bluuebunny/crossref_metadata_2025 huggingface dataset:
Does urbanization lead to parallel demographic shifts across the world in a cosmopolitan plant?
Authors: Caizergues Aude E. , Santangelo James S. , Ness Rob W. , Angeoletto Fabio , Anstett Daniel , Anstett Julia , Baena-Diaz Fernanda , Carlen Elizabeth J. , Chaves Jaime A. , Comerford Mattheau S. , Dyson Karen , Falahati-Anbaran Mohsen , Fellowes Mark D.E. , Hodgins Kathryn A. , Hood Glen R. , Iñiguez-Armijos Carlos , Kooyers Nicholas J. , Lázaro-Lobo Adrián , Moles Angela T. , Munshi-South Jason , Paule Juraj , Porth Ilga M. , Santiago-Rosario Luis Y. , Whitney Kaitlin Stack , Tack Ayko J.M. , Johnson Marc T.J.
Published: August 2023

Urbanization is occurring globally, leading to dramatic environmental changes that are altering the ecology and evolution of species. In particular, the expansion of human infrastructure and the loss and fragmentation of natural habitats in cities is predicted to increase genetic drift and reduce gene flow by reducing the size and connectivity of populations. Alternatively, the “urban facilitation model” suggests that some species will have greater gene flow into and within cities leading to higher diversity and lower differentiation in urban populations. These alternative hypotheses have not been contrasted across multiple cities. Here, we used the genomic data from the Global Urban Evolution project (GLUE), to study the effects of urbanization on non-adaptive evolutionary processes of white clover (Trifolium repens) at a global scale. We found that white clover populations presented high genetic diversity and no evidence of a reduction inNelinked to urbanization. On the contrary, we found that urban populations were less likely to experience a recent decrease in effective population size than rural ones. In addition, we found little genetic structure among populations both globally and between urban and rural populations, which showed extensive gene flow between habitats. Interestingly, white clover displayed overall higher gene flow within urban areas than within rural habitats. Our study provides one of the largest comprehensive tests of demographic effects of urbanization and our results contrast the common perception that heavily altered and fragmented urban environments will reduce the effective population size and genetic diversity of populations and contribute to their isolation.
LrhA promotes CRISPR-Cas immunity by enhancing primed adaptation inEscherichia coli
Authors: Fang Mengdie , Li Na , Gong Mengxin , Fei Mingyue , Lu Yalan , Yu Mingjing , Wu Fabai , Sun Dongchang
Published: August 2023

The CRISPR-based defense system protects prokaryotes against foreign genetic elements. Previous studies indicated that the activity of the CRISPR-Cas system is the outcome of the combined effect of adaptation and interference. However, it remains unclear how coordination of the two processes is regulated to optimize the efficacy of adaptive immunity. Here, we identify the LysR-type transcriptional regulator LrhA as a new CRISPR-Cas activator which plays an important role in coordinating adaptation and interference. Through directly binding to the promoter of thecasoperon, LrhA enhances the CRISPR-Cas adaptive immunity against bacteriophage infection by stimulating the transcription ofcasgenes. Moderate activation ofcasgenes by LrhA efficiently promoted the clearance of horizontally transferred CRISPR-targeted plasmid via increasing the acquisition of new spacers by interference-driven adaptation inEscherichia coli. Our results indicate that intermediate level of transcription ofcasgenes achieved optimal outcomes of the adaptive immunity through triggering positive feedback between adaptation and interference, highlighting the importance of fine-tuning expression of CRISPR-Cas system.
The information theory formalism unifies the detection of the patterns of sexual selection and assortative mating for both discrete and quantitative traits
Authors: Carvajal-Rodríguez A.
Published: August 2023

Sexual selection plays a crucial role in modern evolutionary theory, offering valuable insight into evolutionary patterns and species diversity. Recently, a comprehensive definition of sexual selection has been proposed, defining it as any selection that arises from fitness differences associated with nonrandom success in the competition for access to gametes for fertilization. Previous research on discrete traits demonstrated that non-random mating can be effectively quantified using Jeffreys (or symmetrized Kullback-Leibler) divergence, capturing information acquired through mating influenced by mutual mating propensities instead of random occurrences. This novel theoretical framework allows for detecting and assessing the strength of sexual selection and assortative mating.

In this study, we aim to achieve two primary objectives. Firstly, we demonstrate the seamless alignment of the previous theoretical development, rooted in information theory and mutual mating propensity, with the aforementioned definition of sexual selection. Secondly, we extend the theory to encompass quantitative traits. Our findings reveal that sexual selection and assortative mating can be quantified effectively for quantitative traits by measuring the information gain relative to the random mating pattern. The connection of the information indices of sexual selection with the classical measures of sexual selection is established.

Additionally, if mating traits are normally distributed, the measure capturing the underlying information of assortative mating is a function of the square of the correlation coefficient, taking values within the non-negative real number set [0, +∞).

It is worth noting that the same divergence measure captures information acquired through mating for both discrete and quantitative traits. This is interesting as it provides a common context and can help simplify the study of sexual selection patterns.
Structural and functional analysis of the minimal orthomyxovirus-like polymerase of Tilapia Lake Virus from the highly divergedAmnoonviridaefamily
Authors: Arragain Benoit , Pelosse Martin , Thompson Albert , Cusack Stephen
Published: August 2023

Tilapia Lake Virus (TiLV), a recently discovered pathogen of tilapia fish, belongs to theAmnoonviridaefamily from theArticulaviralesorder. Its ten genome segments have characteristic conserved ends and encode proteins with no known homologues, apart from the segment 1, which encodes an orthomyxo-like RNA-dependent-RNA polymerase core subunit. Here we show that segments 1-3 encode respectively the PB1, PB2 and PA-like subunits of an active heterotrimeric polymerase that maintains all domains found in the distantly related influenza polymerase, despite an unprecedented overall size reduction of 40%. Multiple high-resolution cryo-EM structures of TiLV polymerase in pre-initiation, initiation and active elongation states, show how it binds the vRNA and cRNA promoters and performs RNA synthesis, with both transcriptase and replicase configurations being characterised. However, the highly truncated endonuclease-like domain appears inactive and the putative cap-binding domain is autoinhibited, emphasising that many functional aspects of TiLV polymerase remain to be elucidated.
SuperCellCyto: enabling efficient analysis of large scale cytometry datasets
Authors: Putri Givanna H. , Howitt George , Marsh-Wakefield Felix , Ashhurst Thomas M. , Phipson Belinda
Published: August 2023

Advancements in cytometry technologies have enabled quantification of up to 50 proteins across millions of cells at single cell resolution. Analysis of cytometry data routinely involves tasks such as data integration, clustering, and dimensionality reduction. While numerous tools exist, many require extensive run times when processing large cytometry data containing millions of cells. Existing solutions, such as random subsampling, are inadequate as they risk excluding rare cell subsets. To address this, we propose SuperCellCyto, an R package that builds on the SuperCell tool which groups highly similar cells into supercells. SuperCellCyto is available on GitHub (https://github.com/phipsonlab/SuperCellCyto).
Detecting adaptive changes in gene copy number distribution accompanying the human out-of-Africa expansion
Authors: Otto Moritz , Zheng Yichen , Grablowitz Paul , Wiehe Thomas
Published: August 2023

Genes with multiple copies are likely to be maintained by stabilizing selection that puts a bound to unlimited expansion of copy number. We designed a model where copy number variation is generated by unequal recombination, which fits well to a number of genes, surveyed in three human populations. Based on this theoretical model and on computer simulations, we were interested in answering the question whether gene copy number distribution in the derived European and Asian populations can be explained by a purely demographic scenario or whether shifts in the distribution are signatures of adaptation. Although copy number distribution in most of the analyzed gene clusters can be explained by a bottleneck as in the out of Africa expansion of homo sapiens 60-10kyrs ago, we identified several candidate genes, for instanceAMY1AandPGA3, whose copy numbers are likely to be selected differently among African, Asian and European populations.
SAMD1 suppresses epithelial-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma
Authors: Simon Clara , Brunke Inka D. , Stielow Bastian , Forné Ignasi , Steitz Anna Mary , Geller Merle , Rohner Iris , Weber Lisa M. , Fischer Sabrina , Jeude Lea Marie , Nist Andrea , Stiewe Thorsten , Huber Magdalena , Buchholz Malte , Liefke Robert
Published: August 2023

SAMD1 (SAM-domain containing protein 1), a CpG island-binding protein, plays a pivotal role in the repression of its target genes. Despite its significant correlation with outcomes in various tumor types, the role of SAMD1 in cancer has remained largely unexplored. In this study we focused on pancreatic ductal adenocarcinoma (PDAC) and revealed that SAMD1 acts as a repressor of genes associated with epithelial-mesenchymal transition (EMT). Upon deletion of SAMD1 in PDAC cells, we observed significantly increased migration rates. SAMD1 exerts its effects by binding to specific genomic targets, includingCDH2, encoding N-cadherin, which emerged as a driver of enhanced migration upon SAMD1 knockout. Furthermore, we discovered the FBXO11-containing E3 ubiquitin ligase complex as an interactor of SAMD1. FBXO11 ubiquitinates SAMD1 within its DNA-binding winged helix domain and inhibits SAMD1 chromatin binding genome-wide. HighFBXO11expression in PDAC is associated with poor prognosis and increased expression of EMT-related genes, underlining an antagonistic relationship between SAMD1 and FBXO11. In summary, our findings provide new insights into the regulation of EMT-related genes in PDAC, shedding light on the intricate role of SAMD1 and its interplay with FBXO11 in this cancer type.
Txn1mutation is a monogenic cause of chronic kidney disease associated with mitochondrial dysfunction in rats
Authors: Ohmori Iori , Ouchida Mamoru , Hada Yoshiko , Uchida Haruhito A. , Toyokuni Shinya , Mashimo Tomoji
Published: August 2023

Oxidative stress plays a significant role in the progression of chronic kidney disease. Thioredoxin 1 (Txn1) is one of the enzymatic antioxidants to regulate redox balance. However, the molecular mechanisms by Txn1 affects renal homeostasis remain unclear. This study aimed at elucidating the pathophysiology ofTxn1mutations in renal function. We used rats with theTxn1-F54L mutation generated by N-ethyl-N-nitrosourea mutagenesis. Laboratory tests and pathological examinations were performed in wild-type (WT) rats and in rats with heterozygous and homozygousTxn1-F54L mutations. We performed RNA-seq analysis of the WT and homozygotes. To confirm phenotypic reproducibility, theTxn1-F54L mutation was generated in rats with different genetic backgrounds using CRISPR/Cas9 genome editing technology.Txn1-F54L mutant rats exhibited progressive albuminuria, hypoalbuminemia, hypercholesterolemia, and hypertension. Renal pathology revealed marked nephrosclerosis, tubular dilatation, interstitial fibrosis, and decreased number of mitochondria, mainly in the paroxysmal tubules. We confirmed a similar phenotype of chronic kidney disease (CKD) in different rat strains. RNA-seq showed the downregulation of mitochondria-related genes and significant upregulation of genes associated with inflammation, pyroptosis, apoptosis, and necroptosis in mutant rats. Our results show that theTxn1mutation is a monogenic cause of CKD termination. The underlying pathology involves several regulated cell-death pathways. Thus, our study provides a new animal model of oxidative stress-induced CKD.Txn1-F54L mutant rats will aid in developing therapeutic strategies for CKD.

Translational Statement

We found that the deficiency of thioredoxin (Txn1), which regulates oxidative stress, spontaneously caused chronic kidney disease (CKD) in rats. The Txn1-F54L (Adem) rat is a new model of CKD with complications such as anemia, hypertension, and cardiovascular disease. Renal pathology revealed nephrosclerosis, interstitial fibrosis, and mitochondrial damage. The molecular basis of the underlying pathologies included inflammation, pyroptosis, apoptosis, and necroptosis. These pathological changes are partially linked to renal diseases such as diabetic nephropathy, hypertensive nephrosclerosis, and ischemic reperfusion injury.Ademrats could help understand the common pathological mechanisms of these renal diseases and develop therapeutic strategies.
Cyclic muscle contractions reinforce the acto-myosin motors and mediate the full elongation of C. elegans embryo
Authors: Dai Anna , Ben Amar Martine
Published: August 2023

The paramount importance of mechanical forces in morphogenesis and embryogenesis is widely recognized, but understanding the mechanism at the cellular and molecular level remains challenging. Because of its simple internal organization, Caenorhabditis elegans is a rewarding system of study. As demonstrated experimentally, after an initial period of steady elongation driven by the actomyosin network, muscle contractions operate a quasi-periodic sequence of bending, rotation and torsion, that leads to the final 4-fold size of the embryo before hatching. How actomyosin and muscles contribute to embryonic elongation is investigated here theoretically. A filamentary elastic model that converts stimuli generated by biochemical signals in the tissue into driving forces, explains embryonic deformation under actin bundles and muscle activity, and dictates mechanisms of late elongation based on the effects of energy conversion and dissipation. We quantify this dynamic transformation by stretches applied to a cylindrical structure that mimics the body shape in finite elasticity, obtaining good agreement and understanding for both wild-type and mutant embryos at all stages.
The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program
Authors: Burton Oliver , Bricard Orian , Tareen Samar , Gergelits Vaclav , Andrews Simon , Roca Carlos P. , Whyte Carly , Junius Steffie , Brajic Aleksandra , Pasciuto Emanuela , Ali Magda , Lemaitre Pierre , Schlenner Susan M. , Ishigame Harumichi , Brown Brian D. , Dooley James , Liston Adrian
Published: August 2023

The tissues are the site of many of the most important immunological reactions, yet the immunology of the tissues has remained relatively opaque. Recent studies have identified Foxp3+regulatory T cells (Tregs) in several non-lymphoid tissues. These tissue-resident populations have been ascribed unique characteristics based on comparisons to lymphoid Tregs. Here we performed a systematic analysis of the Treg population residing in non-lymphoid organs throughout the body, revealing shared phenotypes, transient residency and common molecular dependencies. Further, tissue Tregs from different non-lymphoid organs shared T cell receptor (TCR) sequences, with functional capacity to drive multi-tissue Treg entry. Finally, tissue Tregs extracted from non-lymphoid organs were tissue-agnostic on re-entry, without homing preference for their tissue of origin. Together these results demonstrate that the tissue-resident Treg pool in most non-lymphoid organs, other than the gut, is largely constituted by broadly self-reactive Tregs, characterised by transient multi-tissue migration and a common residency program.
Organisation of the nervous system in cysts of the freshwater tardigradeThulinius ruffoi(Parachela, Isohypsibioidea: Doryphoribiidae)
Authors: Janelt Kamil , Poprawa Izabela
Published: August 2023

Encystment is a natural process that involves cyst formation, and at least some species of tardigrades can form cysts. However, the encystment process and cyst structure among tardigrades are still poorly understood. Despite some aspects of the encysted animals’ system organisation being examined in the past, the morphology and structure of the nervous system have never been thoroughly investigated. The present study covers anatomical, histological and morphological details and proposes physiological aspects of the nervous system in encystedThulinius ruffoiup to 11 months duration in encystment. This is the first record of the nervous system organisation in a species belonging to the family Doryphoribiidae and describes morphological changes that occur during cyst formation.
Fecal pH and redox as functional markers in the premature infant gut microbiome
Authors: Letourneau Jeffrey , Walker LaShawndra , Han Se Hyang , David Lawrence A , Younge Noelle
Published: August 2023

The infant gut microbiome is a crucial factor in health and development. In preterm infants, altered gut microbiome composition and function have been linked to serious neonatal complications such as necrotizing enterocolitis and sepsis, which can lead to long-term disability. Although many studies have described links between microbiome composition and disease risk, there is a need for biomarkers to identify infants at risk of these complications in practice. In this study, we obtained stool samples from preterm infant participants longitudinally during the first postnatal months, and measured pH and redox, as well as SCFA content and microbiome composition by 16S rRNA gene amplicon sequencing. These outcomes were compared to clinical data to better understand the role of pH and redox in infant gut microbiome development and overall health, and to assess the potential utility of pH and redox as biomarkers. We found that infants born earlier or exposed to antibiotics exhibited increased fecal pH, and that redox potential increased with postnatal age. These differences may be linked to changes in SCFA content, which was correlated with pH and increased with age. Microbiome composition was also related to birth weight, age, pH, and redox. Our findings suggest that pH and redox may serve as biomarkers of metabolic state in the preterm infant gut.
Field application of de novo transcriptomic analysis to evaluate the effects of sublethal freshwater salinization onGasterosteus aculeatusin urban streams
Authors: Escobar-Sierra Camilo , Lampert Kathrin P.
Published: August 2023

Freshwater salinization poses global challenges for aquatic organisms, impacting their physiology and ecology. However, current salinization research predominantly focuses on mortality endpoints in limited model species, overlooking the sublethal effects on a broader spectrum of organisms and the exploration of adaptive mechanisms and pathways under natural field conditions. To address these gaps, we conducted high-throughput sequencing transcriptomic analysis on the gill tissue of the euryhaline fishGasterosteus aculeatus, investigating its molecular response to salinity stress in the highly urbanized river Boye, Germany. We found that even sublethal concentrations of chloride led to the activation of the energetically costly osmoregulatory system inG. aculeatus, evidenced by the differential expression of genes related to osmoregulation. Our enrichment analysis revealed differentially expressed genes (DEGs) related to transmembrane transport and regulation of transport and other osmoregulation pathways, which aligns with the crucial role of these pathways in maintaining biological homeostasis. Notably, we identified candidate genes involved in increased osmoregulatory activity under salinity stress, including those responsible for moving ions across membranes: ion channels, ion pumps, and ion transporters. Particularly, genes from the solute carrier family SLC, aquaporinAQP1, chloride channelCLC7, ATP-binding cassette transporterABCE1, and ATPases member ATAD2 exhibited prominent differential expression. These findings provide insights into the molecular mechanisms underlying the adaptive response of euryhaline fish to salinity stress and have implications for their conservation and management in the face of freshwater salinization.
A molecular proximity sensor based on an engineered, dual-component guide RNA
Authors: Choi Junhong , Chen Wei , Liao Hanna , Li Xiaoyi , Shendure Jay
Published: August 2023

One of the goals of synthetic biology is to enable the design of arbitrary molecular circuits with programmable inputs and outputs. Such circuits bridge the properties of electronic and natural circuits, processing information in a predictable manner within living cells. Genome editing is a potentially powerful component of synthetic molecular circuits, whether for modulating the expression of a target gene or for stably recording information to genomic DNA. However, programming molecular events such as protein-protein interactions or induced proximity as triggers for genome editing remains challenging. Here we demonstrate a strategy termed “P3 editing”, which linksprotein-proteinproximity to the formation of a functional CRISPR-Cas9 dual-component guide RNA. By engineering the crRNA:tracrRNA interaction, we demonstrate that various known protein-protein interactions, as well as the chemically-induced dimerization of protein domains, can be used to activate prime editing or base editing in human cells. Additionally, we explore how P3 editing can incorporate outputs from ADAR-based RNA sensors, potentially allowing specific RNAs to induce specific genome edits within a larger circuit. Our strategy enhances the controllability of CRISPR-based genome editing, facilitating its use in synthetic molecular circuits deployed in living cells.
Developmental transcriptomes predict adult social behaviors in the socially flexible sweat bee,Lasioglossum baleicum
Authors: Omufwoko Kennedy S. , Cronin Adam L. , Nguyen Thi Thu Ha , Webb Andrew E. , Traniello Ian M. , Kocher Sarah D.
Published: August 2023

Natural variation can provide important insights into the genetic and environmental factors that shape social behavior and its evolution. The sweat bee,Lasioglossum baleicum, is a socially flexible bee capable of producing both solitary and eusocial nests. We demonstrate that within a single nesting aggregation, soil temperatures are a strong predictor of the social structure of nests. Sites with warmer temperatures in the spring have a higher frequency of social nests than cooler sites, perhaps because warmer temperatures provide a longer reproductive window for those nests. To identify the molecular correlates of this behavioral variation, we generated ade novogenome assembly forL. baleicum, and we used transcriptomic profiling to compare adults and developing offspring from eusocial and solitary nests. We find that adult, reproductive females have similar expression profiles regardless of social structure in the nest, but that there are strong differences between reproductive females and workers from social nests. We also find substantial differences in the transcriptomic profiles of stage-matched pupae from warmer, social-biased sites compared to cooler, solitary-biased sites. These transcriptional differences are strongly predictive of adult reproductive state, suggesting that the developmental environment may set the stage for adult behaviors inL. baleicum. Together, our results help to characterize the molecular mechanisms shaping variation in social behavior and highlight a potential role of environmental tuning during development as a factor shaping adult behavior and physiology in this socially flexible bee.
Bacterial degradation of ctenophoreMnemiopsis leidyiorganic matter
Authors: Fadeev Eduard , Hennenfeind Jennifer H , Amano Chie , Zhao Zihao , Klun Katja , Herndl Gerhard J , Tinta Tinkara
Published: August 2023

Blooms of gelatinous zooplankton, an important source of protein-rich biomass in coastal waters, often collapse rapidly, releasing large amounts of labile detrital organic matter (OM) into the surrounding water. Although these blooms have the potential to cause major perturbations in the marine ecosystem, their effects on the microbial community and hence on the biogeochemical cycles have yet to be elucidated. We conducted microcosm experiments simulating the scenario experienced by coastal bacterial communities after the decay of a ctenophore (Mnemiopsis leidyi) bloom in the northern Adriatic Sea. Within 24 h, a rapid response of bacterial communities to theM. leidyiOM was observed, characterized by elevated bacterial biomass production and respiration rates. Compared to our previous microcosm study of jellyfish (Aurelia aurita s.l.),M. leidyiOM degradation revealed that, despite the fundamental genetic and biochemical differences between the two species, a similar pattern in the bacterial community response was observed. Combined metagenomic and metaproteomic analysis indicated that the degradation activity was mainly performed byPseudoalteromonas, producing a large amount of proteolytic exoenzymes and exhibiting high metabolic activity. Interestingly, the reconstructed metagenome-assembled genome (MAG) ofPseudoalteromonas phenolicawas almost identical (average nucleotide identity >99%) to the MAG previously reconstructed in ourA. auritamicrocosm study. Taken together our data suggest that blooms of different gelatinous zooplankton are likely triggering a consistent response from natural bacterial communities, with specific bacterial lineages driving the remineralization of the gelatinous OM.

Importance

Jellyfish blooms are increasingly becoming a recurring seasonal event in marine ecosystems, characterised by a rapid build-up of gelatinous biomass that collapses rapidly. Although these blooms have the potential to cause major perturbations, their impact on marine microbial communities is largely unknown. We conducted an incubation experiment simulating a bloom of the ctenophoreMnemiopsis leidyiin the Northern Adriatic, where we investigated the bacterial response to the gelatinous biomass. We found that the bacterial communities actively degraded the gelatinous organic matter, and overall showed a striking similarity to the dynamics previously observed after a simulated bloom of the jellyfishAurelia aurita s.l. In both cases we found that a single bacterial species,Pseudoalteromonas phenolica, was responsible for most of the degradation activity. This suggests that blooms of different jellyfish are likely to trigger a consistent response from natural bacterial communities, with specific bacterial species driving the remineralisation of gelatinous biomass.
Development of Gemcitabine-Modified miRNA Mimics as Cancer Therapeutics for Pancreatic Ductal Adenocarcinoma
Authors: Yuen John G. , Hwang Ga-Ram , Fesler Andrew , Intriago Erick , Pal Amartya , Ojha Anushka , Ju Jingfang
Published: August 2023

Pancreatic cancer, including its most common subtype, pancreatic adenocarcinoma (PDAC), has the lowest five-year survival rate among patients with pancreatic cancer in the United States. Despite advancements in anticancer treatment, the overall median survival for patients with PDAC has not dramatically improved. Therefore, there is an urgent need to develop new strategies of treatment to address this issue. Non-coding RNAs, including microRNAs (miRNAs), have been found to have major roles in carcinogenesis and the subsequent treatment of various cancer types like PDAC. In this study, we developed a treatment strategy by modifying tumor suppressor miRNAs,hsa-miRNA-15a(miR-15a) andhsa-miRNA-194-1(miR-194), with the nucleoside analog chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics of miR-15a (Gem-miR-15a) and miR-194 (Gem-miR-194). In a panel of PDAC cell lines, we found that Gem-miR-15a and Gem-miR-194 induce cell cycle arrest and apoptosis, and these mimics are potent inhibitors with IC50values up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a and Gem-miR-194 retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a, and FOXA1 for Gem-miR-194. We also found that our Gem-modified miRNA mimics exhibit an enhanced efficacy compared to Gem alone in patient-derived PDAC organoids. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growthin vivowithout observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of Gem-modified miRNAs as a treatment strategy for PDAC.

One Sentence Summary

Yuen and Hwanget. al.have developed a potent therapeutic strategy for patients with pancreatic cancer by modifying microRNAs with gemcitabine.
Electrically controlled interaction between cable bacteria and carbon electrodes
Authors: Bonné Robin , Marshall Ian P.G. , Bjerg Jesper , Marzocchi Ugo , Manca Jean , Nielsen Lars Peter , Aiyer Kartik
Published: August 2023

Cable bacteria couple the oxidation of sulphide in sediments to the reduction of oxygen via long-distance electron transfer through periplasmic wires. While direct electron transfer between cable bacteria cells belonging to the same filament is a well-known phenomenon, electron transfer from the filament to electrodes has remained elusive. In this study, we demonstrate that living cable bacteria are attracted to electrodes in different bioelectrochemical systems. Carbon felt and carbon fibre electrodes poised at +200 mV against an Ag/AgCl reference attracted live cable bacteria from the sediment. When the applied potential was switched off, cable bacteria retracted from the electrode. qPCR and scanning electron microscopy corroborated this finding and revealed cable bacteria adhered onto the electrode surface. These experiments raise new possibilities to cultivate cable bacteria and utilise them for important applications in bioelectrochemical systems.
From paralogy to hybridization: Investigating causes of underlying phylogenomic discordance using the complex genusPackera(Senecioneae; Asteraceae)
Authors: Moore-Pollard Erika R. , Mandel Jennifer R.
Published: August 2023

Premise of the study

Underlying discordance in phylogenomic studies is becoming more common, and the answer is not as simple as adding more data. Biological processes such as polyploidy, hybridization, and incomplete lineage sorting are main contributors to these issues and must be considered when generating phylogenies. Otherwise, interpretations of evolutionary relationships could be misleading.

Methods

To obtain a better understanding of potential gene flow and its effect on phylogenetic trees, we investigated the causes and consequences of nuclear discordance using the genusPackerato understand how they influence the phylogenetic patterns seen in this complex group. To do this, we compared the topology and support values ofPackeraphylogenies resulting from various paralog selection or pruning methods. We then investigated whether pruning the paralogs instead of performing a selection process affected the topology and support of our phylogeny. To investigate hybridization and its effect on species relationships in our tree, we used likelihood methods to infer phylogenetic networks to find any evidence of gene flow among species lineages in this complicated genus.

Key results

We found that performing different paralog selection or pruning methods does impact our understanding of the evolutionary relationships withinPackera, and that addressing these paralogs with more rigorous methods than the typical pipeline increases concordance within the resulting phylogenies. Additionally, investigating reticulation events within highly discordant clades showed that ancestral hybridization and reticulation events are common throughoutPackera.

Conclusions

Investigating underlying biological processes by testing various methods can provide further insight into complex species relationships and levels of discordance within phylogenomic studies.
Gut mucosal cells transfer α-synuclein to the vagus nerve
Authors: Chandra Rashmi , Sokratian Arpine , Chavez Katherine R. , King Stephanie , Swain Sandip M. , Snyder Joshua C. , West Andrew B. , Liddle Rodger A.
Published: August 2023

Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson’s disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.
Pseudomonas aeruginosaMipA-MipB envelope proteins act as new sensors of polymyxin
Authors: Janet-Maitre Manon , Job Viviana , Bour Maxime , Brugière Sabine , Robert-Genthon Mylène , Cobessi David , Couté Yohann , Jeannot Katy , Attrée Ina
Published: August 2023

Due to the rising incidence of antibiotic resistant infections, the last-line antibiotics polymyxins have resurged in the clinics in parallel with new bacterial strategies of escape. The Gram-negative opportunistic pathogenPseudomonas aeruginosadevelops resistance to colistin/polymyxin by distinct molecular mechanisms, mostly through modification of the lipid A component of the LPS by proteins encoded within thearnBCDATEF-ugd(arn) operon. In this work, we characterized a polymyxin-induced operon, namedmipBA, notably present inP. aeruginosastrains devoid of thearnoperon. We showed thatmipBAis activated by ParR/ParS two-component regulatory system in response to polymyxin. MipA and MipB localize to bacterial outer membrane and form a complexin vitro. Structural modeling revealed that the lipoprotein MipB adopts a β-lactamase fold with two additional C-terminal domains,while MipA folds as an outer-membrane β-barrel, harboring an internal negatively charged channel, able to host a polymyxin molecule. Nano differential scanning fluorimetry (DSF) showed that polymyxin stabilized MipA proteinin vitro. Mass spectrometry-based quantitative proteomics on whole bacterial membranes demonstrated that the ΔmipBAmutant synthesized less MexXY-OprA proteins in response to polymyxin compared to the wild-type strain, as a consequence of impaired transcriptional activation of themexoperon. We propose MipA/MipB to act as membrane (co)sensors working in concert to activate ParS histidine kinase and help the bacterium to cope with polymyxin-mediated envelope stress through synthesis of the efflux pomp, MexXY-OprA.
Global nuclear reorganization during heterochromatin replication in the giant-genome plantNigella damascenaL.
Authors: Arifulin Eugene A. , Sorokin Dmitry V. , Anoshina Nadezhda A. , Kuznetsova Maria A. , Valyaeva Anna A. , Potashnikova Daria M. , Omelchenko Denis O. , Schubert Veit , Kolesnikova Tatyana D. , Sheval Eugene V.
Published: August 2023

Among flowering plants, genome size varies remarkably, by >2200-fold, and this variation depends on the loss and gain of non-coding DNA sequences that form distinct heterochromatin complexes during interphase. In plants with giant genomes, most chromatin remains condensed during interphase, forming a dense network of heterochromatin threads called interphase chromonemata. Using super-resolution light and electron microscopy, we studied the ultrastructure of chromonemata during and after replication in root meristem nuclei ofNigella damascenaL. During S-phase, heterochromatin undergoes transient decondensation locally at DNA replication sites. Due to the abundance of heterochromatin, the replication leads to a robust disassembly of the chromonema meshwork and a general reorganization of the nuclear morphology visible even by conventional light microscopy. After replication, heterochromatin recondenses, restoring the chromonema structure. Thus, we show that heterochromatin replication in interphase nuclei of giant-genome plants induces a global nuclear reorganization.
Interpolated retrieval retroactively increases recall and promotes cross-episode memory interdependence
Authors: Wahlheim Christopher N. , Smith Sydney T. , Garlitch Sydney M. , Wiley Robert W.
Published: August 2023

Retrieving existing memories before new learning can lead to retroactive facilitation. Three experiments examined whether interpolated retrieval is associated with retroactive facilitation and memory interdependence that reflects integrative encoding. Participants studied two lists of cue–response word pairs that repeated across lists (A–B, A–B), appeared in list 1 (A–B, —), or included the same cues with changed responses in each list (A–B, A–C). For A–B, A–C pairs, the tasks interpolated between lists required recall of list 1 (B) responses (with or without feedback) or restudy of complete list 1 (A–B) pairs. In list 2, participants only studied pairs (experiment 1) or studied pairs, attempted to detect changed (C) responses, and attempted to recall list 1 responses for detected changes (experiments 2 and 3). On a final cued recall test, participants attempted to recall list 1 responses, indicated whether responses changed between lists, and if so, attempted to recall list 2 responses. Interpolated retrieval was associated with subsequent retroactive facilitation and greater memory interdependence for B and C responses. These correlational findings are compatible with the view that retrieval retroactively facilitates memories, promotes coactivation of existing memories and new learning, and enables integrative encoding that veridically binds information across episodes.
An adaptation of the SAE J4000/2021 standard for assessing lean maturity in Brazilian hospitals
Authors: Fernandes June Marques , Reis Luciana Paula , Mansk Raphael
Published: August 2023

Purpose

This study aims to validate a model to assess the level of lean maturity of Brazilian hospitals based on the adaptation of the SAE J4000/2021 standard.

Design/methodology/approach

The methodology was divided: (1) adaptation of the standard to the health context, (2) application of the questionnaire through a survey, and (3) comparison of the results of the level of maturity in the standard and by the clustering technique, using Minitab.

Findings

The research presents two contributions: (1) validation of a model to assess the level of lean maturity based on the SAE J4000/2021; (2) insights into the level of maturity of Brazilian hospitals. It was observed that only 10% of the sample was classified at maturity level 3 and 75% at level 2. Private and large hospitals showed greater maturity compared to the others.

Research limitations/implications

This includes the limited number of hospitals that participated in the survey, given the difficulty of adherence to due constraints of time and staffing from hospitals, during the COVID-19 pandemic.

Practical implications

This article presents a lean maturity assessment proposal, adapting a consolidated standard in the automobile industry to the health context. Insights on the lean maturity of Brazilian hospitals can contribute to the development of policies to encourage the implementation of the lean philosophy directed to each specific environment.

Social implications

This study serves as a guide for public agents interested in monitoring the quality of hospital indicators through the SAE J4000/2021 standard. From this lean maturity analysis, hospital managers can understand their opportunities for improvement in both human and organizational aspects. This favors the improvement of service delivery to society that depends on health services.

Originality/value

Due to the lack of research that validates lean maturity level assessment models in Brazilian hospitals, this study can be considered a pioneer in this Brazilian research by validating the SAE J4000/2021 standard in its updated version in the health context.
Remimazolam for sedation: A protocol for a systematic review with meta‐analysis, trial sequential analysis, and GRADE approach
Authors: Stehr‐Pingel Lasse , Maagaard Mathias , Tvarnø Casper Duevang , Andersen Lars Peter Kloster , Andersen Jakob Hessel , Mathiesen Ole
Published: August 2023

Background

Procedural sedation aims to facilitate a successful diagnostic or therapeutic procedure. The pharmacokinetic properties and pharmacodynamic effects need to be taken into consideration when choosing the ideal sedative. Midazolam and propofol are frequently employed. However, they are associated with respiratory depression with increasing dosage. Also, midazolam has a potentially unpredictable pharmacodynamic response and propofol may cause hypotension and injection site pain. Remimazolam may provide a superior alternative due to its rapid pharmacodynamic profile and insignificant circulatory effects.

Methods

This protocol employs the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. The review aims to assess the beneficial and harmful clinical effects of remimazolam versus placebo or other sedatives in adult patients requiring sedation in relation to a diagnostic or therapeutic procedure, or due to other circumstances. Three primary outcomes are identified: Sedation success rate, respiratory complications, and hemodynamic complications. Six secondary outcomes are identified: among these are quality of recovery and serious adverse events. All randomized trials are included. The search strategy includes six major biomedical databases. Literature screening and data extraction will be performed independently by two authors. Risk of systemic error will be assessed with Risk of Bias 2 Tool. Risk of random error will be assessed with trial sequential analysis. Heterogeneity will be evaluated by appropriate statistical tests. The certainty of the evidence will be judged using Grading of Recommendations Assessment, Development, and Evaluation. Meta‐analysis will be carried out with Rstudio. A “Summary of Findings” table will be presented with our primary and secondary outcome results.

Discussion

The systematic review with up‐to‐date methodology outlined in this protocol investigates the clinical effects of remimazolam in relation to procedural sedation. The results may guide clinicians in the clinical use of remimazolam.
Pharmacological characterisation of erenumab, Aimovig, at two calcitonin gene‐related peptide responsive receptors
Authors: Garelja Michael L. , Alexander Tyla I. , Bennie Amy , Nimick Mhairi , Petersen Jakeb , Walker Christopher S. , Hay Debbie L.
Published: August 2023

Background and Purpose

Calcitonin gene‐related peptide (CGRP) is involved in migraine pathophysiology. CGRP can signal through two receptors. The canonical CGRP receptor comprises the calcitonin receptor‐like receptor and receptor activity‐modifying protein 1 (RAMP1); the AMY1 receptor comprises the calcitonin receptor with RAMP1. Drugs that reduce CGRP activity, such as receptor antagonists, are approved for the treatment and prevention of migraine. Despite being designed to target the canonical CGRP receptor, emerging evidence suggests that these antagonists, including erenumab (a monoclonal antibody antagonist) can also antagonise the AMY1 receptor. However, it is difficult to estimate its selectivity because direct comparisons between receptors under matched conditions have not been made. We therefore characterised erenumab at both CGRP‐responsive receptors with multiple ligands, including αCGRP and βCGRP.

Experimental Approach

Erenumab antagonism was quantified through IC50 and pKB experiments, measuring cAMP production. We used SK‐N‐MC cells which endogenously express the human CGRP receptor, and HEK293S and Cos7 cells transiently transfected to express either human CGRP or AMY1 receptors.

Key Results

Erenumab antagonised both the CGRP and AMY1 receptors with an ~20–120‐fold preference for the CGRP receptor, depending on the cells, agonist, analytical approach and/or assay format. Erenumab antagonised both forms of CGRP equally, and appeared to act as a competitive reversible antagonist at both receptors.

Conclusion and Implications

Despite being designed to target the CGRP receptor, erenumab can antagonise the AMY1 receptor. Its ability to antagonise CGRP activity at both receptors may be useful in better understanding the clinical profile of erenumab.
Diabetes remission and relapse following an intensive metabolic intervention combining insulin glargine/lixisenatide, metformin and lifestyle approaches: Results of a randomised controlled trial
Authors: McInnes Natalia , Hall Stephanie , Lochnan Heather A. , Harris Stewart B. , Punthakee Zubin , Sigal Ronald J. , Hramiak Irene , Azharuddin Mohammed , Liutkus Joanne F. , Yale Jean‐François , Sultan Farah , Smith Ada , Otto Rose E. , Sherifali Diana , Liu Yan Yun , Gerstein Hertzel C. ,   the REMIT‐iGlarLixi Collaborative Group
Published: August 2023

Aim

Non‐surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short‐term intensive glucose‐lowering therapy.

Methods

In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) <7.3% (56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for an additional 52 weeks. The primary outcome was diabetes relapse defined as HbA1c ≥6.5% (48 mmol/mol) at 24 weeks or thereafter, capillary glucose ≥10 mmol/L on ≥50% of readings, or use of diabetes medications, analysed as time‐to‐event. Main secondary outcomes included complete or partial diabetes remission at 24, 36, 48 and 64 weeks defined as HbA1c <6.5% (48 mmol/mol) off diabetes medications since 12 weeks after randomisation. A hierarchical testing strategy was applied.

Results

The intervention significantly reduced the hazard of diabetes relapse by 43% (adjusted hazard ratio 0.57, 95% confidence interval 0.40‐0.81; p = .002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14‐3.24) and 1.83 (1.03‐3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00‐3.53) at 48 weeks and 2.05 (0.98‐4.29) at 64 weeks.

Conclusions

A 12‐week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes.