bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of expression from a limited number of genes is sufficient to predict flowering time in maize
Authors: Torres-Rodríguez J. Vladimir , Sun Guangchao , Mural Ravi V. , Schnable James c.
Published: December 2022

Changing patterns of weather and climate are limiting breeders’ ability to conduct trials in the same environments in which their released varieties will be grown 7-10 years later. Flowering time plays a crucial role in determining regional adaptation, and mismatch between flowering time and environment can substantially impair yield. Different approaches based on genetic markers or gene expression can be used to predict flowering time before conducting large scale field evaluation and phenotyping. The more accurate prediction of a trait using genetic markers could be hindered due to all the intermediate steps (i.e. transcription, translation, epigenetic modification, and epistasis among others) connecting the trait and their genetic basics. The use of some intermediate steps as predictors could improve the accuracy of the model. Here, we are using two public gene expression (RNA-Seq) data-sets from 14-day-old-maize-seedling roots and whole-seedling tissue at v1 stage (10 day after planting) for which flowering data (days to anthesis and days to silking expressed in growing degree days) and genetic markers were also available to test the predictability of flowering time. In total, 20 different combinations between phenotypic and gene expression data-sets were evaluated. To explore prediction accuracy a random forest model was trained with the expression values of 44,303 gene models hosted in the current B73 maize reference version 5 and then the feature importance was scored based on the decrease in root mean squared error. Later several random forest models with different subsets of the most important features (genes) were trained, and this process was repeated ten times. Results from these analyses show a curve in the prediction accuracy, with an increase in the prediction accuracy as the top most important genes were added. The maximum accuracy was attained when 500 genes for whole-seedling and 100 genes for root gene expression data were used in the analysis, and thereafter adding more genes lead to a decrease in the prediction accuracy. The highest prediction accuracy using the top-most important genes was higher than that of using randomly selected whole-genome 400,000 SNPs. Finally, we described the genes controlling flowering time by looking at the most important genes in the Random forest model with the expression data from all genes. We further found MADS-transcription factor 69 (Mads69) using whole-seedling gene expression and the MADS-transcription factor 67 (Mads67) using root gene expression data, both genes previously described with effect on flowering time. Here, we aim to demonstrate the potential of selecting and using the expression of most informative genes to predict a complex trait, also to demonstrate the robustness and limitations of this analysis by using phenotypic data-sets from different environments.
Bayesian uncertainty quantification to identify population level vaccine hesitancy behaviours
Authors: Warne David J. , Varghese Abhishek , Browning Alexander P. , Krell Mario M. , Drovandi Christopher , Hu Wenbiao , Mira Antonietta , Mengersen Kerrie , Jenner Adrianne L.
Published: December 2022

When effective vaccines are available, vaccination programs are typically one of the best defences against the spread of an infectious disease. Unfortunately, vaccination rates may be suboptimal for a prolonged duration as a result of slow uptake of vaccines by the public. Key factors driving slow vaccination uptake can be a complex interaction of vaccine roll-out policies and logistics, and vaccine hesitancy behaviours potentially caused by an inflated sense of risk in adverse reactions in some populations or community complacency in communities that have not yet experienced a large outbreak. In the recent COVID-19 pandemic, public health responses around the world began to include vaccination programs from late 2020 to early 2021 with an aim of relaxing non-pharmaceutical interventions such as lockdowns and travel restrictions. For many jurisdictions there have been challenges in getting vaccination rates high enough to enable the relaxation of restrictions based on non-pharmaceutical interventions. A key concern during this time was vaccine hestitancy behaviours potentially caused by vaccine safety concerns fuelled by misinformation and community complacency in jurisdictions that had seen very low COVID-19 case numbers throughout 2020, such as Australia and New Zealand. We develop a novel stochastic epidemiological model of COVID-19 transmission that incorporates changes in population behaviour relating to responses based on non-pharmaceutical interventions and community vaccine uptake as functions of the reported COVID-19 cases, deaths, and vaccination rates. Through a simulation study, we develop a Bayesian analysis approach to demonstrate that different factors inhibiting the uptake of vaccines by the population can be isolated despite key model parameters being subject to substantial uncertainty. In particular, we are able to identify the presence of vaccine hesitancy in a population using reported case, death and vaccination count data alone. Furthermore, our approach provides insight as to whether the dominant concerns driving hesitancy are related to vaccine safety or complacency. While our simulation study is inspired by the COVID-19 pandemic, our tools and techniques are general and could be enable vaccination programs of various infectious diseases to be adapted rapidly in response to community behaviours moving forward into the future.
ReIGNITE RT Boost: An international study testing the accuracy and feasibility of using restriction spectrum imaging (RSI) MRI to guide intraprostatic tumor target volume for radiotherapy boost
Authors: Lui Asona J. , Kallis Karoline , Zhong Allison Y. , Hussain Troy S. , Conlin Christopher , Digma Leonardino A. , Phan Nikki , Mathews Ian T. , Do Deondre D. , Rojo Mariluz , Karunamuni Roshan , Kuperman Joshua , Dale Anders M. , Rakow-Penner Rebecca , Hahn Michael E. , Seibert Tyler M.
Published: December 2022

In a phase III randomized trial, adding a radiation boost to visible tumor(s) on MRI improved prostate cancer disease-free and metastasis-free survival without additional toxicity. However, radiation oncologists’ ability to identify prostate tumors is critical and represents a major barrier to widely adopting intraprostatic tumor radiotherapy boost for patients. We previously developed a quantitative diffusion MRI biomarker for prostate cancer, called the Restriction Spectrum Imaging restriction score (RSIrs), that has been shown to improve radiologist identification of clinically significant prostate cancer.

42 radiation oncologists (participants) from multiple, international institutions contoured prostate tumors on 40 patient cases using standard MRI with or without RSIrs map, producing 1646 target volumes. Use of RSIrs maps significantly improved all evaluated accuracy metrics, including participants’ percent overlap with consensus expert target volume (73% vs. 42%, p<0.001). A mixed effects model confirmed that RSIrs maps were the main variable driving the improvement in all metrics. System Usability Scores indicated RSIrs maps significantly improved the contouring experience (72 vs. 58, p<0.002). The expert-defined tumor was completely missed 158 times on standard MRI alone and only 19 times with RSIrs maps. RSIrs maps improve the accuracy of target delineation for prostate tumor boost.

Patient Summary

Adding an extra boost of radiation to tumor(s) visible on MRI has been shown to prevent cancer recurrence and cancer spread beyond the prostate without adding additional side effects; however, drawing the prostate tumor on MRI is difficult, and most radiation oncologists have not been trained to do this. We have developed an advanced MRI technique (RSIrs maps) that increases tumor visibility. We found that RSIrs maps improve radiation oncologists’ accuracy in targeting prostate tumors.
NAD+ biosynthesis as a collateral lethality target for precision oncology
Authors: Muller Florian L. , Deng Pingna , Lin Yu-Hsi , Satani Nikunj , Hammoudi Naima , Mohapatra Gayatry , Asara John M. , DePinho Ronald A.
Published: December 2022

Genomic deletion of tumor suppressor genes (TSG) often encompasses neighboring genes which may be members of multi-gene families encoding cell essential functions. These genomic events create targetable cancer-specific vulnerabilities, termed “collateral lethality” as illustrated by homozygous deletion of the glycolytic geneENO1, which sensitizes glioblastoma (GBM) cells to inhibition of its paralogENO2. Here, we sought to generalize the concept by validating a second multi-gene family in an unrelated metabolic pathway. Nicotinamide-nucleotide adenylyltransferase (NMNAT) is an essential and (unlike the more extensively studied NAMPT) non-bypassable step in NAD biosynthesis encoded by three paralogs, one of which,NMNAT1, is homozygously deleted as part of the 1p36 tumor suppressor locus in TCGA data of GBM, Cholangiocarcinoma and Hepatocellular carcinoma (with near zero expression of found in several other malignancies). In a glioma cell line (Gli56) with homozygous deletion ofNMNAT1expressing NMNAT2 and NMNAT3, shRNA-mediated knockdown of NMNAT2 is selectively toxic to Gli56NMNAT1-deleted but not ectopically rescued cells. As NMNAT1 and NMNAT2 are predominantly localized in the nucleus and cytosol, respectively, these data suggest a functionally common pool of cytosolic and nuclear NAD+. Inducible shRNA-mediated extinction of NMNAT2 decreases NAD+ levels and selectively killsNMNAT1-deleted, but notNMNAT1-rescued cellsin vitroand eradicates intracranial tumorsin vivo. Thus, collateral lethality is a generalizable framework for the development of new classes of targeted agents with an informed clinical development path in cancer.

Statement of significance

An ongoing challenge in precision oncology is the translation of genomic data into actionable therapeutic opportunities with clear clinical benefit. We have demonstrated that genes homozygously deleted by virtue of chromosomal proximity to major tumor suppressor genes can confer cancer-specific vulnerabilities, termed “collateral lethality”. While our previous work validated one such collateral lethality target in glycolysis, we now provide empiricalin vitroandin vivoevidence that this concept applies to another deleted gene governing an altogether distinct biochemical pathway. The generalization of collateral lethality may expand the spectrum of molecular targets in cancer with a genomically-informed path for accurate clinical development.
Spatial transcriptome profiling ofin vitro3D tumouroids to study tumour-stroma interactions
Authors: Bakkalci Deniz , Al-Badri Georgina , Yang Wei , Nam Andy , Liang Yan , Khurram Syed Ali , Heavey Susan , Fedele Stefano , Cheema Umber
Published: December 2022

Bioengineering facets of the tumour microenvironment (TME) are essential in 3D tissue models to accurately recapitulate tumour progression. Stromal cells are key components of the TME and their incorporation into 3D biomimetic bioengineered tumour-stroma models is essential to be able to mimic the TME. By engineering tumouroids with distinct tumour and stromal compartments, it has been possible to identify how gene expression is altered by the presence of different stromal cells using spatial transcriptomics. Ameloblastoma is a benign epithelial tumour of the jawbone and in engineered multi-compartment tumouroids increased expression of oncogenes was found where osteoblasts (bone stroma) were present. Engineering a gingival fibroblast stroma resulted in increased matrix remodelling genes in the ameloblastoma tumour. This study provides evidence to show the stromal specific effect on tumour behaviour and illustrates the importance of engineering biologically relevant stroma for engineered tumour models. Our novel results show that an engineered fibroblast stroma causes the upregulation of matrix remodelling genes in ameloblastoma which directly correlates to measured invasion in the model. In contrast the presence of an osteoblast/bone stroma increases the expression of oncogenes by ameloblastoma cells.
First fully-automated AI/ML virtual screening cascade implemented at a drug discovery centre in Africa
Authors: Turon Gemma , Hlozek Jason , Woodland John G. , Chibale Kelly , Duran-Frigola Miquel
Published: December 2022

We present ZairaChem, an artificial intelligence (AI)- and machine learning (ML)-based tool to train small-molecule activity prediction models. ZairaChem is fully automated, requires low computational resources and works across a broad spectrum of datasets, ranging from whole-cell growth inhibition assays to drug metabolism properties. The tool has been implemented end-to-end at the Holistic Drug Discovery and Development (H3D) Centre, the leading integrated drug discovery unit in Africa, at which no prior AI/ML capabilities were available. We have exploited in-house data collected from over a decade of drug discovery research in malaria and tuberculosis and built models to predict the outcomes of 15 key checkpoint assays. We subsequently deployed these models as a virtual screening cascade at an organisational scale to increase the hit rate of current experimental assays. We show how computational profiling of compounds, prior to synthesis and experimental testing, can increase the rate of progression by up to 40%. Moreover, we demonstrate that the approach can be applied to prioritise small molecules within a chemical series and to assess the likelihood of success of novel chemotypes, promoting efficient usage of limited experimental resources. This project is part of a first-of-its-kind collaboration between the H3D Centre, a research centre operating in a low-resource setting, and the Ersilia Open Source Initiative, a young tech non-profit devoted to building data science capacity in the Global South.
The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy
Authors: Ahrenfeldt J , Christensen D. S. , Østergaard A. B. , Kisistók J. , Sokac M. , Birkbak N. J.
Published: December 2022

Immunotherapy has revolutionised cancer treatment. However, not all cancer patients benefit, and current stratification strategies based primarily on PD1 status and mutation burden is far from perfect. We hypothesised that high activation of an innate response relative to the adaptive response may prevent proper tumour neoantigen identification and decrease the specific anticancer response, both in the presence and absence of immunotherapy. To investigate this, we obtained transcriptomic data from three large publicly available cancer datasets, the Cancer Genome Atlas (TCGA), the Hartwig Medical Foundation (HMF), and a recently published cohort of metastatic bladder cancer patients treated with immunotherapy.

To analyse immune infiltration into bulk tumours, we developed an RNAseq-based model based on previously published definitions to estimate the overall level of infiltrating innate and adaptive immune cells from bulk tumour RNAseq data. From these, the adaptive-to-innate immune ratio (A/I ratio) was defined.

A meta-analysis of 32 cancer types from TCGA overall showed improved overall survival in patients with an A/I ratio above median (Hazard ratio (HR) females 0.73, HR males 0.86, P < 0.05). Of particular interest, we found that the association was different for males and females for eight cancer types, demonstrating a gender bias in the relative balance of the infiltration of innate and adaptive immune cells. For patients with metastatic disease, we found that responders to immunotherapy had a significantly higher A/I ratio than non-responders in HMF (P = 0.036) and a significantly higher ratio in complete responders in a separate metastatic bladder cancer dataset (P = 0.022).

Overall, the adaptive-to-innate immune ratio seems to define separate states of immune activation, likely linked to fundamental immunological reactions to cancer. This ratio was associated with improved prognosis and improved response to immunotherapy, demonstrating potential relevance to patient stratification. Furthermore, by demonstrating a significant difference between males and females that associates with response, we highlight an important gender bias which likely has direct clinical relevance.
Enhanced survival and low proliferation marks multifunctional virus specific memory CD4 T cells
Authors: Westerhof Lotus M , Noonan Jonathan , Hargrave Kerrie E , Chimbayo Elizabeth T , Cheng Zhiling , Purnell Thomas , Jackson Mark R , Borcherding Nicholas , MacLeod Megan KL
Published: December 2022

Cytokine production by memory T cells is a key mechanism of T cell mediated protection. However, we have a limited understanding of the survival and secondary responses of memory T cells with cytokine producing capacities. We interrogate antigen-specific CD4 T cells using a mouse influenza A virus infection model. CD4 T cells with the capacity to produce cytokines survive better than non-cytokine+ cells, displaying a low fold contraction and expressing high levels of pro-survival molecules, CD127 and Bcl2. Transcriptomic analysis reveals a heterogenous population of memory CD4 T cells with three clusters of cytokine+ cells. These clusters match flow cytometry data revealing an enhanced survival signature in cells capable of producing multiple cytokines. These multifunctional cells are, however, less likely to proliferate during and following primary and secondary infections. Despite this, multifunctional memory T cells form a substantial fraction of the secondary memory pool, indicating that survival rather than proliferation may dictate which populations survive within the memory pool.
Bimodal 1/fnoise and anticorrelation between DNA-Water and DNA-Ion energy fluctuations
Authors: Mukherjee Saumyak , Mondal Sayantan , Bagchi Biman
Published: December 2022

Coupling between the fluctuations of DNA and its surroundings consisting of water and ions in solution remains poorly understood and relatively less investigated as compared to proteins. Here, with the help of molecular dynamics simulations and statistical mechanical analyses, we explore the dynamical coupling between DNA, water, and counterions through correlations among respective energy fluctuations in both double (ds-) and single-stranded (ss-) DNA solutions. Fluctuations in the collective DNA-Water and DNA-Ion interaction energies are found to be strongly anti-correlated across all the systems. The fluctuations of DNA self-energy, however, are weakly coupled to DNA-water and DNA-ion interactions in ds-DNA. An enhancement of the DNA-water coupling is observed in ss-DNA, where the system is less rigid. All the interaction energies exhibit 1/fnoise in their energy power spectra with surprisingly prominent bimodality in the DNA-water and DNA-ion fluctuations. The nature of the energy spectra appears to be indifferent to the relative rigidity of the DNA. We discuss the role of the observed correlations in ion-water motions on a DNA duplex in the experimentally observed anomalous slow dielectric relaxation and solvation dynamics, and in furthering our understanding of the DNA energy landscape.

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Local Generation and Efficient Evaluation of Numerous Drug Combinations in a Single Sample
Authors: Elgart Vlad , Loscalzo Joseph
Published: December 2022

We develop a method that allows one to test a large number of drug combinations in a single cell culture sample. We rely on randomness of drug uptake in individual cells as a tool to create and encode drug treatment regimens. A single sample containing thousands of cells is treated with a combination of fluorescently barcoded drugs. We create independent transient drug gradients across the cell culture sample to produce heterogeneouslocaldrug combinations. After incubation period, the ensuing phenotype and corresponding drug barcodes for each cell are recorded. We use these data for statistical prediction of the response to the drugs treatment in a macroscopic population of cells. To further application of this technology, we developed a fluorescent barcoding method that does not require any chemical drug(s) modifications. We also developed segmentation-free image analysis capable of handling large optical fields containing thousands of cells in the sample, even in confluent growth condition. The technology necessary to execute our method is readily available in most biological laboratories, does not require robotic or microfluidic devices, and dramatically reduces resource needs and resulting costs of the traditional high-throughput studies.
MIDAS: a deep generative model for mosaic integration and knowledge transfer of single-cell multimodal data
Authors: He Zhen , Chen Yaowen , Hu Shuofeng , An Sijing , Shi Junfeng , Liu Runyan , Zhou Jiahao , Dong Guohua , Shi Jinhui , Zhao Jiaxin , Wang Jing , Zhu Yuan , Ou-Yang Le , Bo Xiaochen , Ying Xiaomin
Published: December 2022

Abstract

Rapidly developing single-cell multi-omics sequencing technologies generate increasingly large bodies of multimodal data. Integrating multimodal data from different sequencing technologies,i.e. mosaic data, permits larger-scale investigation with more modalities and can help to better reveal cellular heterogeneity. However, mosaic integration involves major challenges, particularly regarding modality alignment and batch effect removal. Here we present a deep probabilistic framework for the mosaic integration and knowledge transfer (MIDAS) of single-cell multimodal data. MIDAS simultaneously achieves dimensionality reduction, imputation, and batch correction of mosaic data by employing self-supervised modality alignment and information-theoretic latent disentanglement. We demonstrate its superiority to other methods and reliability by evaluating its performance in full trimodal integration and various mosaic tasks. We also constructed a single-cell trimodal atlas of human peripheral blood mononuclear cells (PBMCs), and tailored transfer learning and reciprocal reference mapping schemes to enable flexible and accurate knowledge transfer from the atlas to new data. Applications in mosaic integration, pseudotime analysis, and cross-tissue knowledge transfer on bone marrow mosaic datasets demonstrate the versatility and superiority of MIDAS.
Hydrogel mechanics regulate fibroblast DNA methylation and chromatin condensation
Authors: Sumey Jenna L. , Johnston Peyton C. , Harrell Abigail M. , Caliari Steven R.
Published: December 2022

Cellular mechanotransduction plays a central role in fibroblast activation during fibrotic disease progression, leading to increased tissue stiffness and reduced organ function. While the role of epigenetics in disease mechanotransduction has begun to be appreciated, there is little known about how substrate mechanics, particularly the timing of mechanical inputs, regulate epigenetic changes such as DNA methylation and chromatin reorganization during fibroblast activation. In this work, we engineered a hyaluronic acid hydrogel platform with independently tunable stiffness and viscoelasticity to model normal (storage modulus, G’ ∼ 0.5 kPa, loss modulus, G’’ ∼ 0.05 kPa) to increasingly fibrotic (G’ ∼ 3.5 and 8 kPa, G’’ ∼ 0.05 kPa) lung mechanics. Human lung fibroblasts exhibited increased spreading and nuclear localization of myocardin-related transcription factor A (MRTF-A) with increasing substrate stiffness within 1 day, with these trends holding steady for longer cultures. However, fibroblasts displayed time-dependent changes in global DNA methylation and chromatin organization. Fibroblasts initially displayed increased DNA methylation and chromatin decondensation on stiffer hydrogels, but both of these measures decreased with longer culture times. To investigate how culture time affected the responsiveness of fibroblast nuclear remodeling to mechanical signals, we engineered hydrogels amenable toin situsecondary crosslinking, enabling a transition from a compliant substrate mimicking normal tissue to a stiffer substrate resembling fibrotic tissue. When stiffening was initiated after only 1 day of culture, fibroblasts rapidly responded and displayed increased DNA methylation and chromatin decondensation, similar to fibroblasts on static stiffer hydrogels. Conversely, when fibroblasts experienced later stiffening at day 7, they showed no changes in DNA methylation and chromatin condensation, suggesting the induction of a persistent fibroblast phenotype. These results highlight the time-dependent nuclear changes associated with fibroblast activation in response to dynamic mechanical perturbations and may provide mechanisms to target for controlling fibroblast activation.
A cross-sectional survey of material deprivation and suicide-related ideation among Vietnamese technical interns in Japan in 2021
Authors: Yamashita Tadashi , Quy Pham Nguyen , Yamada Chika , Nogami Emi , Seto-Suh Erina , Iwamoto Saori , Kato Kenji
Published: December 2022

Background

Many technical intern trainees in Japan are economically impoverished because of the need to send money back to their home country, debts from the intermediaries that arranged their arrival in Japan, and reduced working hours because of the coronavirus disease 2019 (COVID-19) pandemic. In addition, there is concern that COVID-19 may cause mental instability in response to the life changes experienced by interns. The purpose of this study was to elucidate the experience of material deprivation and the relationship between the state of material deprivation and suicidal ideation among Vietnamese intern trainees in Japan.

Methods

A cross-sectional study was conducted from September to October 2021. Of 310 Vietnamese technical intern trainees who responded, we analyzed data from 200 individuals with no missing or abnormal values. The questionnaire obtained information about gender, age, length of residence in Japan, Japanese language proficiency, changes in income related to the COVID-19 pandemic, material deprivation status, and suicidal ideation. The ninth item of the Patient Health Questionnaire-9 was used to examine suicidal ideation. Logistic regression analysis was used to analyze the relationship between material deprivation items and suicidal ideation.

Results

Respondents’ mean age was 26.0 ± 5.1 years, and 62.0% (n = 124) were male. Regarding material deprivation items, food was reported in 82 (41.0%) cases, cellphone bills were reported in 49 (24.5%) cases, and medical expenses were reported in 34 (22.0%) cases. Forty-six (23.0%) respondents reported experiencing suicidal ideation, and the prevalence was associated with age (p = 0.031, odds ratio [OR] = 0.889, 95% confidence interval [CI] = 0.799–0.990), deprivation regarding food expenses (p = 0.003, OR = 3.897, 95% CI = 1.597–9.511), and deprivation regarding cellphone usage (p = 0.021, OR = 3.671, 95% CI = 1.217–11.075).

Conclusions

Vietnamese technical intern trainees in Japan experienced material deprivation in multiple ways, and exhibited a high prevalence of serious psychological problems. Factors contributing to suicidal ideation included age, experience of deprivation in relation to food expenses, and deprivation in relation to cellphone bills. Inability to pay cellphone bills may have increased isolation among Vietnamese trainees during the COVID-19 pandemic.
Pantothenate auxotrophy in a naturally occurring biocontrol yeast
Authors: Rueda-Mejia Maria Paula , Ortiz-Merino Raúl A. , Lutz Stefanie , Ahrens Christian H. , Künzler Markus , Freimoser Florian M.
Published: December 2022

The genusHanseniasporais characterized by some of the smallest genomes among budding yeasts. These fungi are primarily found on plant surfaces and in fermented products and represent promising biocontrol agents against notorious fungal plant pathogens. In this work, we identify aHanseniaspora meyeriisolate that shows strong antagonism against the plant pathogenFusarium oxysporumas a pantothenate auxotroph. Furthermore, strong biocontrol activityin vitrorequired both pantothenate and biotin in the growth medium. We show that theH. meyeriisolate APC 12.1 can obtain the vitamin from plants and other fungi. The underlying reason for the auxotrophy is the lack of key pantothenate biosynthesis genes, but at least six genes encoding putative pantothenate transporters are present in the genome. By constructing and using aSaccharomyces cerevisiaereporter strain, we identified oneHanseniasporatransporter, out of the six candidate proteins, that conferred pantothenate uptake activity toS. cerevisiae. Pantothenate auxotrophy is rare and has only been described in a few bacteria and inS. cerevisiaestrains that were isolated from sake. Such auxotrophic strains may seem an unexpected and unlikely choice as potential biocontrol agents, but they may be particularly competitive in their ecological niche and their specific growth requirements are an inherent biocontainment strategy preventing uncontrolled growth in the environment. Auxotrophic strains such as theH. meyeriisolate APC 12.1 may thus represent a new strategy for developing biocontrol agents that will be easier to register than prototrophic strains, which are normally used for such applications.

Significance Statement

As a precursor of the essential coenzyme CoA, pantothenate is present in all organisms. Plants, bacteria and fungi are known to synthesize this vitamin, while animals must obtain it through their diet. Pantothenate auxotrophy has not been described in naturally occurring, environmental fungi and is an unexpected property for an antagonistic yeast. Here, we report that yeasts from the genusHanseniasporalack key enzymes for pantothenate biosynthesis and identify a transporter responsible for the acquisition of pantothenate from the environment.Hanseniasporaisolates are strong antagonists of fungal plant pathogens. Their pantothenate auxotrophy is a natural biocontainment feature that could make such isolates interesting candidates for new biocontrol approaches and allow easier registration as plant protection agents compared to prototrophic strains.
Differential adenine methylation analysis reveals increased variability in 6mA in the absence of methyl-directed mismatch repair
Authors: Stone Carl J. , Boyer Gwyneth F. , Behringer Megan G
Published: December 2022

Methylated DNA adenines (6mA) are an important epigenetic modification in bacteria that affect varied cell processes like replication, stress response, and pathogenesis. While much work has been done characterizing the influence of 6mA on specific loci, very few studies have examined the evolutionary dynamics of 6mA over long time scales. Utilizing third-generation sequencing technology, we produced a detailed analysis of 6mA methylation across theEscherichia coliK-12 substr. MG1655 genome. 6mA levels were consistently high across GATC sites; however, we identified regions where 6mA is decreased, particularly in intergenic regions, especially around the -35 promoter element, and within cryptic prophages and IS elements. We further examined 6mA in WT and methyl-directed mismatch repair-knockout (MMR-) populations after 2400 generations of experimental evolution. We find that, after evolution, MMR-populations acquire significantly more epimutations resulting in a genome-wide decrease in 6mA methylation. Here, clones from evolved MMR-populations display non-deterministic sets of epimutations, consistent with reduced selection on these modifications. Thus, we show that characterization of 6mA in bacterial populations is complementary to genetic sequencing and informative for molecular evolution.
Cataloging Viral Diversity from Nonaxenic Terrestrial Cyanobacteria Cultures
Authors: Ettinger Cassandra L. , Paul Sudipto R. , Flores Neptali , Ward Ryan D. , Pietrasiak Nicole , Stajich Jason E.
Published: December 2022

Viruses are exceedingly common, but little is known about their diversity let alone how they behave in extreme environments, and whether viruses facilitate adaptation of their hosts to harsh conditions. To set a foundation for understanding of these understudied viral-host interactions, we created a catalog of viruses through analysis of metagenomes from 50 unialgal but nonaxenic Cyanobacteria cultures with 47 cultures isolated from various terrestrial habitats, including desert soil and rock surfaces, tropical soil, and vernal pools. These cultures represent low diversity microbial consortia dominated by the terrestrial Cyanobacteria and its associated cyanosphere microbiome containing heterotrophic microbes. We identified viral sequences in metagenomes, grouped these into viral operational taxonomic units (vOTUs) and then placed vOTUs into viral clusters (VCs). We also calculated vOTU relative abundance and predicted possible bacterial hosts. In total we predicted 814 viral sequences representing 726 vOTUs. We assigned putative taxonomy to 72 of the 814 putative viral sequences; these were distributed into 15 VCs — mostly assigned to the recently abolished Caudovirales order (now Caudoviricetes class) of viruses. We found that nonaxenic cultures were dominated by unclassified and unclustered viral sequences. Furthermore, we predicted putative bacterial hosts for 211 vOTUs, with the majority of viruses predicted to infect a Proteobacteria (now Pseudomonadota) host. Overall, while limited, these results are consistent with the notion that both viruses and Cyanobacteria isolated from extreme environments are underrepresented in reference datasets. This work increases knowledge of viral diversity and sets a foundation for future exploration of viruses associated with terrestrial Cyanobacteria and their heterotroph associates, such as connecting specific viruses to critical cycling processes and investigating their metabolic functions.
DIS3L, cytoplasmic exosome catalytic subunit, is essential for development but not cell viability in mice
Authors: Brouze Michał , Szpila Marcin , Czerwińska Areta , Antczak Wiktor , Mroczek Seweryn , Kuliński Tomasz M. , Hojka-Osińska Anna , Cysewski Dominik , Adamska Dorota , Gruchota Jakub , Borsuk Ewa , Dziembowski Andrzej
Published: December 2022

Among numerous enzymes involved in RNA decay, processive exoribonucleases are the most prominent group responsible for the degradation of the entire RNA molecules. The role of mammalian cytoplasmic 3’-5’ exonuclease DIS3L at the organismal level remained unknown. Herein we established knock-in and knock-out mouse models to study DIS3L functions in mice. DIS3L is indeed a subunit of the cytoplasmic exosome complex, which disruption leads to severe embryo degeneration and death in mice soon after implantation. These changes could not be prevented by supplementing extraembryonic tissue with functional DIS3L through the construction of chimeric embryos. PreimplantationDis3l-/-embryos were unaffected in their morphology and ability to produce functional embryonic stem cells showing that DIS3L is not essential for cell viability. There were also no major changes in the transcriptome level for both embryonic stem cells and blastocysts, as revealed by RNA sequencing experiments. Notably, however, DIS3L knock-out led to inhibition of the global protein synthesis. These results point to the essential role of DIS3L in mRNA quality control pathways crucial for proper protein synthesis during embryo development.
Nanopore sequencing unveils the complexity of the cold-activated murine brown adipose tissue transcriptome
Authors: Engelhard Christoph Andreas , Khani Sajjad , Derdak Sophia , Bilban Martin , Kornfeld Jan-Wilhelm
Published: December 2022

1.

Alternative transcription increases transcriptome complexity by expression of multiple transcripts per gene and thus fine tunes cellular identity and function. Annotation and quantification of transcripts at complex loci using short-read sequencing is non-trivial. Recent long-read sequencing methods such as those from Oxford Nanopore Technologies (ONT) and Pacific Biosciences aim at overcoming these problems by sequencing full length transcripts. Activation of BAT thermogenesis involves major transcriptomic remodelling and positively affects metabolism via increased energy expenditure and endocrine factors. Here we comprehensively benchmark features of ONT long-read sequencing protocols compared to Illumina shortread sequencing assessing alignment characteristics, gene and transcript detection and quantification, differential gene and transcript expression, transcriptome reannotation and differential transcript usage (DTU). We find that ONT sequencing is superior to Illumina for transcriptome reassembly and reduces the risk of false-positive events due to the ability to unambiguously map reads to transcripts, at the expense of statistical power for calling differentially expressed features. We identified novel isoforms of genes undergoing DTU in cold-activated BAT including Cars2, Adtrp, Acsl5, Scp2, Aldoa and Pde4d, validated by RT-qPCR. Finally, we provide a reannotation of the murine iBAT transcriptome as a valuable resource for researchers interested in the molecular biology underlying the regulation of BAT.
Inhibition of AMPA receptors bound to transmembrane AMPA receptor regulatory protein γ-8 (TARP γ-8) blunts the positive reinforcing properties of alcohol and sucrose in a brain region-dependent manner
Authors: Hoffman Jessica L , Faccidomo Sara P , Taylor Seth M. , DeMiceli Kristina G. , May Ashley M. , Smith Evan N. , Whindleton Ciarra M. , Hodge Clyde W
Published: December 2022

Rationale

The development and progression of alcohol use disorder (AUD) is widely viewed as maladaptive neuroplasticity. The transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) regulatory protein γ8 (TARP γ-8) is a molecular mechanism of neuroplasticity that has not been evaluated in AUD or other addictions.

Objective

To address this gap in knowledge, we evaluated the mechanistic role of TARP γ-8 bound AMPAR activity in the basolateral amygdala (BLA) and ventral CA3 hippocampus (vHPC) in the positive reinforcing effects of alcohol, which drive repetitive alcohol use throughout the course of AUD, in C57BL/6J mice. These brain regions were selected because they exhibit high levels of TARP γ-8 expression and send glutamate projections to the nucleus accumbens (NAc), which is a key nucleus in the brain reward pathway.

Methods and Results

Site-specific pharmacological inhibition of AMPARs bound to TARP γ-8 in the BLA via bilateral infusion of the selective negative modulator JNJ-55511118 significantly decreased operant alcohol self-administration with no effect on sucrose self-administration in behavior-matched controls. Temporal analysis showed that reduction of alcohol-reinforced responding occurred >25 min after the onset of responding, consistent with a blunting of the positive reinforcing effects of alcohol in the absence of nonspecific behavioral effects. In contrast, inhibition of TARP γ-8 bound AMPARs in the vHPC selectively decreased sucrose self-administration with no effect on alcohol.

Conclusions

This study reveals a novel brain region-specific role of TARP γ-8 bound AMPARs as a molecular mechanism of the positive reinforcing effects of alcohol and non-drug rewards.
Impact of supervisor leadership on construction worker safety behavior in China: the moderating role of social capital
Authors: Wu Xiuyu , Qian Qinzhen , Zhang Meng
Published: December 2022

Purpose

Leaders' behavior has a critical impact on workers' safety behavior. However, previous studies have shown contradictive views on the effect of different leadership styles on safety behavior. One reason may be that the effectiveness of leaders' behavior varies according to diverse contexts. This study examines the effect of transformational and transactional leadership (TsL) on the safety behavior of on-site workers under different levels of social capital in construction projects.

Design/methodology/approach

Safety behavior is divided into three types: safety compliance (SC), organizational-oriented safety participation and individual-oriented safety participation (ISP). Questionnaire survey data were collected from 302 construction workers in the Chinese construction industry.

Findings

The results indicate that the positive effect of transformational leadership (TfL) of frontline supervisors on the two types of construction workers' safety participation is enhanced when social capital is high, although TfL has no significant effect on SC behavior. In contrast, TsL can promote construction workers' SC behavior and organizational-oriented safety participation and social capital positively moderating these relationships. TsL has no significant effect on ISP, but its interaction with safety behavior is positively related to ISP.

Research limitations/implications

This study explains the inconsistent findings of previous research related to the role of leadership in safety behavior by introducing the social capitaltheory and distinguishing safety participation into two typesThis study is confined to one specific country, future research may benefit from investigating whether the conclusions of this study will be different in other nations with diverse cultures.

Practical implications

The findings of the study provide frontline supervisors with new insights into improving workers' safety and the efficiency of leadership in safety management.

Originality/value

This study explains the inconsistent findings of previous research related to the role of leadership in safety behavior by introducing the social capital theory and distinguishing safety participation into two types.
Network analysis of comovements among newly-built residential house price indices of seventy Chinese cities
Authors: Xu Xiaojie , Zhang Yun
Published: December 2022

Purpose

Understandings of house prices and their interrelationships have undoubtedly drawn a great amount of attention from various market participants. This study aims to investigate the monthly newly-built residential house price indices of seventy Chinese cities during a 10-year period spanning January 2011–December 2020 for understandings of issues related to their interdependence and synchronizations.

Design/methodology/approach

Analysis here is facilitated through network analysis together with topological and hierarchical characterizations of price comovements.

Findings

This study determines eight sectoral groups of cities whose house price indices are directly connected and the price synchronization within each group is higher than that at the national level, although each shows rather idiosyncratic patterns. Degrees of house price comovements are generally lower starting from 2018 at the national level and for the eight sectoral groups. Similarly, this study finds that the synchronization intensity associated with the house price index of each city generally switches to a lower level starting from early 2019.

Originality/value

Results here should be of use to policy design and analysis aiming at housing market evaluations and monitoring.
Credit constraints in Colombia: evidence from the use of credit cards among low- and middle-income individuals
Authors: Arango Luis E. , Quevedo Ingri K.
Published: December 2022

Purpose

The authors estimate the determinants of the value of purchases of semi-durable goods using permanent and transitory income, and the demographic characteristics of customers. The purpose is to identify whether individuals face remaining liquidity constraints, and how this friction affects their purchases.

Design/methodology/approach

This study uses anonymized data of 516,525 credit card holders, with more than 7,501,065 records of purchases between 2010 and 2015. The authors decompose the income of individuals into permanent and transitory components to test the prevalence of the life cycle–permanent income hypothesis (LC–PIH). Determinants of the value of purchases for constrained and unconstrained consumers are estimated, considering the period in which individual characteristics are valid, the decisions not to make purchases in some months, and the potential endogeneity of the interest rate and the transitory component of income.

Findings

The authors present evidence of liquidity constraints for individuals who have used a high percentage of the credit limit on their cards. For these restricted customers, the value of purchases is inelastic to the interest rate, whereas the response is sizable for customers who are less restricted. The restricted customers increase the value of purchases when faced with increases in their credit limit. The elasticity of the value of purchases of semi-durable goods to permanent income is less than that for transitory income; regardless of the constraints, this still supports the LC–PIH.

Research limitations/implications

This credit card is targeted at low- and middle-income individuals in Bogotá. Although the results might be considered as indicative of the behavior of those with similar characteristics in Colombia, the authors regard this work as the study of a particular case. A limitation of this work is that the authors do not have alternative sources of credit at an individual level.

Practical implications

The broad credit channel of monetary policy does not apply to the restricted customers. This should be considered not only by the monetary authority, to understand the true extent of this policy, but also by the financial institutions that use this business model. The monetary authority should be cautious not to overreact when intervening in the money market to try to prompt an adequate consumer response.

Social implications

Financial institutions have the policy of modifying the credit limits of their customers' credit cards which affects the well-being of restricted customers. Given that the card is aimed at low and middle income individuals, the credit limits of customers who use a high percentage of their credit limit might be increased.

Originality/value

This is the first paper to study liquidity restrictions with a retail credit card in Colombia and Latin America using information on customers' characteristics. The results are highly relevant for the implementation of monetary policy.