bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring
Authors: Yennemadi Anjali S. , Jameson Gráinne , Glass Mary , De Pasquale Carolina , Keane Joseph , Bianchi Massimiliano , Leisching Gina
Published: October 2022

Although clinically effective, the actions of IFNα, either produced endogenously or by therapeutic delivery, remain poorly understood. Emblematic of this research gap is the disparate array of notable side effects that occur in susceptible individuals, such as neuropsychiatric consequences, autoimmune phenomena, and infectious complications. We hypothesised that these complications are driven at least in part by dysregulated cellular metabolism. Male Wistar rats were treated with either 170,000 IU/kg human recombinant IFNα-2a or BSA/saline (0.9% NaCl) three times per week for three weeks. Bone marrow (BM) immune cells were isolated from the excised femurs for glycolytic rate and mitochondrial function assessment using Agilent Seahorse Technology. Frequencies of immune cell populations were assessed by flow cytometry to determine whether leukopoietic changes had occurred in both blood and BM. Plasma levels of lactate and succinate were also determined. BMDMs were metabolically assessed as above, as well as their metabolic response to an antigenic stimulus (iH37Rv). We observed that BM immune cells from IFN-treated rats exhibit a hypermetabolic state (increased basal OCR/GlycoPER) with decreased mitochondrial metabolic respiration and increased non-mitochondrial OCR. Flow cytometry results indicated an increase in immature granulocytes (RP1-SSChi CD45lo) and classical monocytes (CD43lo RP1hi) in the blood, together with increased succinate levels in the plasma. BMDMs from IFN-treated rats retained the hypermetabolic phenotype after differentiation and failed to induce a step-up in glycolysis and mitochondrial respiration after bacterial stimulation. This work provides the first evidence of the effects of IFNα treatment in inducing hypermetabolic immune features that are associated with markers of inflammation, leukopoiesis, and defective responses to bacterial stimulation.
Proteome integral solubility alteration assay combined with multi-criteria decision-making analysis for developing adverse outcome pathways
Authors: Lizano-Fallas Veronica , del Amor Ana Carrasco , Cristobal Susana
Published: October 2022

Understanding the biological impact of chemicals is hindered by the high number and diversity of compounds in the market. To simplify the chemical risk assessment, the adverse outcome pathway (AOP) method has arisen as a framework to predict the impact of chemical exposure on human and environmental health. The development of this predictive tool requires knowledge of the molecular interaction between chemicals and protein targets. Those molecular initiating events connect alterations of cellular function with physiological impairment. This strategy aims to focus on the complex biological interaction to predict the impact on health. The high-throughput identification of all chemical targets can be obtained by a proteomics-based thermal shift assay, however, selecting the priority target candidate is a biased process strongly dependent on expert knowledge and literature. Here, we unravel new molecular initiating event from a tested chemical combining the target deconvolution by the proteome integral solubility alteration (PISA) assay, and the target selection by an analytical hierarchy process (AHP) approach. In the proof-of-concept study, we identified by PISA assay 8 protein targets for 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) from the soluble proteome from hepatic cells containing 2824 proteins. The definition of the AHP approach facilitates the selection of heat shock protein beta-1 (Hspb1) as the most suitable protein for developing AOPs. Our results demonstrated that the process of target identification is independent from a chemical characterization, and that the process of data curation and target selection is less sensitive to lack of toxicological information. We anticipate that this innovative integration of methods could decipher the chemical-protein interactions from new chemicals including the new alternative chemicals designed for chemical replacement and that would discover new molecular initiating events to support more sustainable methodologies to gain time and resources in chemicals assessment.

SYNOPSIS

Our combined methodologies can determine the most suitable target to develop adverse outcome pathways from the proteome-wide protein target identification.
Diverse patterns of secondary structure across genes and transposable elements are associated with siRNA production and epigenetic fate
Authors: Martin Galen , Solares Edwin , Muyle Aline , Bousios Alexandros , Gaut Brandon S.
Published: October 2022

RNA molecules carry information in their primary sequence and also their secondary structure. Secondary structure can confer important functional information, but it is also a potential signal for an RNAi-like host epigenetic response mediated by small interfering RNAs (siRNAs). In this study, we predicted local secondary structures in features of the maize genome, focusing on small regions that had folding energies similar to pre-miRNA loci. We found secondary structures to be common in retrotransposons, inHelitrons, and in genes. These structured regions mapped higher diversities of siRNAs than regions without structure, explaining up to 24% of variation of the siRNA distribution across some TE types. Among genes, those with secondary structure were 1.5-fold more highly expressed, on average, than genes without secondary structure. However, these genes were also more variably expressed across the 26 NAM lines, and this variability correlated with the number of mapping siRNAs. We conclude that local stem-loop structures are a nearly ubiquitous feature of expressed regions of the maize genome, that they correlate with higher siRNA mapping, and that they can represent a trade-off between functional need and the potentially negative consequences of siRNA production.
DISRUPTION OF SYMPATHETIC OUTFLOW TO INTRA-ABDOMINAL ORGANS EMULATES THE METABOLIC EFFECTS OF SLEEVE GASTRECTOMY IN OBESE MICE
Authors: Schwartz Gary J. , Batista Rogerio O. , Lopatinsky Natalie R. , Kraljević Marko , Jiang Caroline S. , Dirnberger Amanda S. , Emiliano Ana B.
Published: October 2022

Although sleeve gastrectomy (SG) is the most commonly performed bariatric surgery in the US, its mechanistic underpinnings have not been fully determined. Thus, we set out to investigate whether SG’s effects on the peripheral sympathetic system could mediate the metabolic effects of SG. The celiac-superior mesenteric ganglia (CSMG) lie juxtaposed to the stomach and supply the sympathetic innervation of the stomach, as well as to numerous intra-abdominal organs relevant to metabolism. Here we investigated the effects of SG on the CSMG. SG led to the degeneration of neurons in the CSMG, as evidenced by chromatolysis, which was not found in control mice. Furthermore, CSMG ablation (CGX) completely recapitulated the glycemic and weight loss effects of SG, promoting weight loss at the expense of fat mass in both males and females. Glycemic improvement was robust in males but much more modest in female mice. Norepinephrine tissue content measurement by high performance liquid chromatography revealed that liver, duodenum, and ileum were organs where both SG and CGX displayed evidence of significant sympathetic denervation. Both SG and CGX were associated with increased levels of glucagon-like peptide 1 (GLP-1) and high free fatty acid content in the stools. In conclusion, CSMG neuronal degeneration caused by SG appears to be a mediator of the metabolic effects of this type of bariatric surgery.
Persistent Homology-based Functional Connectivity Explains Cognitive Ability: Life-span Study
Authors: Ryu Hyunnam , Habeck Christian G. , Stern Yaakov , Lee Seonjoo
Published: October 2022

Brain-segregation attributes in resting-state functional networks have been widely investigated to understand cognition and cognitive aging using various approaches (e.g., average connectivity within/between networks and brain system segregation). While these approaches have assumed that resting-state functional networks operate in a modular structure, a complementary perspective assumes that a core-periphery or rich club structure accounts for brain functions where the hubs are tightly interconnected to each other to allow for integrated processing. We introduce a novel method, persistent homology (PH)-based functional connectivity, to quantify the pattern of information during the integrated processing. We also investigate whether PH-based functional connectivity explains cognitive performance and compare the amount of variability in explaining cognitive performance for three sets of independent variables: (1) PH-based functional connectivity, (2) graph theory-based measures, and (3) brain system segregation. Resting-state functional connectivity data were extracted from 279 healthy participants, and cognitive ability scores were generated in four domains (fluid reasoning, episodic memory, vocabulary, and processing speed). The results first highlight the pattern of brain-information flow over whole brain regions (i.e., integrated processing) accounts for more variance of cognitive abilities than either brain system segregation or the graph theory-based network topology measure. The results also show that fluid reasoning and vocabulary performance significantly decrease as the strength of the additional information flow on functional connectivity with the shortest path increases.
Surface-based Characterization of Gastric Anatomy and Motility using Magnetic Resonance Imaging and Neural Ordinary Differential Equation
Authors: Wang Xiaokai , Cao Jiayue , Han Kuan , Choi Minkyu , She Yushi , Scheven Ulrich , Avci Recep , Du Peng , Cheng Leo K. , Di Natale Madeleine R , Furness John B , Liu Zhongming
Published: October 2022

Gastrointestinal magnetic resonance imaging (MRI) provides rich spatiotemporal data about the volume and movement of the food inside the stomach, but does not directly report on the muscular activity of the stomach itself. Here we describe a novel approach to characterize the motility of the stomach wall that drives the volumetric changes of the gastric content. In this approach, a surface template was used as a deformable model of the stomach wall. A neural ordinary differential equation (ODE) was optimized to model a diffeomorphic flow that ascribed the deformation of the stomach wall to a continuous biomedical process. Driven by this diffeomorphic flow, the surface template of the stomach progressively changes its shape over time or between conditions, while preserving its topology and manifoldness. We tested this approach with MRI data collected from 10 Sprague Dawley rats under a lightly anesthetized condition. Our proposed approach allowed us to characterize gastric anatomy and motility with a surface coordinate system common to every individual. Anatomical and motility features could be characterized for each individual, and then compared and summarized across individuals for group-level analysis. As a result, high-resolution functional maps were generated to reveal the spatial, temporal, and spectral characteristics of muscle activity as well as the coordination of motor events across different gastric regions. The relationship between muscle thickness and gastric motility was also evaluated throughout the entire stomach wall. Such a structure-function relationship was used to delineate two distinctive functional regions of the stomach. These results demonstrate the efficacy of using GI-MRI to measure and model gastric anatomy and function. This approach described herein is expected to enable non-invasive and accurate mapping of gastric motility throughout the entire stomach for both preclinical and clinical studies.
Multi-location trials identify stable high yielding spring bread and durum wheat cultivars in Mexico
Authors: Valenzuela-Antelo Jorge L , Benitez-Riquelme Ignacio , Vargas-Hernandez Mateo , Huerta-Espino Julio , Bentley Alison R , Villaseñor-Mir Hector E , Pinera-Chavez Francisco J
Published: October 2022

Determining the stability and consistency of grain yield performance requires accurate evaluation of genotypes in different environments. In Mexico, annual national spring wheat irrigated trials are conducted to assess elite bread and durum wheat performance in different testing environments (TEs) in the main wheat-growing areas. These trials provide data supporting release of new cultivars and aim to also address Mexican wheat value chain grain needs. In this study we analyzed 30 bread and durum wheat trial results from the 2012/13 and 2013/14 growing cycles conducted across TEs in northwest, north and central Mexico. Environmental variability (location, sowing timing, and irrigation schemes) across the national spring wheat irrigated trials enabled genotype by environment interaction to be effectively evaluated. We identified genotypes with high and stable grain yield across TEs of the wheat-growing areas of Mexico. The bread cultivars Bacorehuis F2015 and Borlaug100 F2014, and the durum cultivars Barobampo C2015, CONASIST C2015 and Anatoly C2011 were high yielding and gave stable performance in most of the TEs. This analysis demonstrates the utility of multi-year, multi-environment testing and analysis to identify improved wheat cultivars to meet wheat production demand in Mexico.
Highly Excretable Gold Supraclusters for TranslatableIn VivoRaman Imaging of Tumors
Authors: Yu Jung Ho , Jeong Myeong Seon , Cruz Emma Olivia , Alam Israt S. , Tumbale Spencer K. , Zlitni Aimen , Lee Song Yeul , Park Yong Il , Ferrara Katherine , Kwon Seung-Hae , Gambhir Sanjiv S. , Rao Jianghong
Published: October 2022

Raman spectroscopy provides excellent specificity forin vivopreclinical imaging through a readout of fingerprint-like spectra. To achieve sufficient sensitivity forin vivoRaman imaging, metallic gold nanoparticles larger than 10 nm were employed to amplify Raman signals via surface-enhanced Raman scattering (SERS). However, the inability to excrete such large gold nanoparticles has restricted the translation of Raman imaging. Here we present Raman-active metallic gold supraclusters that are biodegradable and excretable as nanoclusters. Although the small size of the gold nanocluster building blocks compromises the electromagnetic field enhancement effect, the supraclusters exhibit bright and prominent Raman scattering comparable to that of large gold nanoparticle-based SERS nanotags due to high loading of NIR-resonant Raman dyes and much suppressed fluorescence background by metallic supraclusters. The bright Raman scattering of the supraclusters was pH-responsive, and we successfully performedin vivoRaman imaging of acidic tumors in mice. Furthermore, in contrast to large gold nanoparticles that remain in the liver and spleen, the supraclusters dissociated into small nanoclusters, and 73% of the administered dose to mice was excreted over 4 months. The highly excretable Raman supraclusters demonstrated here offer great potential for clinical applications ofin vivoRaman imaging by replacing non-excretable large gold nanoparticles.
The genome ofLactuca saligna, a wild relative of lettuce, provides insight into non-host resistance to the downy mildewBremia lactucae
Authors: Xiong Wei , Berke Lidija , Michelmore Richard , van Workum Dirk-Jan M. , Becker Frank F.M. , Schijlen Elio , Bakker Linda V. , Peters Sander , van Treuren Rob , Jeuken Marieke , Bouwmeester Klaas , Schranz M. Eric
Published: October 2022

Lactuca salignaL. is a wild relative of cultivated lettuce (Lactuca sativaL.), with which it is partially interfertile. Hybrid progeny suffer from hybrid incompatibilities (HI), resulting in reduced fertility and distorted transmission ratios.Lactuca salignadisplays broad spectrum resistance against lettuce downy mildew caused byBremia lactucaeRegel and is considered a non-host species. This phenomenon of resistance inL. salignais called non-host resistance (NHR). One possible mechanism behind this NHR is through the plant–pathogen interaction triggered by pathogen-recognition receptors, including nucleotide-binding leucin-rich repeats (NLRs) and receptor-like kinases (RLKs). We report a chromosome-level genome assembly ofL. saligna(accession CGN05327), leading to the identification of two large paracentric inversions (>50 Mb) betweenL. salignaandL. sativa. Genome-wide searches delineated the major resistance clusters as regions enriched inNLRs andRLKs. Three of the enriched regions co-locate with previously identified NHR intervals. RNA-seq analysis ofBremiainfected lettuce identified several differentially expressedRLKs in NHR regions. Three tandem wall-associated kinase-encoding genes (WAKs) in the NHR8 interval display particularly high expression changes at an early stage of infection. We proposeRLKs as strong candidate(s) for determinants for the NHR phenotype ofL. saligna.
Biostatistics and its impact on hazard characterization using in vitro developmental neurotoxicity assays
Authors: Keßel Hagen Eike , Masjosthusmann Stefan , Bartmann Kristina , Blum Jonathan , Dönmez Arif , Förster Nils , Klose Jördis , Mosig Axel , Pahl Melanie , Leist Marcel , Scholze Martin , Fritsche Ellen
Published: October 2022

In the field of hazard assessment, Benchmark concentrations (BMC) and their associated uncertainty are of particular interest for regulatory decision making. The BMC estimation consists of various statistical decisions to be made, which depend largely on factors such as experimental design and assay endpoint features. In current data practice, the experimenter is often responsible for the data analysis and therefore relies on statistical software without being aware about the software default settings and how they can impact the outputs of data analysis. To provide more insight into how statistical decision making can influence the outcomes of data analysis and interpretation, we have used case studies on a large dataset produced by a developmental neurotoxicity (DNT) in vitro battery (DNT IVB). Here we focused on the BMC and its confidence interval (CI) estimation, as well as on the final hazard classification. We identified five crucial statistical decisions experimenter have to face during data analysis: choice of replicate averaging, response data normalization, regression modelling, BMC and CI estimation, as well as choice of benchmark response levels. In addition, the strength of our data evaluation platform is the integration of endpoint-specific hazard classifications, including flagging systems for uncertain cases, which none of the so far existing statistical data analysis platforms provide. The insights gained in this study demonstrate how important fit-for-purpose, internationally harmonized and accepted data evaluation and analysis procedures are for an objective hazard classification.
Genetic architecture of behavioural resilience to ocean acidification
Authors: Lehmann Robert , Schunter Celia , Welch Megan J. , Arold Stefan T. , Nilsson Göran E. , Tegner Jesper N. , Munday Philip L. , Ravasi Timothy
Published: October 2022

Genetic variation is essential for adaptation to rapid environmental changes. Identifying genetic variation associated with climate-change related phenotypes is therefore the necessary first step towards predictive models of genomic vulnerability.

Here we used a whole-genome scan to identify candidate genetic variants associated with differences in behavioural resilience to ocean acidification in a coral reef fish. We identified three genomic regions that differ between individuals that are behaviourally tolerant compared with behaviourally sensitive to elevated CO2. These include a dopamine receptor (drd4rs), cadherin related family member 5-like (cdhr5l), Synapse-associated protein 1 (syap1), and GRB2 Associated Regulator of MAPK1 Subtype 2 (garem2), which have previously been found to modify behaviour related to boldness, novelty seeking, and learning in other species, and differ between behaviourally tolerant and sensitive individuals.

Consequently, the identified genes are promising candidates in the search of the genetic underpinnings and adaptive potential of behavioural resilience to ocean acidification in fishes.
A mechanistic insight intoNigella sativamediated anticancer effect on breast cancer through regulation of various miRNAs: Anin vitro&in vivostudy
Authors: Das Shaswati , Ghosh Avijit , Upadhyay Priyanka , Sarker Sushmita , Bhattacharjee Mousumi , Gupta Payal , Ghosh Swatilekha , Chattopadhyay Sreya , Dhar Pubali , Adhikary Arghya
Published: October 2022

Background

Cancer continues to threat the mortal alongside scientific community with its burgeoning grasp. Although efforts have been directed to tame cancer by radiotherapy, photodynamic therapy, chemotherapy it came at a cost of fatal side effects.

Purpose

Plant derived bioactive compounds carries an inevitable advantage of being safer, bioavailable & less toxic compared to contemporary chemotherapeutics. This study analyzed anti-cancerous potential of volatile oil, extracted fromNigella sativa, in-vitro against MDA-MB-231, MCF-7 & in-vivo on tumor growth in mice after successful oral administration.

Study Design

Our strategic approach employed solvent extraction of black seed oil (BSO) to highlight orchestrated use of its potent integrants - TQ, Carvacrol & TA which in modest amounts show anti-cancerous properties compared to their individual treatment.

We attempted to show this cost effective, safe & bioavailable form of dealing with the atrocities of breast cancer by means of MTT, Apoptotic, Western Blot Assays besides Transwell & Wound healing Assay. Reduction in the solid tumour in-vivo & near normalcy restoration of tissue section architecture from the BSO treated tumour sets are indicative of the better anti-tumorigenic potential of BSO.

Methods

BSO’s Solvent extraction was performed followed by its characterization. MTT aided cytotoxicity study of BSO alongside major components in PBMC & cancer cells while its efficacy was presented by flow cytometric ROS analysis, cell cycle arrest & apoptosis assessment. Anti-migratory potential evaluated by Wound Healing, Transwell Migration & Western Blot while the expression study of a wide range of proteins, miRNAs & the in-vivo studies undertaken climaxed the confirmation of the anti-cancerous potential of BSO.

Results

Comparatively reduced concentrations of TQ, TA & Carvacrol in BSO played a synergistic role to enhance apoptotic potential via Caspase 7 & 9, through enhanced ROS & expression of apoptotic family of proteins, miRNAs besides uplifting the anti-migratory perspective by effectively enhancing E-cad & downregulating lamellipodia, filopodia assembly & MMPs in MCF-7 & MDA-MB-231. Similar observations in-vivo outlined the therapeutic potential of BSO.

Conclusion

This study culminates isolation & processing of BSO in a simplified procedure, thereby aiming at a more lucrative paradigm to be accepted in contemporary phytomedicine research.
Transcriptome characterization of the common cockle (Cerastoderma edule) after exposure to aMarteilia cochilliaoutbreak
Authors: Pardo B. G. , Fernández C. , Pampín M. , Blanco A. , Iglesias D. , Cao A. , Carballal M.J. , Villalba A. , Martínez P.
Published: October 2022

The edible cockle (Cerastoderma edule) is a widely cultivated bivalve with relevant ecological value roles and high value for shellfisheries in different European regions. The emergence of new threats, such as the parasiteMarteilia cochillia, has impaired the production and ecosystem of shellfish beds where the parasite was detected. Knowledge of the molecular mechanisms involved in cockle immune response to this parasite is essential to devise strategies for its control. With this aim, a transcriptomic study of the digestive gland (target organ of the parasite) and the whole cockle meat in response toM. cochilliainfection was carried out in heavily impacted area in the Northwest of Spain (Lombos do Ulla, Ria de Arousa). A total of 2079 million raw RNA-seq reads were obtained after filtering and used for annotation of 9049 genes following a conservative bioinformatic pipeline using the chromosome-level cockle genome as reference. Gene expression analysis identified a total of 973 consistent differentially expressed genes (DEGs) between comparisons across a temporal series involving cockles with different degrees of infection. DEGs increased with the level of infection within each temporal sample, but the higher DEGs number were detected when comparing temporal samples. Enrichment analysis of DEGs showed an increased expression of molecular functions related to hydrolase, peptidase activity, carbohydrate binding and active transmembrane transporter activity; cellular components such as extracellular matrix and extracellular regions; and a few biological functions associated with immunity and defence response. This information will be valuable for further studies focused on DEGs and associated SNP markers to develop reliant cockle strains to marteiliosis.
Body temperature rebounds on sea ice and is elevated by mercury contamination in a keystone predator
Authors: Grunst Melissa L. , Grunst Andrea S. , Grémillet David , Sato Akiko , Gentès Sophie , Fort Jérôme
Published: October 2022

Despite overall stability, plasticity in endothermic body temperature (Tb) occurs, which may facilitate maintenance of crucial activities in the face of climate change-related environmental variations. However, this plasticity may be limited by physiological or energetic constraints, which are potentially exacerbated by other environmental stressors. For instance, chemical contamination may elevate energetic costs and have endocrine disrupting effects that undermine thermoregulation. We leveraged advanced biologging techniques to elucidate how Tbvaries with different behavioral states and environmental conditions in a keystone Arctic seabird, the little auk (Alle alle). We additionally evaluated whether mercury (Hg) contamination independently affected Tb, or limited or increased state-dependent changes in Tb. Tbwas highest and relatively invariable when birds were at the colony, and rebounded when birds were resting on sea ice, following declines while foraging (diving) in polar waters. These results suggest that the colony and sea ice function as thermal refuges for little auks. In addition, Tbincreased with ambient temperature and relative humidity across behavioral states, and increased with wind speed when birds were flying. Little auks with higher Hg levels had higher, less variable, Tbacross behaviors and environmental contexts, perhaps reflecting increased metabolic rates linked to detoxification costs. Results provide evidence for environment- and contaminant-related effects on Tb, but not interactive effects between the two, and suggest that loss of sea ice and increased environmental contamination under global change may have serious implications for Tbregulation and energy balance.
L-lactic and 2-ketoglutaric acids, odors from human skin, govern attraction and landing in host-seeking femaleAedes aegyptimosquitoes
Authors: Sumner Benjamin D. , Amos Brogan A. , Bello Jan E. , Cardé Ring T.
Published: October 2022

Aedes aegypti, presented with a source of L-lactic and 2-ketoglutaric acid in a wind-tunnel bioassay, takeoff, fly upwind, and land on the blend at rates comparable those exhibited by mosquitoes presented with a skin odor stimulus. Addition of carbon dioxide decreased takeoff latency but was not required to elicit upwind flight nor landings. Ketoglutaric acid, a recently identified component of human skin odor, combined with lactic acid elicits the full repertoire of mosquito host-seeking behaviors.
Broad-scale factors shaping the ecological niche and geographic distribution ofSpirodela polyrhiza
Authors: Cobos Marlon E. , Peterson A. Townsend
Published: October 2022

The choice of appropriate independent variables to create models characterizing ecological niches of species is of critical importance in distributional ecology. This set of dimensions in which a niche is defined can inform about what factors limit the distributional potential of a species. We used a multistep approach to select relevant variables for modeling the ecological niche of the aquaticSpirodela polyrriza,taking into account variability arising from using distinct algorithms, calibration areas, and spatial resolutions of variables. We found that, even after an initial selection of meaningful variables, the final set of variables selected based on statistical inference varied considerably depending on the combination of algorithm, calibration area, and spatial resolution used. However, variables representing extreme temperatures and dry periods were more consistently selected than others, highlighting their importance in shaping the distribution of this species. Other variables related to seasonality of solar radiation, summer solar radiation, and some soil proxies of nutrients in water, were selected commonly but not as frequently as the ones mentioned above. We suggest that the these later variables are also important to understanding the distributional potential of the species, but that their effects may be less pronounced at the scale at which they are represented for the needs of this type of modeling.
Suppression of vitamin D metabolizing enzyme CYP24A1 provides increased sensitivity to chemotherapeutic drugs in breast cancer
Authors: Kamiya Sakura , Yuna Nakamori , Takasawa Akira , Takasawa Kumi , Kyuno Daisuke , Ono Yusuke , Magara Kazufumi , Osanai Makoto
Published: October 2022

Vitamin D is an essential nutrient for the human body that plays an important role in homeostasis and contributes to cell fate decision including proliferation, differentiation and cell viability. Accumulated epidemiological data suggest a relationship between vitamin D deficiency and carcinogenesis in various organs. However, the underlying mechanism remains to be further clarified. In this study, we showed that vitamin D metabolizing enzyme CYP24A1 promotes the oncogenic property of breast carcinoma cells. In addition, expression of CYP24A1 is elevated in invasive breast carcinoma and decreases the overall survival. Importantly, CYP24A1 suppression significantly enhances cell death sensitivity to two pharmacologically different acting anticancer drugs, cisplatin and gefitinib. The results of our study suggest the possibility of CYP24A1-inhibiting therapy for breast malignancy.
Divergent functions of two clades of flavodoxin in diatoms mitigate oxidative stress and iron limitation
Authors: van Creveld Shiri Graff , Coesel Sacha N. , Blaskowski Stephen , Groussman Ryan D. , Schatz Megan J. , Armbrust E. Virginia
Published: October 2022

Phytoplankton rely on diverse mechanisms to adapt to the decreased iron bioavailability and oxidative stress-inducing conditions of today’s oxygenated oceans, including replacement of the iron-requiring ferredoxin electron shuttle protein with a less-efficient iron-free flavodoxin under iron limiting conditions. And yet, diatoms transcribe flavodoxins in high-iron regions in contrast to other phytoplankton. Here, we show that the two clades of flavodoxins present within diatoms exhibit a functional divergence, with only clade II flavodoxins displaying the canonical role in adaptation to iron limitation. We created CRISPR/Cas9 knock-outs of the clade I flavodoxin from the model diatomThalassiosira pseudonanaand found these cell lines are hypersensitive to oxidative stress, while maintaining a wild-type response to iron limitation. Within natural diatom communities, clade I flavodoxin transcript abundance is regulated over the diel cycle rather than in response to iron availability, whereas clade II transcript abundances increase either in iron-limiting regions or under artificially induced iron-limitation. The observed functional specialization of two flavodoxin variants within diatoms reiterates two major stressors associated with contemporary oceans and illustrates diatom strategies to flourish in diverse aquatic ecosystems.
A developmental program that regulates mammalian organ size offsets evolutionary distance
Authors: Shimamura Yuko , Tanaka Junichi , Kakiuchi Miwako , Sarmah Hemanta , Miura Akihiro , Hwang Youngmin , Sawada Anri , Ninish Zurab , Yamada Kazuhiko , Cai James J. , Mori Munemasa
Published: October 2022

Pigs are evolutionarily more distant from humans than mice, but their physiological organs are closest to humans. The molecular program leading to a more than 1,000-fold increase in organ size in pigs and humans over that of mice across evolution has not been elucidated. We generated large-scale transcriptional landscapes throughout swine lung development. Our cross-species single-cell molecular atlas let us discover swine progenitor identities, stage-specific markers, and a core organ-size regulation program (COSRP), well-conserved in swine and humans but less so in mice. Across eight mammalian species, human COSRP promoters showed higher homologies to evolutionary-distant large animals, including pigs, than evolutionary-close small animals. Our study provides a molecular foundation during swine lung development that unveils animal size regulation conserved in the COSRP promoter, independent of genome-wide evolution. COSRP is a critical paradigm for studying thousands-fold changes in biological sizes in evolution, development, cancer, zoology, respirology, organoids, and biotechnology, particularly human-compatible organ generation.

One Sentence Summary

A cross-species developmental molecular atlas identified the indicator of lung and animal size beyond evolution
Hymenoptera (Insecta) telomerase RNAs switched to plant/ciliate-like biogenesis
Authors: Fajkus Petr , Adamik Matej , Nelson Andrew D.L. , Kilar Agata M. , Franek Michal , Bubenik Michal , Capkova Radmila Frydrychova , Votavova Alena , Sykorova Eva , Fajkus Jiri , Peska Vratislav
Published: October 2022

In contrast to the catalytic subunit of telomerase, its RNA subunit (TR) is highly divergent in size, sequence and biogenesis pathways across eukaryotes. Current views on TR evolution assume a common origin of TRs transcribed with RNA polymerase II in Opisthokonta (the supergroup including Animalia and Fungi) and Trypanosomida on one hand, and TRs transcribed with RNA polymerase III under the control of type 3 promoter, found in TSAR and Archaeplastida supergroups (including e.g., ciliates and Viridiplantae taxa, respectively). Here we focus on unknown TRs in one of the largest Animalia order - Hymenoptera (Arthropoda) with more than 300 available representative genomes. Using a combination of bioinformatic and experimental approaches, we identify their TRs. In contrast to the presumed type of TRs (H/ACA box snoRNAs transcribed with RNA Polymerase II) corresponding to their phylogenetic position, we find here short TRs of the snRNA type, likely transcribed with RNA polymerase III under the control of the type 3 promoter. The newly described insect TRs thus question the hitherto assumed monophyletic origin of TRs across Animalia and point to an evolutionary switch in TR type and biogenesis that was associated with the divergence of Arthropods.

Graphical abstract
Using a Bayesian network model to predict effects of pesticides on aquatic community endpoints in a rice field – A southern European case study
Authors: Mentzel Sophie , Martínez-Megías Claudia , Grung Merete , Rico Andreu , Tollefsen Knut Erik , Van den Brink Paul J. , Moe S. Jannicke
Published: October 2022

In recent years, Bayesian network (BN) models have become more popular as a tool to support probabilistic environmental risk assessments (ERA). They can better account for and communicate uncertainty compared to the deterministic approaches currently used in traditional ERA. In this study, we used the BN as a meta-model to predict the potential effect of various pesticides on different biological levels in the aquatic ecosystem. The meta-model links the inputs and outputs of a process-based exposure model (RICEWQ), that is run with various scenarios combination built on meteorological, hydrological, and agricultural scenarios, and a probabilistic case-based effect model (PERPEST), which bases its prediction on a database of microcosm and mesocosm experiments. The research focused on the pesticide exposure in rice fields surrounding a Spanish Natural Park, considering three selected pesticides for this case study: acetamiprid (insecticide), MCPA (herbicide), and azoxystrobin (fungicide). For each of the pesticide types, the developed BN model enabled the prediction of their effects on biological endpoints, endpoint groups, and community in an aquatic ecosystem. Also, it enables comparison between the different pesticide types, their effects on endpoint groups and community. While directly linking future scenarios of climate and agricultural practice to the exposure concentration and indirectly linking them to the effect on biological endpoints as well as community. In summary, azoxystrobin and MCPA seem to have a higher predicted risk for the community with at least one of the biological endpoint being effected compared to acetamiprid. Generally, the developed approach facilitates the communication of uncertainties associated with the predicted effect on different biological levels of the aquatic ecosystem. This transparency in all model components can aid risk management and decision making.
Identification of pre-synaptic density networks using SV2A PET imaging and ICA in healthy and diseased mice
Authors: Akkermans Jordy , Zajicek Franziska , Miranda Alan , Adhikari Mohit , Bertoglio Daniele
Published: October 2022

Background

Synaptic vesicle glycoprotein 2A (SV2A) is a vesicle glycoprotein involved in neurotransmitter release. SV2A is located on the pre-synaptic terminals of neurons and visualized using the radioligand [11C]UCB-J and positron emission tomography (PET) imaging. Thus, SV2A PET imaging can provide a proxy for pre-synaptic density in health and disease. This study aims to apply independent component analysis (ICA) to SV2A PET data acquired in mice to identify pre-synaptic density networks (pSDNs), explore how ageing affects these pSDNs, and determine the impact of a neurological disorder on these networks.

Methods

We used [11C]UCB-J PET imaging data (n=135) available at different ages (3, 7, 10, and 16 months) in wild-type (WT) C57BL/6J mice and in diseased mice (mouse model of Huntington’s disease, HD). First, ICA was performed on a healthy dataset after it was split into two equal-sized samples (n=36 each) and the analysis was repeated 50 times in different partitions. We tested different model orders (8, 12, and 16) and identified the pSDNs. Next, we investigated the effect of age on the loading weights of the identified pSDNs. Additionally, the identified pSDNs were compared to those of diseased mice to assess the impact of disease on each pSDNs.

Results

Model order 12 resulted in the preferred choice to provide six reliable and reproducible independent components (ICs) as supported by the cluster-quality index (IQ) and regression coefficients (β) values. Temporal analysis showed age-related statistically significant changes on the loading weights in four ICs. ICA in an HD model revealed a statistically significant disease-related effect on the loading weights in several pSDNs in line with the progression of the disease.

Conclusion

This study validated the use of ICA on SV2A PET data acquired with [11C]UCB-J for the identification of cerebral pre-synaptic density networks in mice in a rigorous and reproducible manner. Furthermore, we showed that different pSDNs change with age and are affected in a disease condition. These findings highlight the potential value of ICA in understanding pre-synaptic density networks in the mouse brain.
Training stochastic stabilized supralinear networks by dynamics-neutral growth
Authors: Soo Wayne W.M. , Lengyel Máté
Published: October 2022

There continues to be a trade-off between the biological realism and performance of neural networks. Contemporary deep learning techniques allow neural networks to be trained to perform challenging computations at (near) human-level, but these networks typically violate key biological constraints. More detailed models of biological neural networks can incorporate many of these constraints but typically suffer from subpar performance and trainability. Here, we narrow this gap by developing an effective method for training a canonical model of cortical neural circuits, the stabilized supralinear network (SSN), that in previous work had to be constructed manually or trained with undue constraints. SSNs are particularly challenging to train for the same reasons that make them biologically realistic: they are characterized by strongly-connected excitatory cells and expansive firing rate non-linearities that together make them prone to dynamical instabilities unless stabilized by appropriately tuned recurrent inhibition. Our method avoids such instabilities by initializing a small network and gradually increasing network size via the dynamics-neutral addition of neurons during training. We first show how SSNs can be trained to perform typical machine learning tasks by training an SSN on MNIST classification. We then demonstrate the effectiveness of our method by training an SSN on the challenging task of performing amortized Markov chain Monte Carlo-based inference under a Gaussian scale mixture generative model of natural image patches with a rich and diverse set of basis functions – something that was not possible with previous methods. These results open the way to training realistic cortical-like neural networks on challenging tasks at scale.
Remodeling and compaction of the inactive X is regulated byXistduring female B cell activation
Authors: Sierra Isabel , Nguyen Son C. , Barnett R. Jordan , Cook Ashley L. , Ryu Han-Seul , Beethem Zachary T. , Philips-Cremins Jennifer E. , Joyce Eric F. , Anguera Montserrat C.
Published: October 2022

X Chromosome Inactivation (XCI) equalizes X-linked gene expression between sexes. B cells exhibit unusually dynamic XCI, as Xist RNA/heterochromatic marks on the inactive X (Xi) are absent in naïve B cells, but return following mitogenic stimulation. Xi gene expression analysis supports dosage compensation, but reveals high levels of XCI escape genes in both naive and activated B cells. Allele-specific OligoPaints indicate similar Xi and Xa territories in B cells that is less compact than in fibroblasts. Allele-specific Hi-C maps reveal a lack of TAD-like structures on the Xi of naïve B cells, and alterations in TADs and stronger TAD boundaries at Xi escape genes after mitogenic stimulation. Notably,Xistdeletion in B cells reduces Xi compaction and changes TAD boundaries, independent of its localization to the Xi. Our findings provide the first evidence that Xi compaction/small scale organization in lymphocytes impact XCI maintenance and female biased X-linked gene expression.
MTM: a multi-task learning framework to predict individualized tissue gene expression profiles
Authors: He Guangyi , Chen Maiyue , Bian Yingnan , Yang Ence
Published: October 2022

Predicting tissue expression profiles from peripheral ‘surrogate’ samples, especially blood transcriptome, has become an effective alternative when invasive procedures are not ideal. However, existing approaches ignore tissue-shared intrinsic relevance, inevitably limiting predictive performance. Here, we propose a unified deep learning-based multi-task learning framework, Multi-tissue Transcriptome Mapping (MTM), enabling the prediction of individualized expression profiles from any available tissue of an individual. By jointly leveraging individualized cross-tissue information through multi-task learning, MTM achieves superior sample-level and gene-level performance. With the high prediction accuracy and the ability to preserve individualized biological variations, MTM could facilitate both fundamental and clinical biomedical research.
ROS induction as a strategy to target persister cancer cells with low metabolic activity in NRAS mutated melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas ,   TuPro Consortium, Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: October 2022

Metabolic reprogramming is an emerging hallmark of resistance to cancer therapy but may generate vulnerabilities that can be targeted with small molecules. Multi-omics analysis revealed that NRAS-mutated melanoma cells with a mesenchymal transcriptional profile adopt a quiescent metabolic program to resist cellular stress response induced by MEK-inhibitor resistance. However, as a result of elevated baseline ROS levels, these cells become highly sensitive to ROS induction.In vivoxenograft experiments and single-cell RNA sequencing demonstrated that intra-tumor heterogeneity requires the combination of a ROS-inducer and a MEK-inhibitor to target both tumor growth and metastasis. Byex vivopharmacoscopy of 62 human metastatic melanomas, we found that MEK-inhibitor resistant tumors significantly benefitted from the combination therapy.

Finally, we profiled 486 cancer cell lines and revealed that oxidative stress responses and translational suppression are biomarkers of ROS-inducer sensitivity, independent of cancer indication. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS-inducers in melanoma and other cancers.

Statement of Significance

Targeted-therapy resistance in cancer arises from genetic selection and both transcriptional and metabolic adaptation. We show that metabolic reprogramming sensitizes resistant cells to ROS-induction in combination with pathway inhibitors. Predictive biomarkers of metabolic sensitivity to ROS-inducing agents were identified in many cancer entities, highlighting the generalizability of this treatment approach.

Graphical summary