bluuebunny/crossref_metadata_2025 huggingface dataset:
Habitat structural complexity increases age-class coexistence and population growth rate through relaxed cannibalism in medaka fish
Authors: Edeline Eric , Bennevault Yoann , Rozen-Rechels David
Published: July 2023

Structurally-complex habitats harbour more taxonomically-diverse and more productive communities, a phenomenon generally ascribed to habitat complexity relaxing the strength of inter-specific predation and competition. Here, we challenge this classical, community-centred view by showing that positive complexity-diversity and complexity-productivity relationships may also emerge from between-age-class,intra-specific interactions at a single-population level. In the laboratory, we show that medaka fish (Oryzias latipes) are strongly cannibalistic in complexity-free habitats, and that cannibalism may occur over a wide range of victim/cannibal body size ratios. In replicated outdoor pond populations, we manipulated habitat structural complexity using floating artificial structures, which selectively hampered movements of large-bodied medaka. Habitat structural complexity relaxed the strength of cannibalism, resulting in (1) increased survival of age-0+ individuals, (2) elevated age-class diversity through more balanced age-class proportions, (3) a 80 % increase in population growth rate, (4) dampened negative density-dependence in the effects of age-1+ medaka on the recruitment of age-0+ medaka, resulting in elevated habitat carrying capacity. The resultant higher population density in complex habitats was associated with increased competition for food among both age-0+ and age-1+ individuals. Our results highlight that positive complexity-diversity and complexity-productivity relationships may be considered as a generally-emergent property of size-structured populations and communities in which a larger body size brings a predation or interference advantage. Hence, enhancement of habitat structural complexity may be seen as a pivotal management strategy not only in favour of taxonomic diversity, but also to increase the productivity of exploited populations and to improve the conservation status of endangered species.
RIF1 integrates DNA repair and transcriptional requirements during the establishment of humoral immune responses
Authors: Rahjouei Ali , Kabrani Eleni , Berruezo-Llacuna Maria , Altwasser Robert , Delgado-Benito Veronica , Pavri Rushad , Virgilio Michela Di
Published: July 2023

The establishment of protective immune responses relies on the ability of terminally differentiated B cells to secrete a broad variety of antigen-specific antibodies with different effector functions. RIF1 is a multifunctional protein that promotes antibody isotype diversificationviaits DNA end protection activity during class switch recombination (CSR). In this study, we showed that RIF1 ablation resulted in increased plasmablast (PB) formationex vivoand enhanced terminal differentiation into plasma cells (PCs) upon immunization. Mechanistically, this phenotype is independent from RIF1’s role in DNA repair and CSR, and reflects its ability to modulate the transcriptional status of a subset of BLIMP1 target genes. Therefore, in addition to promoting antibody isotype diversification, RIF1 fine-tunes the kinetics of late B cell differentiation, thus providing an additional layer of control in the establishment of humoral immunity.
A Refined Phylochronology of the Second Plague Pandemic in Western Eurasia
Authors: Keller Marcel , Guellil Meriam , Slavin Philip , Saag Lehti , Irdt Kadri , Niinemäe Helja , Solnik Anu , Malve Martin , Valk Heiki , Kriiska Aivar , Cessford Craig , Inskip Sarah A. , Robb John E. , Cooper Christine , von Planta Conradin , Seifert Mathias , Reitmaier Thomas , Baetsen Willem A. , Walker Don , Lösch Sandra , Szidat Sönke , Metspalu Mait , Kivisild Toomas , Tambets Kristiina , Scheib Christiana L.
Published: July 2023

Although dozens of ancientYersinia pestisgenomes and a vast corpus of documentary data are available, the origin and spread of consecutive outbreaks of the Second Plague Pandemic in Europe (14th–18th c.) are still poorly understood. For the majority of ancient genomes, only radiocarbon dates spanning several decades are available, hampering an association with historically recorded plague outbreaks. Here, we present new genomic evidence of the Second Pandemic from 11 sites in England, Estonia, the Netherlands, Russia, and Switzerland yielding 11Y. pestisgenomes with >4-fold mean coverage dating to between 1349 and 1710. In addition, we present a novel approach for integrating the chronological information retrieved from phylogenetic analysis with their respective radiocarbon dates, based on a novel methodology offering more precise dating intervals. Together with a fine-grained analysis of documentarily recorded plague outbreaks, this allows us to tentatively associate all availableY. pestisgenomes of the Second Pandemic with historically documented plague outbreaks. Through these combined multidisciplinary analytical efforts, our newly sequenced genomes can be attributed to the Black Death in Cambridge (England), thepestis tertiaorpestis quartain the late 14th century (Estonia), previously unknown branches emerging in the 15th century (Estonia, the Netherlands and England), and a widespread pandemic in Eastern Europe around 1500 (western Russia), which all seem to have originated from one or multiple reservoirs located in Central Europe. While the latter continued to harbour a majorY. pestislineage at least until the 1630s, represented by new genomes of the Thirty Years’ War plague (Switzerland), another lineage consecutively spread into Europe between the 17th and 18th century from the Ottoman Empire, as evidenced by a genome associated with the Great Northern War plague (Estonia). By combining phylogenetic analysis with a systematic historical reconstruction based on textual sources and an innovative phylogenetically informed radiocarbon modelling (PhIRM), we offer a new groundbreaking interdisciplinary approach that solves several fundamental methodological challenges associated with phylogenetic and spatio-temporal reconstruction of historical pandemics.
Conjugation ofcis-OPDA with amino acids is a conserved pathway affectingcis-OPDA homeostasis upon stress responses
Authors: Brunoni Federica , Široká Jitka , Mik Václav , Pospíšil Tomáš , Kralová Michaela , Ament Anita , Pernisová Markéta , Karady Michal , Htitich Mohamed , Ueda Minoru , Floková Kristýna , Wasternack Claus , Strnad Miroslav , Novák Ondřej
Published: July 2023

Jasmonates (JAs) are a family of oxylipin phytohormones regulating plant development and growth and mediating ‘defenseversusgrowth’ responses. The upstream JA biosynthetic precursorcis-(+)-12-oxo-phytodienoic acid (cis-OPDA) has been reported to act independently of the COI1-mediated JA signaling in several stress-induced and developmental processes. However, its means of perception and metabolism are only partially understood. Furthermore,cis-OPDA, but not JA, occurs in non-vascular plant species, such as bryophytes, exhibiting specific functions in defense and development. A few years ago, a low abundant isoleucine analog of the biologically active JA-Ile, OPDA-Ile, was detected in wounded leaves of flowering plants, opening up to the possibility that conjugation ofcis-OPDA to amino acids might be a relevant mechanism forcis-OPDA regulation. Here, we extended the analysis of amino acid conjugates ofcis-OPDA and identified naturally occurring OPDA-Val, OPDA-Phe, OPDA-Ala, OPDA-Glu, and OPDA-Asp in response to biotic and abiotic stress in Arabidopsis. The newly identified OPDA-amino acid conjugates showcis-OPDA-related plant responses in a JAR1-dependent manner. We also discovered that the synthesis and hydrolysis ofcis-OPDA amino acid conjugates are regulated by members of the amidosynthetase GH3 and the amidohydrolase ILR1/ILL families. Finally, we found that thecis-OPDA conjugative pathway already functions in non-vascular plants and gymnosperms. Thus, one level of regulation by which plants modulatecis-OPDA homeostasis is the synthesis and hydrolysis of OPDA-amino acid conjugates, which temporarily storecis-OPDA in stress responses.
Microfluidic organotypic device to test intestinal mucosal barrier permeability ex vivo
Authors: Cherwin Amanda E , Templeton Hayley N , Ehrlich Alexis T , Patlin Brielle H , Henry Charles S , Tobet Stuart A
Published: July 2023

To protect the body from external pathogens, the intestines have sophisticated epithelial and mucosal barriers. Disruptions to barrier integrity are associated with a variety of disorders such as irritable bowel disease, Crohn’s Disease, and celiac disease. One critical component of all barriers are collagens in the extracellular matrix. While the importance of the intestinal barrier is established, current models lack the ability to represent the complex biology that occurs at these barriers. For the current study a microfluidic device model was modified to determine the effectiveness of collagen breakdown to cause barrier disruption. Bacterial collagenase was added for 48 h to the luminal channel of a dual flow microfluidic device to examine changes in intestinal barrier integrity. Tissues exhibited dose-dependent alterations in immunoreactive collagen-1 and claudin-1, and coincident disruption of the epithelial monolayer barrier as indicated by goblet cell morphologies. This ex vivo model system offers promise for further studies exploring factors that affect gut barrier integrity and potential downstream consequences that cannot be studied in current models.
Metformin acts directly in the brain to slow features of neurodegeneration
Authors: Harding Edward C. , Chen Hsiao-Jou Cortina , Shepilov Dmytro , Welzer Marc , Macarelli Viviana , Schwiening Alix , Rowley Christine , Aggarwal Sanya , Swinden Dean , Kronenberg-Versteeg Deborah , Merkle Florian T.
Published: July 2023

Dementia is a largely untreatable syndrome that is epidemiologically associated with metabolic diseases such as type 2 diabetes (T2D) and obesity. Drugs used to treat T2D such as metformin are inexpensive, safely given to millions of people, and have also been reported to slow neurodegeneration. We hypothesised that the neuroprotective benefits of metformin might extend to metabolically healthy individuals and tested this hypothesis in a mouse prion model that recapitulates key features of human neurodegenerative disease, including synaptic loss and motor impairment. These features and the time course of this model (24 weeks) allows the effects of metabolic risk factors and metformin to be tested and potentially generalised to other forms of neurodegenerative disease. Mice fed a high fat diet (HFD) developed high adiposity with impaired glucose and insulin homeostasis, similar to the effects of chronic obesity seen in humans whereas mice on matched control diet (CD) remain metabolically healthy. Chronic treatment with metformin in HFD-fed mice significantly increased survival and health span relative to vehicle-treated mice. Mice fed a HFD also had a modestly extended health span relative to mice fed CD, as measured by development of motor signs of prion disease. Metformin also significantly extended health span in metabolically healthy CD-fed mice. Using targeted mass spectrometry, we found that metformin reached deep brain structures at functional concentrations, driving a reduction in pPERK and changing the activity of microgliain vivo. Metformin was able to alter ER stress pathways at the same concentrations in healthy animals and using human iPSC-derived microglia and mouse organotypic slices we show that the action of metformin at these concentrations does not require a systemic mechanism, necessary for the treatment of diabetes, and is likely a result of direct secondary pharmacology in the brain. Together, these data broadly support the premise of repurposing metformin for neuroprotection, even in metabolically healthy individuals.
Determinants of Astrocytic Pathology in Stem Cell Models of Primary Tauopathies
Authors: Fiock Kimberly L. , Hook Jordan , Hefti Marco M.
Published: July 2023

Astrocytic tau aggregates are seen in several primary and secondary tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). In all cases, astrocytic tau consists exclusively of the longer (4R) tau isoform, even when adjacent neuronal aggregates consist of a mixture of 3- and 4R tau, as in CTE. The reasons for this and the mechanisms by which astrocytic tau aggregates form remain unclear. We used a combination of RNAin situhybridization and immunofluorescence in post-mortem human brain tissue, as well as tau uptake studies in human stem cell-derived astrocytes, to determine the origins of astrocytic tau in 4R tauopathies. We found that astrocytes across tauopathies do not upregulate tau mRNA expression between diseases or between tau-positive and -negative astrocytes within PSP. We then found that stem cell-derived astrocytes preferentially take up long isoform (4R) labeled recombinant tau and that this uptake is impaired by induction of reactivity with inflammatory stimuli or nutritional stress. Astrocytes exposed to either 3R or 4R tau also showed downregulation of genes related to astrocyte differentiation. Our findings suggest that astrocytes preferentially take up neuronal 4R tau from the extracellular space, which potentially explains why astrocytic tau aggregates contain only 4R tau, and that tau uptake is impaired by decreased nutrient availability or neuroinflammation, both of which are common in the aging brain.
BRAIDing receptors for cell-specific targeting
Authors: Chen Hui , Lee Sung-Jin , Li Ryan , Sura Asmiti , Suen Nicholas , Dilip Archana , Pomogov Yan , Vuppalapaty Meghah , Suen Timothy T. , Lu Chenggang , Post Yorick , Li Yang
Published: July 2023

Systemic toxicity is a major challenge in the development of therapeutics. Consequently, cell-type-specific targeting is needed to improve on-target efficacy while reducing off-target toxicity. Here, we describe a cell-targeting system we have termed BRAID (BRidgedActivation byIntra/intermolecularDivision) whereby an active molecule is divided into two inactive or less active parts that are subsequently brought together via a so-called ‘bridging receptor’ on the target cell. This concept was validated using the WNT/β-catenin signaling system, demonstrating that a multivalent WNT agonist molecule divided into two inactive components assembled from different epitopes via the hepatocyte receptor βKlotho induces signaling specifically on hepatocytes. These data provide proof-of-concept for this cell-specific targeting strategy and in principle, this may also allow activation of multiple signaling pathways where desirable. This approach has broad application potential for other receptor systems.
Antimicrobial activity of iron-depriving pyoverdines against human opportunistic pathogens
Authors: Vollenweider Vera , Rehm Karoline , Chepkirui Clara , Pérez-Berlanga Manuela , Polymenidou Magdalini , Piel Jörn , Bigler Laurent , Kümmerli Rolf
Published: July 2023

The global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here we show that the iron chelating pyoverdines, siderophores produced by environmentalPseudomonasspp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 naturalPseudomonasisolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogensAcinetobacter baumannii,Klebsiella pneumoniaeandStaphylococcus aureusin a concentration- and iron-dependent manner. Pyoverdine increased survival of infectedGalleria mellonellahost larvae, and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution combined with whole-genome sequencing revealed reduced potentials for resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens.
The miR-144/Hmgn2 regulatory axis orchestrates chromatin organization during erythropoiesis
Authors: Kretov Dmitry A. , Folkes Leighton , Mora-Martin Alexandra , Syedah Noreen , Walawalkar Isha A. , Vanyustel Kim , Moxon Simon , Murphy George J. , Cifuentes Daniel
Published: July 2023

Differentiation of stem and progenitor cells is a highly regulated process that involves the coordinated action of multiple layers of regulation. Here we show how the post-transcriptional regulatory layer instructs the level of chromatin regulation via miR-144 and its targets to orchestrate chromatin condensation during erythropoiesis. The loss of miR-144 leads to impaired chromatin condensation during erythrocyte maturation. Among the several targets of miR-144 that influence chromatin organization, the miR-144-dependent regulation of Hmgn2 is conserved from fish to humans. Our genetic probing of the miR-144/Hmgn2 regulatory axis established that intact miR-144 target sites in the Hmgn2 3’UTR are necessary for the proper maturation of erythrocytes in both zebrafish and human iPSC-derived erythroid cells while loss of Hmgn2 rescues in part the miR-144 null phenotype. Altogether, our results uncover miR-144 and its target Hmgn2 as the backbone of the genetic regulatory circuit that controls the terminal differentiation of erythrocytes in vertebrates.
Analysis of small EV proteomes reveals unique functional protein networks regulated by VAP-A
Authors: Barman Bahnisikha , Ramirez Marisol , Dawson T. Renee , Liu Qi , Weaver Alissa M
Published: July 2023

Extracellular vesicles (EVs) influence cell phenotypes and functions via protein, nucleic acid and lipid cargoes. EVs are heterogeneous, due to diverse biogenesis mechanisms that remain poorly understood. Our previous study revealed that the endoplasmic rectiulum (ER) membrane contact site (MCS) linker protein VAP-A drives biogenesis of a subset of RNA-enriched EVs. Here, we examine the protein content of VAP-A-regulated EVs. Using label-free proteomics, we identified down- and up-regulated proteins in sEVs purified from VAP-A knockdown (KD) colon cancer cells. Gene set enrichment analysis (GSEA) of the data revealed protein classes that are differentially sorted to SEVs dependent on VAP-A. STRING protein-protein interaction network analysis of the RNA-binding protein (RBP) gene set identified several RNA functional machineries that are downregulated in VAP-A KD EVs, including ribosome, spliceosome, mRNA surveillance, and RNA transport proteins. We also observed downregulation of other functionally interacting protein networks, including cadherin-binding, unfolded protein binding, and ATP-dependent proteins.

Significance of the study

Little is known about biogenesis mechanisms that underlie EV heterogeneity. This study explores the protein repertoire of a specific subset of EVs that we recently identified to be generated at ER MCS and that are highly enriched in RNAs. We find that proteins from several classes of RNA machineries, including spliceosomes, are downregulated in EVs purified from cells knocked down for the ER MCS linker protein VAP-A. These data suggest that dynamic regulation of these protein machineries at ER MCS are involved in the sorting of RNA-RBP complexes into EVs.
Estimating error rates for single molecule protein sequencing experiments
Authors: Smith Matthew Beauregard , VanderVelden Kent , Blom Thomas , Stout Heather D. , Mapes James H. , Folsom Tucker M. , Martin Christopher , Bardo Angela M. , Marcotte Edward M.
Published: July 2023

The practical application of new single molecule protein sequencing (SMPS) technologies requires accurate estimates of their associated sequencing error rates. Here, we describe the development and application of two distinct parameter estimation methods for analyzing SMPS reads produced by fluorosequencing. A Hidden Markov Model (HMM) based approach, extendswhatprot, where we previously used HMMs for SMPS peptide-read matching. This extension offers a principled approach for estimating key parameters for fluorosequencing experiments, including missed amino acid cleavages, dye loss, and peptide detachment. Specifically, we adapted the Baum-Welch algorithm, a standard technique to estimate transition probabilities for an HMM using expectation maximization, but modified here to estimate a small number of parameter values directly rather than estimating every transition probability independently, which should help prevent overfitting. We demonstrate a high degree of accuracy on simulated data, but on experimental datasets, we observed that the model needed to be augmented with an additional error type, N-terminal blocking. This, in combination with data pre-processing, results in reasonable parameterizations of experimental datasets that agree with controlled experimental perturbations. A second independent implementation using a hybrid of DIRECT and Powell’s method to reduce the root mean squared error (RMSE) between simulations and the real dataset was also developed. We compare these methods on both simulated and real data, finding that our Baum-Welch based approach outperforms DIRECT and Powell’s method by most, but not all, criteria. Although some discrepancies between the results exist, we also find that both approaches provide similar error rate estimates from experimental single molecule fluorosequencing datasets.
Distinct haplogroups with star-like diversification in the APOBEC3 regulatory region indicate ancient viral pandemics before and during the Out-of-Africa migration of modern humans
Authors: Fujito Naoko T , Sundaramoorthy Revathi Devi , Satta Yoko , Inoue Ituro
Published: July 2023

APOBEC3s are powerful human anti-viral proteins that inhibit viral replication and proliferation by inducing mutations in viral genomes. We found that in the regulatory region of the APOBEC3 cluster on human chromosome 22, there exist three distinct haplogroups that began to have diverged nearly 1 million years ago and have since been maintained in both African and non-African populations today. Despite the long persistence time of the haplogroups, one of which is shared by archaic hominins, we also found that the nucleotide diversity within each haplogroup is extremely low. With a simulation-based method, the observed low diversity within haplogroups and large divergence between haplogroups suggested that these haplogroups have been maintained by special forms of positive Darwinian selection. Repeated occurrence of such selection entails the enhanced substitution rate in this regulatory region in both the human and chimpanzee lineages. The causal events of such positive selection, which are most likely viral epidemics, are shown to have occurred at least three times in the modern human population: one before the Out-of-Africa migration and another two in the common ancestors of non-Africans.
Contextual AI models for single-cell protein biology
Authors: Li Michelle M. , Huang Yepeng , Sumathipala Marissa , Liang Man Qing , Valdeolivas Alberto , Ananthakrishnan Ashwin N. , Liao Katherine , Marbach Daniel , Zitnik Marinka
Published: July 2023

Understanding protein function and developing molecular therapies require deciphering the cell types in which proteins act as well as the interactions between proteins. However, modeling protein interactions across biological contexts remains challenging for existing algorithms. Here, we introduce Pinnacle, a geometric deep learning approach that generates context-aware protein representations. Leveraging a multi-organ single-cell atlas, Pinnaclelearns on contextualized protein interaction networks to produce 394,760 protein representations from 156 cell type contexts across 24 tissues. Pinnacle’s embedding space reflects cellular and tissue organization, enabling zero-shot retrieval of the tissue hierarchy. Pretrained protein representations can be adapted for downstream tasks: enhancing 3D structure-based representations for resolving immuno-oncological protein interactions, and investigating drugs’ effects across cell types. Pinnacleoutperforms state-of-the-art models in nominating therapeutic targets for rheumatoid arthritis and inflammatory bowel diseases, and pinpoints cell type contexts with higher predictive capability than context-free models. Pinnacle’s ability to adjust its outputs based on the context in which it operates paves way for large-scale context-specific predictions in biology.
Understanding the structural basis for differential binding of lapachol with PfHSP70s
Authors: Singh Bikramjit , Kaur Satinder , Sandhu Komalpreet Kaur , Nainani Chanchal , Upadhyay Vipul , Hora Rachna , Mishra Prakash Chandra
Published: July 2023

The 70 kDa heat shock proteins fromPlasmodium falciparum(PfHSP70) are an important family of proteins that may be exploited for antimalarial design. Plant derived inhibitor ‘lapachol’ is reported to efficiently inhibit the exported PfHSP70-x while having poor activity against the parasite PfHSP70-1. In the present study, we have usedin silicotools including molecular docking to understand the molecular basis for the above differences in lapachol inhibition activity against PfHSP70s. We found a significant gap in the binding energies and hence affinity of PfHSP70-1 and PfHSP70-x for lapachol with the latter having a better binding propensity. Our data highlight notable differences in the type of interactions between the two complexes. Detailed molecular analysis of the complexes has helped us to predict specific amino acid residues from both these PfHSP70 homologs that may be involved in lapachol binding. The above information may be utilized for design of PfHSP70 inhibitors with antimalarial potential.
Hundreds of independent midsize deletions mediate DNA loss in wild relatives of Red Jungle Fowl
Authors: Sharma Ashutosh , Shinde Sagar Sharad , Vijay Nagarjun
Published: July 2023

Small and midsize deletions and insertions (InDels) are major events that play a crucial role in the evolution of genome size and contribute to the genetic and phenotypic diversity of species. In recent years, considerable attention has been given to studying small indels associated with various developmental, growth, and production traits in domestic chicken breeds. Additionally, small and midsize indels have been studied between chicken and phylogenetically more distant species such as duck, turkey, rock pigeon, and other passerine birds. However, the investigation of small and midsize deletions in the wild relatives of chickens has been relatively overlooked until now. To address this gap, our study aimed to identify the presence and distribution of midsize deletions (> 1 Kb) in the wild relatives of chickens. We conducted a comparative genomic analysis using high-quality genomic data from four species belonging to theGallusgenus. Our analysis revealed the existence of more than 125 midsize deletions in the three other species compared toGallus gallus(red junglefowl). These midsize deletions were found to be distributed in intergenic regions and within introns of various protein-coding genes but not in the exonic regions of protein-coding genes. Furthermore, we observed a trend between the number of midsize deletions and the phylogenetic distance in the phylogeny of theGallusgenus. The most ancestral species,Gallus varius(green junglefowl), exhibited the highest deletions, followed byGallus lafayettii(Ceylon junglefowl) andGallus sonneratii(grey junglefowl). Some protein-coding genes harboring deletions in their introns and upstream regions were associated with body development, production, growth traits, abdominal fat deposition, behavioral patterns such as stress, fear, anxiety, plumage color, and adaptation to extreme climatic conditions. Our study finds that the midsize deletions identified in wild relatives of red junglefowl contribute less than 1% of DNA loss with a rate of 8-44 Kb/My during the evolution of theGallusgenus.
Impact of Microscopic Quantum Mechanisms on Macroscopic Epigenetic Regulation through Histone Deacetylation
Authors: Yasuda Takeshi , Ogi Tomoo , Nakajima Nakako , Yanaka Tomoko , Tanaka Izumi , Tajima Katsushi
Published: July 2023

The question of whether physical phenomena at a quantum level significantly impact aspects of macroscopic life has long remained unanswered. Histone modification by acetylation regulates the transcriptional activity of genes, and thereby broadly impacts cellular metabolism. In chemical reactions, the quantum tunneling effect is a phenomenon in which a small quantum particle of the reactant can pass through the potential energy barrier, even if it does not have sufficient energy to overcome the barrier. Here, we demonstrated that quantum effects are involved in the enzymatic reaction of histone deacetylation, by monitoring kinetic isotope effects due to hydrogen isotopes of water molecules and their temperature dependence as indicators. Due to the kinetic isotope effects associated with the quantum effects, the reaction rate balance between histone acetylation and deacetylation in cells was altered with heavy water, which changed epigenetic transcription regulation in the cells. Thus, microscopic quantum mechanisms exist in histone deacetylation, thereby broadly impacting macroscopic life phenomena through epigenetic regulation.

Teaser

Quantum effects in enzymatic reaction of histone deacetylation latently influence life phenomena through epigenetic regulation.
Effects of Alternative Splicing-Specific Knockdown of Tjp1 α+ by Rbm47 on Tight Junctions Assembly during Blastocyst Development
Authors: Jeong Jiyeon , Choi Inchul
Published: July 2023

Tjp1 α+ is considered a crucial protein involved in the stepwise assembly of tight junctions (TJs) between compaction and blastocoel cavitation in early development. In this study, we investigated the specific role of Tjp1 α+ in TJ formation by employing an alternative splicing-specific knockdown of the Tjp1 α+ exon. To deplete Tjp1 α+ expression, we used siRNA targeting RNA-binding protein 47 (Rbm47), which induces the inclusion of the α+ exon in Tjp1 mRNA. The knockdown resulted in approximately 85% reduction in Rbm47 mRNA levels and 75% reduction in Tjp1 α+ mRNA levels in blastocysts. Surprisingly, despite this knockdown, blastocyst development and TJ permeability of trophectoderm were unaffected. Additionally, we observed an interaction between Tjp1 α- and Ocln in Rbm47 knockdown blastocysts, suggesting a compensatory role of Tjp1 α-. Overall, our findings indicate that Tjp1 α+ is not essential for the stepwise assembly of TJs and the completion of TJ biogenesis during blastocyst development in mice although a minimal amount of remaining Tjp1 α+ is sufficient for TJs assembly.

Summary statement

Selective loss of Tjp1 α+ mediated by Rbm47 knockdown did affect mouse blastocyst development, suggesting that Tjp1 α+ may not be crucial for stepwise TJs assembly during blastocyst development
A multistagePlasmodiumCRL4WIG1ubiquitin ligase is critical for the formation of functional microtubule organisation centres in microgametocytes
Authors: Rashpa Ravish , Smith Cameron , Artavanis-Tsakonas Katerina , Brochet Mathieu
Published: July 2023

Malaria is a mosquito-borne infectious disease caused by unicellular eukaryotic parasites of thePlasmodiumgenus. Protein ubiquitination by E3 ligases is a critical post-translational modification required for various cellular processes during the lifecycle ofPlasmodiumparasites. However, little is known about the repertoire and function of these enzymes inPlasmodium.Here we show thatPlasmodiumexpresses a conserved cullin RING E3 ligase (CRL) complex that is functionally related to the eukaryotic CRL4. InP. falciparumasexual blood stages, a cullin-4 scaffold interacts with the RING protein RBX1, the adaptor protein DDB1 and a set of putative receptor proteins that may determine substrate specificity for ubiquitination. These receptor proteins contain WD40-repeat domains and includeWD-repeat protein Important forGametogenesis 1 (WIG1). This CRL4-related complex is also expressed inP. bergheigametocytes, with WIG1 being the only putative receptor detected in both schizont and gametocyte stages. While WIG1 is not required for the proliferation ofP. bergheiasexual blood stages, its disruption leads to a complete block in microgamete formation. Proteomic analyses indicate thatWIG1disruption alters proteostasis of ciliary proteins and components of the DNA replication machinery during gametocytogenesis. Further analysis by ultrastructure expansion microscopy (U-ExM) indicates that WIG1-dependent depletion of ciliary proteins is associated with impaired formation of the microtubule organisation centres that coordinate mitosis with axoneme formation and altered DNA replication during microgametogenesis. This work identifies a CRL4-related ubiquitin ligase inPlasmodiumthat is critical for the transmission of malaria parasites by regulating proteostasis of ciliary and DNA replication proteins.
A neuropsychological basis for temptation-resistant voluntary exercise
Authors: Tesmer Alexander L. , Li Xinyang , Schmandt Cyra , Polania Rafael , Peleg-Raibstein Daria , Burdakov Denis
Published: July 2023

Despite well-known health benefits of physical activity, many people under-exercise, and what drives prioritization of exercise over other alternatives is unclear. We implement a novel paradigm allowing to study how freely behaving mice rapidly display such prioritizing between time spent on wheel-running and other temptations such as palatable food. Causal manipulations and correlative analyses of underlying appetitive and consummatory psychobehavioral processes revealed this prioritizing to be instantiated by hypothalamic hypocretin/orexin neurons.
ThePlasmodium falciparumCCCH zinc finger protein MD3 regulates male gametocytogenesis through its interaction with RNA-binding proteins
Authors: Farrukh Afia , Musabyimana Jean Pierre , Distler Ute , Mahlich Vanessa Jil , Mueller Julius , Bick Fabian , Tenzer Stefan , Pradel Gabriele , Ngwa Che Julius
Published: July 2023

Malaria transmission to mosquitoes is dependent on the formation of gametocytes. When fully matured, gametocytes are able to transform into gametes in the mosquito’s midgut, a process accompanied with their egress from the enveloping erythrocyte. Gametocyte maturation and gametogenesis require a well-coordinated gene expression programme that involves a wide spectrum of regulatory proteins, ranging from histone modifiers to transcription factors to RNA-binding proteins. Here, we investigated the role of the CCCH-zinc finger protein MD3 inP. falciparumgametocytogenesis. MD3 was originally identified by us as an epigenetically regulated protein of immature gametocytes and recently shown to be involved in male development in a barcode-based screen inP. berghei. We here show that MD3 is mainly present in the cytoplasm of immature maleP. falciparumgametocytes. Parasites deficient of MD3 are impaired in gametocyte maturation and male gametocyte exflagellation. BioID analysis in combination with co-immunoprecipitation assays unveiled an interaction network of MD3 with RNA-binding proteins like PABP1 and ALBA3, with translational initiators, regulators and repressors like elF4G, PUF1, NOT1 and CITH, and with other regulators of gametocytogenesis, including ZNF4, MD1 and GD1. We conclude that MD3 is part of a regulator complex crucial for post-transcriptional fine-tuning of male gametocytogenesis.
Deciphering the spatio-temporal transcriptional and chromatin accessibility of human retinal organoid development at the single cell level
Authors: Dorgau Birthe , Collin Joseph , Rozanska Agata , Boczonadi Veronika , Moya-Molina Marina , Hussain Rafiqul , Coxhead Jonathan , Dhanaseelan Tamil , Armstrong Lyle , Queen Rachel , Lako Majlinda
Published: July 2023

Molecular information on the early stages of human retinal development remains scarce due to limitations in obtaining early human eye samples. Pluripotent stem cell-derived retinal organoids provide an unprecedented opportunity for studying early retinogenesis. Using a combination of single cell RNA-Seq and spatial transcriptomics we present for the first-time a single cell spatio-temporal transcriptome of retinal organoid development. Our data demonstrate that retinal organoids recapitulate key events of retinogenesis including optic vesicle/cup formation, formation of a putative ciliary margin zone, emergence of retinal progenitor cells and their orderly differentiation to retinal neurons. Combining the scRNA-with scATAC-Seq data, we were able to reveal cell-type specific transcription factor binding motifs on accessible chromatin at each stage of organoid development and to show that chromatin accessibility is highly correlated to the developing human retina, but with some differences in the temporal emergence and abundance of some of the retinal neurons.
Evaluating the bioactivities of natural and synthetic fungal tropolone sesquiterpenoids in various cell lines
Authors: Bergmann Timna C. , Menssen Max , Schotte Carsten , Cox Russell J. , Lee-Thedieck Cornelia
Published: July 2023

Fungal specialized metabolites are known for their potent biological activities, among which tropolone sesquiterpenoids (TS) stand out for their diverse bioactivities. Here, we report bioactive effects of the recently discovered TS compounds 4–hydroxyxenovulene B and 4– dihydroxy norpycnidione, and the structurally related 4-hydroxy norxenovulene B and xenovulene B. Inhibition of metabolic activity after TS treatment was observed in Jurkat, PC–3 and FAIK3–5 cells, whereas MDA-MB-231 cells were unresponsive to treatment. Structurally similar epolones were shown to induce erythropoietin (EPO). Therefore, FAIK3-5 cells, which can naturally produce EPO, were applied to test the compounds in this regard. While no effect on EPO production in FAIK3-5 cells could be demonstrated, effects on their proliferation, viability, and morphology were observed depending on the presence of tropolone moieties in the molecules. Our study underlines the importance of relevant cell models for bioactivity testing of compounds with unknown mechanisms of action.
Multiple objects evoke fluctuating responses in several regions of the visual pathway
Authors: Schmehl Meredith N. , Caruso Valeria C. , Chen Yunran , Jun Na Young , Willett Shawn M. , Mohl Jeff T. , Ruff Douglas A. , Cohen Marlene , Ebihara Akinori F. , Freiwald Winrich , Tokdar Surya T. , Groh Jennifer M.
Published: July 2023

How neural representations preserve information about multiple stimuli is mysterious. Because tuning of individual neurons is coarse (for example, visual receptive field diameters can exceed perceptual resolution), the populations of neurons potentially responsive to each individual stimulus can overlap, raising the question of how information about each item might be segregated and preserved in the population. We recently reported evidence for a potential solution to this problem: when two stimuli were present, some neurons in the macaque visual cortical areas V1 and V4 exhibited fluctuating firing patterns, as if they responded to only one individual stimulus at a time. However, whether such an information encoding strategy is ubiquitous in the visual pathway and thus could constitute a general phenomenon remains unknown. Here we provide new evidence that such fluctuating activity is also evoked by multiple stimuli in visual areas responsible for processing visual motion (middle temporal visual area, MT), and faces (middle fundus and anterolateral face patches in inferotemporal cortex – areas MF and AL), thus extending the scope of circumstances in which fluctuating activity is observed. Furthermore, consistent with our previous results in the early visual area V1, MT exhibits fluctuations between the representations of two stimuli when these form distinguishable objects but not when they fuse into one perceived object, suggesting that fluctuating activity patterns may underlie visual object formation. Taken together, these findings point toward an updated model of how the brain preserves sensory information about multiple stimuli for subsequent processing and behavioral action.

Impact Statement

We find neural fluctuations in multiple areas along the visual cortical hierarchy that could allow the brain to represent distinct co-occurring visual stimuli.
Modeling Type 1 Diabetes progression from single-cell transcriptomic measurements in human islets
Authors: Patil Abhijeet R. , Schug Jonathan , Liu Chengyang , Lahori Deeksha , Descamps Hélène C. ,   the Human Pancreas Analysis Consortium, Naji Ali , Kaestner Klaus H. , Faryabi Robert B. , Vahedi Golnaz
Published: July 2023

Type 1 diabetes (T1D) is a chronic condition in which the insulin-producing beta cells are destroyed by immune cells. Research in the past few decades characterized the immune cells involved in disease pathogenesis and has led to the development of immunotherapies that can delay the onset of T1D by two years. Despite this progress, early detection of autoimmunity in individuals who will develop T1D remains a challenge. Here, we evaluated the potential of combining single-cell genomics and machine learning strategies as a prime approach to tackle this challenge. We used gradient-boosting-based machine learning algorithms and modeled changes in transcriptional profiles of single cells from pancreatic tissues in T1D and nondiabetic organ donors collected by the Human Pancreas Analysis Program. We assessed whether mathematical modelling could predict the likelihood of T1D development in nondiabetic autoantibody-positive organ donors. While the majority of autoantibody-positive organ donors were predicted to be nondiabetic by our model, select donors with unique gene signatures were classified with the T1D group. Remarkably, our strategy also revealed a shared gene signature in distinct T1D associated models based on different cell types including alpha cells, beta cells and acinar cells, suggesting a common effect of the disease on transcriptional outputs of these cells. Together, our strategy presents the first report on the utility of machine learning algorithms in early detection of molecular changes in T1D.
The evolution of service toward automated customer assistance: there is a difference
Authors: Roberts Chris , Maier Thomas
Published: July 2023

Purpose

The purpose of this paper is to explore the distinction between human-delivered service and technology-based, automated customer assistance.

Design/methodology/approach

This is a conceptual paper. There is no methodology.

Findings

The concept of service is primarily delivered when a human helps another. When technology is infused into the process and becomes the major component of delivering the aid that is requested, the process is automated customer assistance. Thus, “self-service” is not service. It is automated customer assistance.

Research limitations/implications

The definition of service is refined to describe the process of a human helping another person. When technology is used to provide the needed aid, it is no longer a service. Instead, it is automated customer assistance. The implication is that researchers should closely examine how users assess and perceive the two separate approaches to providing the needed aid.

Practical implications

The definition of service is refined to describe the process of a human helping another person. When technology is used to provide the needed aid, it is no longer a service. Instead, it is automated customer assistance. Researchers should closely examine how users assess and perceive the two separate approaches. Industry professionals should be mindful of the distinction between the delivery of service, which requires staff, and the provisioning of technology to provide assistance, which requires little to no staff. Intentionality should drive when customers are better helped by a human or by technology.

Originality/value

The value provided helps both providers create and users express when human-based service is needed versus assistance provided by technology.
Relevance of Stephen Covey's theory on the circle of life in the context of student decision-making to enroll for higher education
Authors: Srivastava Khusboo , Dhamija Somesh
Published: July 2023

Purpose

This study attempts to elucidate the role of key influencers impacting the student decision-making process of enrollment for higher education in India from the lenses of Stephen Covey's theory on circles of life.

Design/methodology/approach

A sample of 556 students of Delhi NCR, India was selected based on a multi-staged sampling method. PLS-SEM was subsequently applied for statistical data analysis.

Findings

This quantitative finding voiced the relationships among the constructs in the proposed theoretical framework, i.e. Stephen Covey's circle of life theory. Additionally, it tinted the crucial role of “College attributes” in reconnoitering the relationship dynamics between key influencers (Circle of Influence and Circle of Concern) and student college choice (Circle of Control).

Research limitations/implications

The present study incorporates only the first-year student population of undergraduate management courses in private universities from Delhi NCR, India limiting the generalization of findings substantially.

Practical implications

The study garners the attention of education policymakers on the cognizance of the role played by parents and cohorts in driving the student's decision-making process of college choice under the circle of influence.

Originality/value

This study is pioneering research disseminating a comprehensive outlook of the circle of life theory of great Stephen Covey engrained upon a compendious conceptual model which enlightens the landscape of the decision-making process of student on enrollment under the influence of key influencers.
International entrepreneurship: an approach for entrepreneurial skill development
Authors: Sousa Maria José , Moreira Ana , Leão João , Sousa Miguel , Biancone Paolo Pietro , Lanzalonga Federico
Published: July 2023

Purpose

The research aims to investigate the changing skills required for international entrepreneurship (IE) and the awareness of these skills among students and professionals in four European countries. The study intends to investigate students' and professionals' perceptions of entrepreneurial skills and the potential for educational programs to improve their awareness of these skills.

Design/methodology/approach

This quantitative cross-sectional analysis uses an online questionnaire to collect data from 75 university students and 75 entrepreneurs in four European countries. Several tests validate the data, and Cronbach's alpha succeeded in measuring internal consistency. The results showed differences in the perception of skills between students and entrepreneurs.

Findings

Entrepreneurs had developed all competencies except access to finance, while students had lower perceptions of their skills, except for collaboration. Students needed to improve significantly in access to finance, business planning, financial skills, knowledge of the labour market and digital marketing. Practitioners only required significant improvement in access to finance and digital marketing.

Practical implications

Education programs should fit the needs of different groups: a broader program for students and more specific courses on access to finance and digital marketing for practitioners.

Originality/value

The present research's original feature highlights the need to monitor and adapt to the constantly changing skills for IE and the importance of hard and soft skills. The paper provides insights into the subject's awareness and perceived standard, with reflections for policymakers and practitioners.