagnosis. This dataset identifies considerable transcriptomic diversity among individual T-ALL cell populations. Notably however, 11 of the 18 patients exhibit a small T-ALL cell subpopulation with a shared set of gene regulatory networks characterized by a common set of active regulons, expression patterns and splice isoforms. This profile involves the upregulation of a stem-like cell signature with enrichment of cell adhesion, and inhibition of the cell cycle and metabolic activity. Comprehensive investigations of these networks identify transcripts enforcing drug resistance through NF-κB expression and TGF-β signaling and of anti-apoptotic T cell signaling. Longitudinal monitoring of these stem-like cells demonstrates this subpopulation to account for only a small proportion of leukemia cells initially with a substantial expansion at relapse suggesting resistance to first line therapy. Chemotherapy resistance is functionally corroborated throughin vitroandin vivodrug testing. We thus report the discovery of inherently treatment-resistant stem-like T-ALL cell populations underscoring the potential for devising future therapeutic strategies aimed at targeting stemness pathways in pediatric T-ALL.

Key Points

Single-cell full-length RNA sequencing reveals dormant, treatment-resistant cells expanding upon T cell acute lymphoblastic leukemia relapse.

Stem-like T-ALL cells exhibit a shared gene regulatory network conferring chemotherapy resistance and relapse.
Distinct attentional profile and functional connectivity of neurons with visual feature coding in the primate brain
Authors: Zhang Jie , Cao Runnan , Zhu Xiaocang , Zhou Huihui , Wang Shuo
Published: June 2024

Visual attention and object recognition are two critical cognitive functions that significantly influence our perception of the world. While these neural processes converge on the temporal cortex, the exact nature of their interactions remains largely unclear. Here, we systematically investigated the interplay between visual attention and object feature coding by training macaques to perform a free-gaze visual search task using natural face and object stimuli. With a large number of units recorded from multiple brain areas, we discovered that units exhibiting visual feature coding displayed a distinct attentional response profile and functional connectivity compared to units not exhibiting feature coding. Attention directed towards search targets enhanced the pattern separation of stimuli across brain areas, and this enhancement was more pronounced for units encoding visual features. Our findings suggest two stages of neural processing, with the early stage primarily focused on processing visual features and the late stage dedicated to processing attention. Importantly, feature coding in the early stage could predict the attentional effect in the late stage. Together, our results suggest an intricate interplay between visual feature and attention coding in the primate brain, which can be attributed to the differential functional connectivity and neural networks engaged in these processes.
CREEPING STEM1 Regulates Directional Auxin Transport for Lodging Resistance in Soybean
Authors: Xu Zhiyong , Zhang Liya , Kong Keke , Kong Jiejie , Ji Ronghuan , Liu Jun , Li Hongyu , Ren Yulong , Zhou Wenbin , Zhao Tao , Zhao Tuanjie , Liu Bin
Published: June 2024

Soybean, a staple crop on a global scale, frequently encounters challenges due to lodging under high planting densities, which results in significant yield losses. Despite extensive research, the fundamental genetic mechanisms governing lodging resistance in soybeans remain elusive. In this study, we identify and characterize theCreeping Stem 1(CS1) gene, which plays a crucial role in conferring lodging resistance in soybeans. TheCS1gene encodes a HEAT-repeat protein that modulates hypocotyl gravitropism by regulating amyloplast sedimentation. Functional analysis reveals that the loss ofCS1activity disrupts polar auxin transport, vascular bundle development, and the biosynthesis of cellulose and lignin, ultimately leading to premature lodging and aberrant root development. Conversely, increasingCS1expression significantly enhances lodging resistance and improves yield under conditions of high planting density. Our findings shed light on the genetic mechanisms that underlie lodging resistance in soybeans and highlight the potential ofCS1as a valuable target for genetic engineering to improve crop lodging resistance and yield.
The STAT3-VDAC1 Axis Modulates Mitochondrial Function and Plays a Critical Role in the Survival of Acute Myeloid Leukemia Cells
Authors: Gil Kellen B. , Borg Jamie , Moreira Pereira Rosana , Inguva-Sheth Anagha , Araujo Geovana , Rahkola Jeremy , Showers William , Grier Abby , D’Alessandro Angelo , Smith Clayton , McMahon Christine , Pollyea Daniel A. , Gillen Austin E. , Amaya Maria L.
Published: June 2024

Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, particularly when phosphorylated at the serine 727 (pSTAT3 S727) residue. Inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria that provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also results in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.
TwoStabiliserloci inAntirrhinumsuppress the transposition of Tam3 without compromising transposase production
Authors: Wang Shasha , Uchiyama Takako , Kuwabara Hiroyuki , Hirata Megumi , Yuasa Ikumi , Nakahara Kenji , Martin Cathie , Kishima Yuji
Published: June 2024

Antirrhinum majushas been known to exhibit occasional instabilities that are manifested as variegations and morphological chimeras.Stabiliser(St) is a historical locus that stabilizes phenotypically unstable or mutable traits inAntirrhinum. Here, we characterized twoStloci, the previously describedOld Stabiliser(OSt) andNew Stabiliser(NSt), inAntirrhinumthat specifically suppress the transposition of the Class II DNA transposable element, Tam3. BothStloci involve derivatives of Tam3 with unique structures:OSthas a pseudo-Tam3 copy whose 5’-terminal region has been rearranged compared to the cognate Tam3 element, andNStconsists of two intact copies of Tam3 in a head-to-head orientation. Neither locus interferes with the production of the intact Tam3 transposase (TPase) or the nuclear import of TPase.

BothOStandNStproduce specific sRNAs from their 5’ terminal regions containing multiple TPase binding motifs. These specific sRNAs could repress Tam3 transposition by interacting with the TPase binding motifs within the Tam3 element or with the TPase itself.
Optimizing single-cell RNA sequencing methods for human colon biopsies: droplet-based vs. picowell-based platforms
Authors: Downie Jonathan M. , Musich Ryan J. , Geraghty Connor M. , Caraballo Alexander , He Shijie , Khawaled Saleh , Lachut Kylor , Long Timothy , Zhou Julie Y. , Yilmaz Omer H. , Stappenbeck Thaddeus , Chan Andrew T. , Drew David A.
Published: June 2024

Background & Aims

Single-cell RNA sequencing (scRNA) has empowered many insights into gastrointestinal microenvironments. However, profiling human biopsies using droplet-based scRNA (D-scRNA) is challenging since it requires immediate processing to minimize epithelial cell damage. In contrast, picowell-based (P-scRNA) platforms permit short-term frozen storage before sequencing. We compared P- and D-scRNA platforms on cells derived from human colon biopsies.

Methods

Endoscopic rectosigmoid mucosal biopsies were obtained from two adults and conducted D-scRNA (10X Chromium) and P-scRNA (Honeycomb HIVE) in parallel using an individual’s pool of single cells (> 10,000 cells/participant). Three experiments were performed to evaluate 1) P-scRNA with cells under specific storage conditions (immediately processed [fresh], vs. frozen at -20C vs. -80C [2 weeks]); 2) fresh P-scRNA versus fresh D-scRNA; and 3) P-scRNA stored at -80C with fresh D-scRNA.

Results

Significant recovery of loaded cells was achieved for fresh (80.9%) and -80C (48.5%) P-scRNA and D-scRNA (76.6%), but not -20C P-scRNA (3.7%). However, D-scRNA captures more typeable cells among recovered cells (71.5% vs. 15.8% Fresh and 18.4% -80C P-scRNA), and these cells exhibit higher gene coverage at the expense of higher mitochondrial read fractions across most cell types. Cells profiled using D-scRNA demonstrated more consistent gene expression profiles among the same cell type than those profiled using P-scRNA. Significant intra-cell-type differences were observed in profiled gene classes across platforms.

Conclusions

Our results highlight non-overlapping advantages of P-scRNA and D-scRNA and underscore the need for innovation to enable high-fidelity capture of colonic epithelial cells. The platform-specific variation highlights the challenges of maintaining rigor and reproducibility across studies that use different platforms.
Causal, Predictive or Observational? Different Understandings of Key Event Relationships for Adverse Outcome Pathways and Their Implications on Practice
Authors: Zhou Zheng , Pennings Jeroen L.A. , Sahlin Ullrika
Published: June 2024

The Adverse Outcome Pathways (AOPs) framework is pivotal in toxicology, but the terminology describing Key Event Relationships (KERs) varies within AOP guidelines. This study examined the usage of causal, observational and predictive terms in AOP documentation and their adaptation in AOP development. A literature search and text analysis of key AOP guidance documents revealed nuanced usage of these terms, with KERs often described as both causal and predictive. The adaptation of terminology varies across AOP development stages. Evaluation of KER causality often relies targeted blocking experiments and weight-of-evidence assessments in the putative and qualitative stages. Our findings highlight a potential mismatch between terminology in guidelines and methodologies in practice, particularly in inferring causality from predictive models. We argue for careful consideration of terms like causal and essential to facilitate interdisciplinary communication. Furthermore, integrating known causality into quantitative AOP models remains a challenge.
Functional consequences of a p53-MDM2-p21 incoherent feedforward loop
Authors: Dean Jamie A , Reyes Jose , Tsabar Michael , Jambhekar Ashwini , Lahav Galit , Michor Franziska
Published: June 2024

Genetically identical cells can respond heterogeneously to cancer therapy, with a subpopulation of cells often entering a temporarily arrested treatment-tolerant state before repopulating the tumor. To investigate how heterogeneity in the cell cycle arrest protein p21 arises, we imaged the dynamics of p21 transcription and protein expression along with those of p53, its transcriptional regulator, in single cells using live cell fluorescence microscopy. Surprisingly, we found that the rate of p21 transcription depends on the change in p53 rather than its absolute level. Through combined theoretical and experimental modeling, we determined that p21 transcription is governed by an incoherent feedforward loop mediated by MDM2. This network architecture facilitates rapid induction of p21 expression and variability in p21 transcription. Abrogating the feedforward loop overcomes rapid S-phase p21 degradation, with cells transitioning into a quiescent state that transcriptionally resembles a treatment-tolerant persister state. Our findings have important implications for therapeutic strategies based on activating p53.
TGFβ signaling in cancer-associated fibroblasts drives a hepatic gp130-dependent pro-metastatic inflammatory program in CMS4 colorectal cancer subtype
Authors: Harryvan TJ , Abudukelimu S , Stouten I , van der Wel EJ , Janson SGT , Lenos KJ , Lannagan TRM , White M , Sansom OJ , Verdegaal EME , Hawinkels LJAC
Published: June 2024

Current molecular classification of colorectal cancer (CRC), the Consensus Molecular Subtypes (CMS), has highlighted the biological heterogeneity of CRC and enables patient stratification based on the molecular subtype of their tumor. The CMS4 subtype shows the worst prognosis and is linked to the highest occurrence of hepatic metastasis but the underlying molecular mechanisms remain unclear. In this study, we show that the molecular features that largely define CMS4 classification, i.e. abundance of cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) and active TGFβ signaling, converge to promote liver metastasis. Studying TGFβ signaling in CRC patient-derived CAFs from the primary tumor revealed that all three TGFβ isoforms induce expression of different IL-6 cytokine family members, particularly IL-6 and IL-11. This primary tumor-derived IL-6 and IL-11 in turn induce upregulation of myeloid chemoattractants, including SAA1, in hepatocytes. Chemical inhibition and genetic ablation experiments revealed that gp130, the IL-6 family of cytokine co-receptor, through JAK/STAT signaling is crucial for the induction of neutrophil chemoattractants by hepatocytes and mediates the migration of potential pro-metastatic neutrophils towards the liver. This IL-6 family-JAK/STAT stromal signaling axis is active in both a murine model of CMS4 as well as in human CRC patientsin vivo. Combined, our data reveal that TGFβ signaling in CAFs actively contributes to the formation of a neutrophil-dependent, pre-metastatic hepatic niche and that this mechanism might play a role in the metastatic phenotype of CMS4 subtype CRC.