bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of universal Ebola virus vaccine candidatesviaimmunofocusing
Authors: Xu Duo , Powell Abigail E. , Utz Ashley , Sanyal Mrinmoy , Do Jonathan , Patten J.J. , Moliva Juan I. , Sullivan Nancy J. , Davey Robert A. , Kim Peter S.
Published: October 2023

Ebola virus causes hemorrhagic fever in humans and poses a significant threat to global public health. Although two viral vector vaccines have been approved to prevent Ebola virus disease, they are distributed in the limited ring vaccination setting and only indicated for prevention of infection fromorthoebolavirus zairense(EBOV) – one of threeorthoebolavirusspecies that have caused previous outbreaks. Ebola virus glycoprotein GP mediates viral infection and serves as the primary target of neutralizing antibodies. Here we describe a universal Ebola virus vaccine approach using structure-guided design of candidates with hyperglycosylation that aims to direct antibody responses away from variable regions and toward conserved epitopes of GP. We first determined the hyperglycosylation landscape on Ebola virus GP and used that to generate hyperglycosylated GP variants with two to four additional glycosylation sites to mask the highly variable glycan cap region. We then created vaccine candidates by displaying wild-type or hyperglycosylated GP variants on ferritin nanoparticles (Fer). Immunization with these antigens elicited potent neutralizing antisera against EBOV in mice. Importantly, we observed consistent cross-neutralizing activity against Bundibugyo virus and Sudan virus from hyperglycosylated GP-Fer with two or three additional glycans. In comparison, elicitation of cross-neutralizing antisera was rare in mice immunized with wild-type GP-Fer. These results demonstrate a potential strategy to develop universal Ebola virus vaccines that confer cross-protective immunity against existing and emerging filovirus species.

SIGNIFICANCE STATEMENT

Ebola virus outbreaks cause hemorrhagic fever with high mortality rates. Current viral vaccines require cold-chain storage and are distributed in limited ring vaccination settings. They are only indicated for protection againstorthoebolavirus zairense(EBOV), one of three human-pathogenic Ebola virus species. Here we harness hyperglycosylation as an immunofocusing approach to design universal Ebola virus vaccine candidates based on Ebola virus glycoprotein (GP) displayed on ferritin nanoparticles (Fer). Compared with wild-type GP-Fer, immunization with hyperglycosylated GP-Fer elicited potently neutralizing antisera against EBOV, and more importantly, consistent cross-neutralizing activity against the other two orthoebolavirus species. Our work shows that immunofocusing antibody responses toward conserved and neutralizing epitopes of GP represents a promising strategy for vaccine design against antigenically diverse Ebola virus species.
Spatial processing of limbs reveals the center-periphery bias in high level visual cortex follows a nonlinear topography
Authors: Daniel Hertz Edan , Yao Jewelia K. , Gregorek Sidney , Hoyos Patricia M. , Gomez Jesse
Published: October 2023

Human visual cortex contains regions selectively involved in perceiving and recognizing ecologically important visual stimuli such as people and places. Located in the ventral temporal lobe, these regions are organized consistently relative to cortical folding, a phenomenon thought to be inherited from how centrally or peripherally these stimuli are viewed with the retina. While this eccentricity theory of visual cortex has been one of the best descriptions of its functional organization, whether or not it accurately describes visual processing in all category-selective regions is not yet clear. Through a combination of behavioral and functional MRI measurements, we demonstrate that a limb-selective region neighboring well-studied face-selective regions defies predictions from the eccentricity theory of cortical organization. We demonstrate that the spatial computations performed by the limb-selective region are consistent with visual experience, and in doing so, make the novel observation that there may in fact be two eccentricity gradients, forming a parabolic topography across visual cortex. These data expand the current theory of cortical organization to provide a unifying principle that explains the broad functional features of many visual regions, showing that viewing experience interacts with innate wiring principles to drive the location of cortical specialization.
Viromes vs. mixed community metagenomes: choice of method dictates interpretation of viral community ecology
Authors: Kosmopoulos James C. , Klier Katherine M. , Langwig Marguerite V. , Tran Patricia Q. , Anantharaman Karthik
Published: October 2023

Background

Viruses, the majority of which are uncultivated, are among the most abundant biological entities on Earth. From altering microbial physiology to driving community dynamics, viruses are fundamental members of microbiomes. While the number of studies leveraging viral metagenomics (viromics) for studying uncultivated viruses is growing, standards for viromics research are lacking. Viromics can utilize computational discovery of viruses from total metagenomes of all community members (hereafter metagenomes) or use physical separation of virus-specific fractions (hereafter viromes). However, differences in the recovery and interpretation of viruses from metagenomes and viromes obtained from the same samples remain understudied.

Results

Here, we compare viral communities from paired viromes and metagenomes obtained from 60 diverse samples across human gut, soil, freshwater, and marine ecosystems. Overall, viral communities obtained from viromes were more abundant and species rich than those obtained from metagenomes, although there were some exceptions. Despite this, metagenomes still contained many viral genomes not detected in viromes. We also found notable differences in the predicted lytic state of viruses detected in viromes vs metagenomes at the time of sequencing. Other forms of variation observed include genome presence/absence, genome quality, and encoded protein content between viromes and metagenomes, but the magnitude of these differences varied by environment.

Conclusions

Overall, our results show that the choice of method can lead to differing interpretations of viral community ecology. We suggest that the choice of whether to target a metagenome or virome to study viral communities should be dependent on the environmental context and ecological questions being asked. However, our overall recommendation to researchers investigating viral ecology and evolution is to pair both approaches to maximize their respective benefits.
Does Bodily Action Shape Spatial Representation? Evidence from Virtual Reality, Sensory Augmentation and Map Learning
Authors: Kuske Nicolas , Clay Viviane
Published: October 2023

Spatial relations can be defined with respect to the body (egocentric) or among environmental objects only (allocentric). Egocentric relations are necessarily transformed through bodily action. To what extent allocentric cognitive representations are shaped by the body remains unclear. In our study, participants navigate a virtual-reality (VR) city over multiple days in one of three embodiment conditions. In two VR conditions, the participants sit on a swivel chair actively changing navigation direction through bodily rotation. In one of these groups the VR participants wear a sensory augmentation belt which indicates the cardinal direction of north through vibration. The third group of participants navigates a two-dimensional map of the city. After each exploration session, participants complete tasks asking for allocentric spatial relations. We find that the performance in the spatial tasks interacts with the duration of exploration time and the embodiment condition. These findings indicate allocentric spatial representations to be structured by bodily action.
Bioinformatics Illustrations Decoded by ChatGPT: The Good, The Bad, and The Ugly
Authors: Wang Jinge , Ye Qing , Liu Li , Guo Nancy Lan , Hu Gangqing
Published: October 2023

Emerging studies underscore the promising capabilities of large language model-based chatbots in conducting fundamental bioinformatics data analyses. The recent feature of accepting image-inputs by ChatGPT motivated us to explore its efficacy in deciphering bioinformatics illustrations. Our evaluation with examples in cancer research, including sequencing data analysis, multimodal network-based drug repositioning, and tumor clonal evolution, revealed that ChatGPT can proficiently explain different plot types and apply biological knowledge to enrich interpretations. However, it struggled to provide accurate interpretations when quantitative analysis of visual elements was involved. Furthermore, while the chatbot can draft figure legends and summarize findings from the figures, stringent proofreading is imperative to ensure the accuracy and reliability of the content.
Proteome-wide Mendelian randomization identifies candidate causal proteins for cardiovascular diseases
Authors: Li Chen , Jay Nicolas De , Sharma Supriya , Catalano Katrina A. , Holzinger Emily R. , Sridharan Venkatesh , Wang Zhaoqing , Zhao Lei , Szustakowski Joseph D. , Chang Ching-Pin , Maranville Joseph C. , Kvikstad Erika M.
Published: October 2023

Background

Cardiovascular diseases (CVD) remain the leading cause of death worldwide, while a lack of clarity on underlying mechanisms has hindered development of novel therapies. Integration of human genetics and proteomics across different ancestries can provide novel, affordable, and systematic approach for target identification and prioritization.

Methods

Mendelian randomization approach was applied to unravel causal associations between 2,940 circulating proteins and 21 CVD. Genome-wide summary statistics from the largest genetic mapping of human plasma proteome and meta-analyses on CVD across FinnGen, UK Biobank and Biobank Japan were used. Forward and reverse causation were studied to distinguish respective targets and biomarkers. Genetic instruments for Europeans and East Asians were derived separately and applied to the cardiovascular outcomes in cohorts from corresponding ancestries. We further prioritized drug targets by integrating biological, clinical and population study evidence from cross-database annotations and literature review. Single-cell enrichment analysis and phenome-wide causality scan were performed to further understand target mechanism of action.

Results

We found 221 novel candidate causal proteins that impacted risk of one or more CVD through forward MR, and 16 biomarkers whose expression levels were affected by CVD through reverse MR (Bonferroni-adjustedP-value <= 0.05). Forward and reverse MR found largely non-overlapping proteins among CVD (only 2 overlapped: LGALS4 and MMP12), suggesting distinct proteomic causes and consequences of CVD. Many of the candidate causal proteins (73.4%) identified are supported by strong literature evidence for a role in immune response and atherosclerotic lesion formation, angiogenesis and vascular remodeling, myogenesis and cardiac progenitor cell differentiation, and energy metabolism. Single cell integration further prioritized ADAM23 for cardiomegaly, PAM for stable angina pectoris and ventricular arrythmia and LPL for peripheral artery disease, whose transcript expression were enriched in cardiomyocytes. Three protein functional groups were highlighted in the phenome-wide scan for their specific enrichment for CVD, including blood coagulation and fibrinolysis, angiogenesis and vascular remodeling, and cell proliferation and myogenesis.

Conclusions

Our study identified potential therapeutic targets for CVD and distinguished them from biomarkers due to reverse causation. This study provides human genetics-based evidence of novel candidate genes, a foundational step towards full-scale causal human biology-based drug discovery for CVD.
Evolutionary transitions from female to hermaphrodite reproduction remodel olfactory and mating-receptive behaviors
Authors: Ebert Margaret S. , Bargmann Cornelia I.
Published: October 2023

Male/hermaphrodite species have arisen multiple times from a male/female ancestral state in nematodes, providing a model to study behavioral adaptations to different reproductive strategies. Here we examined the mating behaviors of male/female (gonochoristic)Caenorhabditisspecies in comparison to male/hermaphrodite (androdiecious) close relatives. We find that females from two species in theElegansgroup chemotax to volatile odor from males, a behavior described in only a few animal species. The females also display known mating-receptive behaviors such as sedation when male reproductive structures contact the vulva. Focusing on the male/female speciesC. nigoni,we show that female chemotaxis to males is limited to adult females approaching adult or near-adult males, and relies upon the AWA neuron-specific transcription factor ODR-7, as does male chemotaxis to female odor as previously shown inC. elegans. However, female receptivity during mating contact isodr-7-independent. All female behaviors are suppressed by mating, and all are absent in young hermaphrodites from the sister speciesC. briggsae. However, latent receptivity during mating contact can be uncovered in mutant or agedC. briggsaehermaphrodites that lack self-sperm. Young hermaphrodites from a second androdioecious species,C. tropicalis, are similarly unreceptive to males, but recover all female behaviors upon aging. These results reveal two mechanistically distinct components of the shift from female to hermaphrodite behavior: the loss of female-specificodr-7-dependent chemotaxis, and a sperm-dependent state of reduced receptivity to mating contact. The recovery of receptivity after sperm depletion has the potential to maximize hermaphrodite fitness across the lifespan.

Highlights

Female and hermaphrodite mating behaviors differ in closely related nematode species

Females are attracted to volatile male odors, but hermaphrodites are not

The same olfactory neuron pair drives female attraction to males and vice versa

Latent female mating behaviors are revealed in hermaphrodites that lack self-sperm
Macrophage differentiation requires DNA damage caused by Caspase-Activated DNase
Authors: Maurya Deepak , Rai Gayatri , Mandal Debleena , Mondal Bama Charan
Published: October 2023

Phagocytic macrophages are crucial for innate immunity and tissue homeostasis. Most macrophages develop from embryonic precursors that populate every organ before birth to self-renew lifelong. However, the mechanisms for macrophage differentiation remain unknown. Using in vivo genetic analysis of theDrosophilalarval hematopoietic organ, the lymph gland, we show that the developmentally regulated transient activation of Caspase-Activated DNase (CAD)-mediated DNA breaks in intermediate progenitors is essential for macrophage differentiation. Insulin receptor-mediated PI3K/Akt signaling triggers apoptotic signaling and causes DNA breaks during macrophage development. However, the same Akt signaling attenuates Apoptosis signal-regulating kinase 1 (Ask1) to control apoptotic and JNK activity in differentiating macrophages. DNA-damaged differentiating cells display autophagy activity as a survival strategy. Furthermore, caspase activity is required for embryonic-origin macrophage development and efficient phagocytosis. This study reveals a previously unknown relationship between developmental signals and caspase-activated DNA breaks necessary for multifunctional macrophage differentiation.
Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury
Authors: Li Herman , Le Linh , Marrero Mariah , David-Bercholz Jennifer , Caceres Ana I , Lim Claire , Chiang Wesley , Majewska Ania K , Terrando Niccolò , Gelbard Harris A
Published: October 2023

Background

Links between acute lung injury (ALI), infectious disease, and neurological outcomes have been frequently discussed over the past few years, especially due to the COVID-19 pandemic. Yet, much of the cross-communication between organs, particularly the lung and the brain, has been understudied. Here, we have focused on the role of neutrophils in driving changes to the brain endothelium with ensuing microglial activation and neuronal loss in a model of ALI.

Methods

We have applied a three-dose paradigm of 10µg/40µl intranasal lipopolysaccharide (LPS) to induce neutrophilia accompanied by proteinaceous exudate in bronchoalveolar lavage fluid (BALF) in adult C57BL/6 mice. Brain endothelial markers, microglial activation, and neuronal cytoarchitecture were evaluated 24hr after the last intranasal dose of LPS or saline. C57BL/6-Ly6g(tm2621(Cre-tdTomato)Arte (Catchup mice) were used to measure neutrophil and blood-brain barrier permeability following LPS exposure with intravital 2-photon imaging.

Results

Three doses of intranasal LPS induced robust neutrophilia accompanied by proteinaceous exudate in BALF. ALI triggered central nervous system pathology as highlighted by robust activation of the cerebrovascular endothelium (VCAM1, CD31), accumulation of plasma protein (fibrinogen), microglial activation (IBA1, CD68), and decreased expression of proteins associated with postsynaptic terminals (PSD-95) in the hippocampal stratum lacunosum moleculare, a relay station between the entorhinal cortex and CA1 of the hippocampus. 2-photon imaging of Catchup mice revealed neutrophil homing to the cerebral endothelium in the blood-brain barrier and neutrophil extravasation from cerebral vasculature 24hr after the last intranasal treatment.

Conclusions

Overall, these data demonstrate ensuing brain pathology resulting from ALI, highlighting a key role for neutrophils in driving brain endothelial changes and subsequent neuroinflammation. This paradigm may have a considerable translational impact on understanding how infectious disease with ALI can lead to neurodegeneration, particularly in the elderly.
Exploring the bounded rationality in human decision anomalies through an assemblable computational framework
Authors: Lu Yi-Long , Lu Yang-Fan , Ren Xiangjuan , Zhang Hang
Published: October 2023

Some seemingly irrational decision behaviors (anomalies), once seen as flaws in human cognition, have recently received explanations from a rational perspective. The basic idea is that the brain has limited cognitive resources to process the quantities (e.g., value, probability, time, etc.) required for decision making, with specific biases arising as byproducts of the resource allocation that is optimized for the environment. While appealing for providing normative accounts, the existing resource-rational models have limitations such as inconsistent assumptions across models, a focus on single environmental factors, and limited coverage of decision anomalies. One challenging anomaly is the peanuts effect, a pervasive phenomenon in decision-making under risk that implies an interdependence between the processing of value and probability. To extend the resource rationality approach to explain the peanuts effect, here we develop a computational framework—the Assemblable Resource-Rational Modules (ARRM)—that integrates ideas from different lines of boundedly-rational decision models as freely assembled modules. The framework can accommodate the joint functioning of multiple environmental factors, and allow new models to be built and tested along with the existing ones, potentially opening a wider range of decision phenomena to bounded rationality modeling. For one new and three published datasets that cover two different task paradigms and both the gain and loss domains, our boundedly-rational models reproduce two characteristic features of the peanuts effect and outperform previous models in fitting human decision behaviors.
Evidence on the use of Birthrate Plus® to guide safe staffing in maternity services – a systematic scoping review
Authors: Griffiths Peter , Turner Lesley , Lown Jenny , Sanders Julia
Published: October 2023

Background

Birthrate Plus® is a widely used tool that informs decisions about the number of midwifery staff needed to provide safe and high quality care in maternity services.

Evidence about the effectiveness, validity, reliability, and feasibility of tools such as this is needed.

Objective

To identify, describe and analyse the available evidence supporting the use of Birthrate Plus.

Methods

We searched PubMed, Medline, CINAHL, Google Scholar, Scopus, Academic Search, British Library Ethos, Directory of Open Access Journals and Science Direct. Studies were eligible if they reported empirical data relevant to the validity, reliability, or useability of Birthrate Plus or if they measured the impact on staffing levels, outcomes, costs or provided a comparison with other methods.

Results

23 sources of evidence were identified and reviewed. We found no prospective intervention studies on the use of Birthrate Plus to demonstrate outcomes for mothers, babies or staff wellbeing. Nor did we find studies comparing the tool to other methods or addressing resource use. Most of the evidence was descriptive, focussing on the use of the tool or the results of Birthrate Plus assessments. There is some evidence of the reliability of application of categories within the tool, the ability of the tool to detect variation in demand and to highlight staff shortages.

Conclusions

In terms of traditional hierarchies of evidence, the evidence for Birthrate Plus is weak. There is a need for more independent research or simulation using real world data to understand how the tool performs in the current context of midwifery practice.

Statement of significance

Problem or Issue

It is important to ensure that there are sufficient midwives to provide safe and effective care and support positive experiences for women during pregnancy and child birth.

What is Already Known

Birthrate Plus is a widely used tool to calculate staffing requirements, which is promoted by the company as being ‘evidence based’.

What this Paper Adds

This review of evidence found major gaps. There is no direct evidence that Birthrate Plus calculates the correct level of staffing or performs better than other systems or professional judgement alone.
High-Resolution Melt Curve Analysis: An Approach for Mutation Detection in the TPO Gene of Congenital Hypothyroid Patients in Bangladesh
Authors: Begum Mst. Noorjahan , Mahtarin Rumana , Islam Md Tarikul , Antora Nusrat Jahan , Sarker Suprovath Kumar , Sultana Nusrat , Sajib Abu A. , Islam Abul B.M.M.K , Banu Hurjahan , Hasanat M A , Shyamaly Kohinoor Jahan , Begum Suraiya , Konika Tasnia Kawsar , Haque Shahinur , Hasan Mizanul , Sultana Sadia , Bhuiyan Taufiqur Rahman , Mannoor Kaiissar , Qadri Firdausi , Akhteruzzaman Sharif
Published: October 2023

Thyroid Peroxidase (TPO) is known to be the major gene involved in Congenital hypothyroid patients with thyroid dyshormonogenesis. This present study aimed to establish high-resolution melting (HRM) curve analysis as a supplementary mutation detection approach of Sanger sequencing targeting commonly found mutations c.1117G>T, c.1193G>C, and c.2173A>C in the TPO gene in Bangladeshi patients. We enrolled 36 confirmed cases of congenital hypothyroid patients with dyshormonogenesis to establish the HRM method. Blood samples were collected, and genomic DNA was isolated for molecular techniques. Among the 36 specimens, 20 were pre-sequenced, and mutations were characterized through Sanger sequencing. The pre-sequenced specimens (n=20) were then subjected to real-time PCR-HRM curve analysis to get the appropriate HRM condition capable of differentiating heterozygous and homozygous states for the three mutations from the wild-type state. Furthermore, 16 unknown specimens were subjected to HRM analysis to validate the method. This method showed 100 percent sensitivity and specificity to distinguish wild-type alleles from homozygous or heterozygous states (c.1117G>T, c.1193G>C, and c.2173A>C) of alleles commonly found in Bangladeshi patients. The HRM data was found to be similar to the sequencing result, thus confirming the validity of the HRM approach forTPOgene mutation.

In conclusion, the established HRM-based molecular technique targeting c.1117G>T, c.1193G>C, and c.2173A>C mutations could be used as a high throughput, rapid, reliable, and cost-effective screening approach for the detection of all common mutations inTPOgene in Bangladeshi patients with dyshormonogenesis.
Ranked severe maternal morbidity index for population-level surveillance at delivery hospitalization based on hospital discharge data
Authors: Kuklina Elena V. , Ewing Alexander C. , Satten Glen A. , Callaghan William M. , Goodman David A. , Ferre Cynthia D. , Ko Jean Y. , Womack Lindsay S. , Galang Romeo R. , Kroelinger Charlan D.
Published: October 2023

Background

Severe maternal morbidity (SMM) is broadly defined as an unexpected and potentially life-threatening event associated with labor and delivery. The Centers for Disease Control and Prevention (CDC) produced 21 different indicators based on International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) hospital diagnostic and procedure codes to identify cases of SMM.

Objectives

To examine existing SMM indicators and determine which indicators identified the most in-hospital mortality at delivery hospitalization.

Methods

Data from the 1993–2015 and 2017–2019 Healthcare Cost and Utilization Project’s National Inpatient Sample were used to report SMM indicator-specific prevalences, in-hospital mortality rates, and population attributable fractions (PAF) of mortality. We hierarchically ranked indicators by their overall PAF of in-hospital mortality. Predictive modeling determined if SMM prevalence remained comparable after transition to ICD-10-CM coding.

Results

The study population consisted of 18,198,934 hospitalizations representing 87,864,173 US delivery hospitalizations. The 15 top ranked indicators identified 80% of in-hospital mortality; the proportion identified by the remaining indicators was negligible (2%). The top 15 indicators were: restoration of cardiac rhythm; cardiac arrest; mechanical ventilation; tracheostomy; amniotic fluid embolism; aneurysm; acute respiratory distress syndrome; acute myocardial infarction; shock; thromboembolism, pulmonary embolism; cerebrovascular disorders; sepsis; both DIC and blood transfusion; acute renal failure; and hysterectomy. The overall prevalence of the top 15 ranked SMM indicators (∼22,000 SMM cases per year) was comparable after transition to ICD-10-CM coding.

Conclusions

We determined the 15 indicators that identified the most in-hospital mortality at delivery hospitalization in the US. Continued testing of SMM indicators can improve measurement and surveillance of the most severe maternal complications at the population level.
Xrs2 C-terminus mediates Tel1-dependent meiotic double-strand break interference
Authors: Dorme Marie , Aithal Rakesh , Cayrou Christelle , Vernerey Julien , Llorente Bertrand , Garcia Valérie
Published: October 2023

During meiosis, the programmed formation of DNA double-strand breaks (DSBs) by Spo11, a conserved topoisomerase-like protein, initiates homologous recombination that leads to crossovers between homologous chromosomes, essential for accurate segregation and genome evolution. Because DSBs are a threat to genome integrity, their number, distribution and timing of formation are regulated during the meiotic program. InS. cerevisiae, DSB interference prevents the coincident formation of DNA double-strand breaks (DSBs) in neighboring hotspots through a Tel1/ATM dependent mechanism that remains unexplored. Here, we demonstrate that Tel1 is recruited to meiotic DSBs hotspots in response to Spo11-DSB formation. Tel1 also localizes to chromosomal axis sites in a DSB-dependent manner, thus supporting the TLAC model that postulates meiotic DSBs are being formed within the chromosome axis environment. Tel1 recruitment to meiotic DSBs, DSB interference and the meiotic DNA damage checkpoint are dependent on both the Tel1-FATC domain and the C-terminal moiety of Xrs2, known to mediate Tel1-Xrs2 interaction in somatic cells. However, in a Xrs2 (FxF/Y) mutant DSBs interference remains functional despite Tel1 binding to DSB sites being significantly reduced and the Tel1-dependent DNA damage checkpoint abolished. Altogether, this work highlights the complex regulation of Tel1 multiple functions in meiotic cells, and fine-tuning through interaction with Xrs2.
Mechanisms of theFTOlocus association with obesity: Irx3 controls a sumoylation-dependent switch between adipogenesis and osteogenesis
Authors: Bjune Jan-Inge , Laber Samantha , Lawrence-Archer Laurence , Zhao Xu , Yamada Shuntaro , Al-Sharabi Niyaz , Mustafa Kamal , Njølstad Pål R. , Claussnitzer Melina , Cox Roger D. , Chymkowitch Pierre , Mellgren Gunnar , Dankel Simon N.
Published: October 2023

Background

IRX3 is implicated in genetic predisposition to obesity via theFTOvariant locus.IRX3showsFTOrisk allele-dependent upregulation specifically during early adipogenesis, leading to a shift from energy-dissipation to fat storage in mature adipocytes. However, how changes inIRX3expression at one developmental stage affect cellular phenotype at a later stage remains unclear. We here hypothesize that IRX3 regulates adipocyte development via transcriptional modulation of epigenetic reprogramming factors.

Methods

We combined ChIP-, ATAC- and RNA-sequencing to map direct Irx3 target genes in regions of open chromatin during early adipogenesis of wild-type andIrx3-KO preadipocytes. Gene ontology analyses was performed to identify significantly enriched biological pathways. Denaturing western blotting was used to assess sumoylation levels, and the inhibitor ML-792 was used to specifically block sumoylation. Luciferase assays were performed to estimate effects of ML-792 on Pparγ activity. Bodipy lipid staining, immunofluorescence and qPCR were employed to assess adipogenic differentiation in 3D culture. Alkaline phosphatase and Alizarine Red S staining, as well as immunofluorescence and qPCR were used to assess osteogenic differentiation in 3D culture.

Results

We identified more than 300 Irx3 binding sites in preadipocytes, and these were almost exclusively restricted to promoter regions, with a strong enrichment of genes related to sumoylation, histone modifications and chromatin remodeling. Genes from every step of the sumoylation cycle were bound by Irx3 and differentially expressed in response toIrx3-KO, leading to increased global sumoylation levels in the KO cells. Irx3 ablation and elevated sumoylation inhibited Pparγ activity and adipogenic differentiation in preadipocytes, both of which could be restored by pharmacological inhibition of sumoylation. TheIrx3-KO cells demonstrated reduced epigenetic suppression against osteogenesis, resulting in increased osteogenesis in 3D culture. Finally, osteogenesis induced by Irx3 ablation could partially be reversed by inhibition of sumoylation.

Conclusions

Our study has uncovered IRX3 as a novel upstream regulator of sumoylation, and a potent controller of epigenetic regulators, both directly and indirectly via suppressing global sumoylation levels. This study indicates that theFTOlocus promotes obesity via IRX3-mediated suppression of sumoylation, which promotes adipogenic commitment and differentiation through epigenetic programming.

Graphical abstract
Cockayne syndrome patient iPSC-derived brain organoids and neurospheres show early transcriptional dysregulation of biological processes associated with brain development and metabolism
Authors: Szepanowski Leon-Phillip , Wruck Wasco , Kapr Julia , Rossi Andrea , Fritsche Ellen , Krutmann Jean , Adjaye James
Published: October 2023

Cockayne syndrome is a rare hereditary autosomal recessive disorder characterized by diverse neurological afflictions. However, little is known about the cerebral development in CS patients.

We generated neurospheres and cerebral organoids utilizing Cockayne Syndrome B Protein (CSB) deficient induced pluripotent stem cells derived from two patients with distinct severity levels of CS and healthy controls. The transcriptome of both developmental timepoints was explored using RNA-Seq and bioinformatic analysis to identify dysregulated biological processes common to both CS patients in comparison to control. CSB-deficient neurospheres displayed upregulation of VEGFA-VEGFR2 signaling pathway, Vesicle-Mediated transport and head development. CSB-deficient cerebral organoids exhibited downregulation of brain development, neuron projection development and synaptic signalling. We further identified upregulation of Steroid Biosynthesis as common to both timepoints, in particular upregulation of the Cholesterol Biosynthesis branch.

Our results provide insights into the neurodevelopmental dysregulation in CS patients and strengthen the theory, that CS is not only a neurodegenerative, but also a neurodevelopmental disorder.
Binge feeding-induced Olfactory Cortex Suppression Reduces Satiation
Authors: Lo Hung , Tantirigama Malinda L.S. , Schoenherr Anke , Moreno-Velasquez Laura , Faiss Lukas , Rost Benjamin R. , Larkum Matthew E. , Judkewitz Benjamin , Stumpenhorst Katharina , Rivalan Marion , Winter York , Schmitz Dietmar , Johenning Friedrich W.
Published: October 2023

Binge eating commonly leads to overeating, but the exact mechanism is unclear. While it is known that experiencing flavor contributes to satiety, the interactions between flavor, feeding rate, and food intake remain unknown. Here, we demonstrate a novel feeding rate-dependent feedback loop between olfactory flavor representation in the anterior olfactory (piriform) cortex (aPC) and food intake. Using miniscopes forin vivocalcium imaging in freely foraging mice, we identified specific excitatory neuronal responses to food and water during slow feeding. Switching to binge feeding transformed these specific responses into unspecific global suppression of neuronal activity. Food consumption was predicted by the degree of suppression of neuronal activity in the aPC during binge feeding. Also, food deprivation enhanced neuronal activity suppression. We confirmed the hypothesis that aPC suppression promotes food intake with closed-loop optogenetics experiments. Together, we show that olfactory sensory representation in the aPC reciprocally interacts with consummatory behavior to enhance food intake.
Identification of Evolutionarily Conserved VSX2 Enhancers in Retinal Development
Authors: Honnell Victoria , Sweeney Shannon , Norrie Jackie , Ramirez Cody , Xu Beisi , Teubner Brett , Lee Ah Young , Bell Claire , Dyer Michael A.
Published: October 2023

Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of master regulatory transcription factorVsx2in a developmental stage- and cell-type specific manner.Vsx2is expressed in retinal progenitor cells as well as differentiated bipolar neurons and Müller glia. Mutations inVSX2in humans and mice lead to microphthalmia due to a defect in retinal progenitor cell proliferation. Deletion of a single module within theVsx2SE leads to microphthalmia. Deletion of a separate module within the SE leads to a complete loss of bipolar neurons, yet the remainder of the retina develops normally. Furthermore, theVsx2SE is evolutionarily conserved in vertebrates, suggesting that these modules are important for retinal development across species. In the present study, we examine the ability of these modules to drive retinal development between species. By inserting the human build of oneVsx2SE module into a mouse with microphthalmia, eye size was rescued. To understand the implications of these SE modules in a model of human development, we generated human retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module leads to a complete loss of ON cone bipolar neurons. This prototypical SE serves as a model for uncoupling developmental stage- and cell-type specific effects of neurogenic transcription factors with complex expression patterns. Moreover, by elucidating the gene regulatory mechanisms, we can begin to examine how dysregulation of these mechanisms contributes to phenotypic diversity and disease.

Summary Statement

Herein, we describe how conserved modules within a single super-enhancer can regulateVSX2gene expression across species in both mice and human retinal organoids.
Functional analysis of chromatin-associated proteins inSordaria macrosporareveals similar roles for RTT109 and ASF1 in development and DNA damage response
Authors: Breuer Jan , Ferreira David Emanuel Antunes , Kramer Mike , Bollermann Jonas , Nowrousian Minou
Published: October 2023

We performed a functional analysis of two potential partners of ASF1, a highly conserved histone chaperone that plays a crucial role in the sexual development and DNA damage resistance in the ascomyceteSordaria macrospora. ASF1 is known to be involved in nucleosome assembly and disassembly, binding histones H3 and H4 during transcription, replication and DNA repair and has direct and indirect roles in histone recycling and modification as well as DNA methylation, acting as a chromatin modifier hub for a large network of chromatin-associated proteins. Here, we functionally characterized two of these proteins, RTT109 and CHK2. RTT109 is a fungal-specific histone acetyltransferase, while CHK2 is an ortholog to PRD-4, a checkpoint kinase ofNeurospora crassathat performs similar cell cycle checkpoint functions as yeast RAD53. Through the generation and characterization of deletion mutants, we discovered striking similarities between RTT109 and ASF1 in terms of their contributions to sexual development, histone acetylation and protection against DNA damage. Phenotypic observations revealed a developmental arrest at the same stage in Δrtt109 and Δasf1 strains, accompanied by a loss of H3K56 acetylation, as detected by western blot analysis. Deletion mutants ofrtt109andasf1are sensitive to the DNA damaging agent MMS (methylmethane sulfonate), but not HU (hydroxyurea). In contrast,chk2mutants are fertile and resistant to MMS, but not HU. Our findings suggest a close functional association between ASF1 and RTT109 in the context of development, histone modification and DNA damage response, while indicating a role for CHK2 in separate pathways of the DNA damage response.

Article summary

In the filamentous fungusSordaria macrospora, the conserved histone chaperone ASF1, which interacts with histones H3 and H4, was previously shown to be required for multicellular development and DNA damage response. Here, we have analyzed two additional chromatin-associated proteins.rtt109encodes a histone acetyltransferase, and deletion of the gene inS. macrosporaresults in a phenotype similar to that of a Δasf1 mutant, whereaschk2is involved in different aspects of the DNA damage response, but not in development.
Caller identification and characterization of individual humpback whale acoustic behavior
Authors: Zeh Julia M , Perez-Marrufo Valeria , Adcock Dana L , Jensen Frants H , Knapp Kaitlyn J , Robbins Jooke , Tackaberry Jennifer E , Weinrich Mason , Friedlaender Ari S , Wiley David N , Parks Susan E
Published: October 2023

Acoustic recording tags are biologging tools that provide fine scale data linking acoustic signaling with individual behavior; however, when an animal is in a group, it is challenging to tease apart calls of other conspecifics and identify which individuals produce each call. This, in turn, prohibits robust assessment of individual acoustic behavior including call rates and silent periods, call bout production within and between individuals, and caller location. To overcome this challenge, we simultaneously instrumented small groups of humpback whales on a western North Atlantic feeding ground with sound and movement recording tags. This simultaneous tagging approach enabled us to compare the relative amplitude of each call across individuals and infer caller identity though amplitude differences. Focusing on periods when the tagged animals were isolated from other conspecifics, we were able to assign caller ID for 97% of calls in this dataset. From these labeled calls, we found that humpback whale individual call rates are highly variable across individuals and groups (0-89 calls/h), with calls produced throughout the water column and in bouts with short inter-call intervals (ICI = 2.2 s). Most calls received a likely response from a conspecific within 100 s. These results are important for modelling signal detection range for passive acoustic monitoring and density estimation. Future studies can expand on these methods for caller identification and further investigate the nature of sequence production and counter-calling in humpback whale social calls. Finally, this approach can be helpful for understanding intra-group communication in social groups across other taxa.

Summary statement

Tagging entire humpback whale social groups with sound and movement recording tags allows us to for the first time parse out call behavior within groups and understand individual acoustic behavior.
Characterization of human transcription factor function and patterns of gene regulation in HepG2 cells
Authors: Moyers Belle A. , Partridge E. Christopher , Mackiewicz Mark , Betti Michael J. , Darji Roshan , Meadows Sarah K. , Newberry Kimberly M. , Brandsmeier Laurel A. , Wold Barbara J. , Mendenhall Eric M. , Myers Richard M.
Published: October 2023

Transcription factors (TFs) aretrans-acting proteins that bindcis-regulatory elements (CREs) in DNA to control gene expression. Here, we analyzed the genomic localization profiles of 529 sequence-specific TFs and 151 cofactors and chromatin regulators in the human cancer cell line HepG2, for a total of 680 broadly termed DNA-associated proteins (DAPs). We used this deep collection to model each TF's impact on gene expression, and identified a cohort of 26 candidate transcriptional repressors. We examine high occupancy target (HOT) sites in the context of three-dimensional genome organization and show biased motif placement in distal-promoter connections involving HOT sites. We also found a substantial number of closed chromatin regions with multiple DAPs bound, and explored their properties, finding that a MAFF/MAFK TF pair correlates with transcriptional repression. Altogether, these analyses provide novel insights into the regulatory logic of the human cell line HepG2 genome and show the usefulness of large genomic analyses for elucidation of individual TF functions.
Communicating financial stability in monetary policy reports: a text-mining experiment in postcommunist countries
Authors: Kurowski Łukasz , Smaga Paweł
Published: October 2023

Purpose

Financial stability has become a focal point for central banks since the global financial crisis. However, the optimal mix between monetary and financial stability policies remains unclear. In this study, the “soft” approach to such policy mix was tested – how often monetary policy (in inflation reports) analyses financial stability issues. This paper aims to discuss the aforementioned objective.

Design/methodology/approach

A total of 648 inflation reports published by 11 central banks from post-communist countries in 1998-2019 were reviewed using a text-mining method.

Findings

Results show that financial stability topics (mainly cyclical aspects of systemic risk) on average account for only 2%of inflation reports’ content. Although this share has grown somewhat since the global financial crisis (in CZ, HU and PL), it still remains at a low level. Thus, not enough evidence was found on the use of a “soft” policy mix in post-communist countries.

Practical implications

Given the strong interactions between price and financial stability, this paper emphasizes the need to increase the attention of monetary policymakers to financial stability issues.

Originality/value

The study combines two research areas, i.e. monetary policy and modern text mining techniques on a sample of post-communist countries, something which to the best of the authors’ knowledge has not been sufficiently explored in the literature before.
Exploring students’ perceptions toward the use of augmented reality for digital library services
Authors: Taha Sawsan , Kaba Abdoulaye , Al-Qeed Marzouq Ayed
Published: October 2023

Purpose

This study aims to investigate whether students would accept augmented reality technology in Al Ain University (AAU) libraries as part of digital library services.

Design/methodology/approach

This study used a modified technology acceptance model–based survey instrument for data collection. Data was collected through an online questionnaire, which was sent to 400 students via email in March 2023. Out of the total participants, 176 students completed the questionnaire.

Findings

This study found that AAU students have a positive perception of augmented technology use in the library. They believe that augmented technology will be useful and easy to use, and students are willing to use it to access library resources and services.

Originality/value

This study contributes to the digital library perspectives in academic libraries.
How negative workplace gossip undermines employees’ career growth: from a reputational perspective
Authors: Cheng Bao , Peng Yan , Tian Jian , Shaalan Ahmed
Published: October 2023

Purpose

This study aims to explore how and when negative workplace gossip damages hospitality employees’ career growth, based on social information processing (SIP) and social cognitive career theories.

Design/methodology/approach

The authors gathered data from 379 individuals working in Guangzhou’s hospitality industry with a multi-wave survey.

Findings

This research found that negative workplace gossip harms career growth by damaging one’s personal reputation, and concern for reputation plays a moderating role. In particular, employees displaying greater concern for reputation are more inclined to perceive a diminished personal reputation when exposed to negative workplace gossip, resulting in more negative assessments of their career growth prospects in their organization.

Practical implications

This study has some practical implications. It highlights the need to mitigate negative workplace gossip by fostering a harmonious work environment, implementing reputation-focused training programs and providing support to employees who are particularly concerned about their personal reputations.

Originality/value

This research contributes to the knowledge by empirically revealing the career consequences of negative workplace gossip, incorporating personal reputation and concern for reputation in the theoretical model and advancing research in the vocational and gossip domains. It also enriches SIP and social cognitive career theories while focusing on the hospitality industry.