bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of the innate immune system accelerates growth in cooperation with oncogenic Ras
Authors: Brutscher Fabienne , Germani Federico , Hausmann George , Jutz Lena , Basler Konrad
Published: May 2024

Innate immunity in Drosophila acts as an organismal surveillance system that measures external stimuli or cellular fitness and triggers context-specific responses to fight infections and maintain tissue homeostasis. However, uncontrolled activation of innate immune pathways can be detrimental to the system. In mammals, innate immune signaling is often overactivated in malignant cells and contributes to tumor progression. Drosophila tumor models have been instrumental in the discovery of interactions between pathways that promote tumorigenesis, but little is known about whether and how the Toll innate immune pathway interacts with oncogenes. Here we use a Drosophila epithelial in vivo model to investigate the interplay between Toll signaling and oncogenic Ras. In absence of oncogenic Ras, Toll signaling suppresses differentiation and induces apoptosis. In contrast, in the context of RasV12, cells are protected from cell death and Dorsal promotes cell survival and proliferation to drive hyperplasia. Taken together, we show that the tissue-protective functions of innate immune activity can be hijacked by pre-malignant cells to induce oncogenic transformation.
Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote asymptomatic colonization
Authors: Dai Yiwei , Yu Qian , Edwards Vonetta , Tettelin Hervé , Stein Daniel C. , Song Wenxia
Published: May 2024

Gonorrhea, caused by the human-restricted pathogenNeisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women’s vaginocervix without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both pro- (IL-1β and TNF-α) and anti-inflammatory (IL-10) cytokines during the first 24-h. Cytokine induction required GC expression of an Opa isoform that binds the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-κB activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-κB activation, which reduced GC-induced IL-1β and TNF-α, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, reduced GC-induced IL-10 secretion. These results show that GC induce local IL-10 secretion at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding while suppressing inflammation activation, providing a potential mechanism for GC asymptomatic infection in women.
Targeting both GD2 and B7-H3 using bispecific antibody improves tumor selectivity for GD2-positive tumors
Authors: Rosenkrans Zachary T. , Erbe Amy K. , Clemons Nathan B. , Feils Arika S. , Medina-Guevara Yadira , Jeffery Justin J. , Barnhart Todd E. , Engle Jonathan W. , Sondel Paul M. , Hernandez Reinier
Published: May 2024

Objectives

Disialoganglioside 2 (GD2), overexpressed by cancers such as melanoma and neuroblastoma, is a tumor antigen for targeted therapy. The delivery of conventional IgG antibody technologies targeting GD2 is limited clinically by its co-expression on nerves that contributes to toxicity presenting as severe neuropathic pain. To improve the tumor selectivity of current GD2-targeting approaches, a next-generation bispecific antibody targeting GD2 and B7-H3 (CD276) was generated.

Methods

Differential expression of human B7-H3 (hB7-H3) was transduced into GD2+B78 murine melanoma cells and confirmed by flow cytometry. We assessed the avidity and selectivity of our GD2-B7-H3 targeting bispecific antibodies (INV34-6, INV33-2, and INV36-6) towards GD2+/hB7-H3-B78 cells relative to GD2+/hB7-H3+B78 cells using flow cytometry and competition binding assays, comparing results an anti-GD2 antibody (dinutuximab, DINU). The bispecific antibodies, DINU, and a non-targeted bispecific control (bsAb CTRL) were conjugated with deferoxamine for radiolabeling with Zr-89 (t1/2= 78.4 h). Using positron emission tomography (PET) studies, we evaluated the in vivo avidity and selectivity of the GD2-B7-H3 targeting bispecific compared to bsAb CTRL and DINU using GD2+/hB7-H3+and GD2+/hB7-H3-B78 tumor models.

Results

Flow cytometry and competition binding assays showed that INV34-6 bound with high avidity to GD2+/hB7-H3+B78 cells with high avidity but not GD2+/hB7-H3+B78 cells. In comparison, no selectivity between cell types was observed for DINU. PET in mice bearing the GD2+/hB7-H3-and GD2+/hB7-H3+B78 murine tumor showed similar biodistribution in normal tissues for [89Zr]Zr-Df-INV34-6, [89Zr]Zr-Df-bsAb CTRL, and [89Zr]Zr-Df-DINU. Importantly, [89Zr]Zr-Df-INV34-6 tumor uptake was selective to GD2+/hB7-H3+B78 over GD2+/hB7-H3-B78 tumors, and substantially higher to GD2+/hB7-H3+B78 than the non-targeted [89Zr]Zr-Df-bsAb CTRL control. [89Zr]Zr-Df-DINU displayed similar uptake in both GD2+tumor models, with uptake comparable to [89Zr]Zr-Df-INV34-6 in the GD2+/hB7-H3+B78 model.

Conclusion

The GD2-B7-H3 targeting bispecific antibodies successfully improved selectivity to cells expressing both antigens. This approach should address the severe toxicities associated with GD2-targeting therapies by reducing off-tumor GD2 binding in nerves. Continued improvements in bispecific antibody technologies will continue to transform the therapeutic biologics landscape.

Graphical Abstract
Comprehensive gene expression analysis of organoid-derived healthy human colonic epithelium and cancer cell line by stimulated with live probiotic bacteria
Authors: Sen Akira , Imai Atsuki , Yanagisawa Kota , Miyauchi Eiji , Oda Tsukasa , Sasaki Fuki , Uchida Shintaro , Okada Takuhisa , Yokobori Takehiko , Saeki Hiroshi , Odamaki Toshitaka , Sasaki Nobuo
Published: May 2024

The large intestine has a dense milieu of indigenous bacteria, generating a complex ecosystem with crosstalk between individual bacteria and host cells.In vitrohost cell modeling and bacterial interactions at the anaerobic interphase have elucidated the crosstalk molecular basis. Although classical cell lines derived from patients with colorectal cancer including Caco-2 cells are used, whether they adequately mimic normal colonic epithelial physiology is unclear. To address this, we performed transcriptome profiling of Caco-2 and Monolayer cells derived from healthy Human Colonic Organoid (MHCO) cultured hemi-anaerobically. Coculture with the anaerobic gut bacteria,Bifidobacterium longumsubsp.longumdifferentiated the probiotic effects of test cells from those of physiologically normal intestinal and colorectal cancer cells. We cataloged non- or overlapping gene signatures where gene profiles of Caco-2 cells represented absorptive cells in the small intestinal epithelium, and MHCO cells showed complete colonic epithelium signature, including stem/progenitor, goblet, and enteroendocrine cells colonocytes. Characteristic gene expression changes related to lipid metabolism, inflammation, and cell-cell adhesion were observed in cocultured liveBifidobacterium longumand Caco-2 or MHCO cells.B. longum-stimulated MHCO cells exhibited barrier-enhancing characteristics, as demonstrated in clinical trials. Our data represent a valuable resource for understanding gut microbe and host cell communication.
The CSF transcriptome in pneumococcal meningitis reveals compartmentalised host inflammatory responses associated with mortality
Authors: Guerra-Assunção José Afonso , Chakravarty Probir , Pollara Gabriele , Venturini Cristina , Mlozowa Veronica S , Denis Brigitte , Nyirenda Mulinda , Lalloo David G , Noursadeghi Mahdad , Brown Jeremy S , Heyderman Robert S , Wall Emma C
Published: May 2024

Abstract

Background

Pneumococcal meningitis (PM) has persistently poor clinical outcomes, especially in sub- Saharan Africa. To better characterise the inflammatory response and identify factors associated with mortality we compared paired peripheral blood and cerebrospinal fluid (CSF) transcriptomes before the initiation of antibiotics in Malawian adults with proven PM.

Results

Blood transcriptional profiles were obtained in 28 patients with PM, with simultaneous paired with CSF profiles available for 13 patients. 15/28 (52%) patients died. Comparison of the transcriptome between CSF and blood compartments showed upregulation of 2293 differentially expressed genes in CSF and 909 in blood; enriched pathways in CSF included inflammasome activity and neutrophil migration/activation in the CSF, contrasting with enrichment for pathways including platelet and endothelial activation, cell cycle, cytokine release and oxidative stress in the blood transcriptome. Comparison of CSF profiles between survivors and non-survivors revealed 1829 differentially expressed genes, non- survivor CSF was enriched for multiple innate inflammatory pathways, including IL-17A and Type 1 interferons and proteolysis. In contrast, minimal transcriptomic differences between outcome groups were detected in blood.

Conclusion

Inflammation in PM is characterised by compartmentalised responses in blood and CSF. Poorer outcomes are associated with an dysregulated innate immune host response toS. pneumoniaein the CSF compartment.
Deciphering cis-regulatory elements using REgulamentary
Authors: Riva Simone G. , Georgiades Emily , Herrmann Jennifer C. , Gür E. Ravza , Sanders Edward , Sergeant Martin , Baxter Matthew , Hughes Jim R.
Published: May 2024

With the boom in Genome-Wide Association Studies (GWAS), it has become apparent that many disease-associated genetic variants lie in the non-coding regions of the genome. In order to prioritise these variants and disentangle their functional significance, it is important to be able to accurately classify cis-regulatory elements within these non-coding regions of the genome. Historically, the classification of cis-regulatory elements relied purely on the presence of characteristic histone marks, with recent advancements in their classification using more sophisticated Hidden Markov Model (HMM)-based approaches. The limitation of the HMM-based approaches is that the output of these models is an arbitrary chromatin state, which then requires the user to manually assign these states to a particular class of cis-regulatory elements. Here we present a new tool, REgulamentary, which enablesde novogenome-wide annotation of cis-regulatory elements in a cell-type specific manner. We benchmarked REgulamentary against GenoSTAN, the most popular existing published chromatin annotation and regulatory element identification tool, to demonstrate the advancements REgulamentary can provide in assigning chromatin states. Finally, as an example of REgulamentary’s utility in solving complex disease traitloci, we applied REgulamentary to published GWAS data to demonstrate how this tool can be used to prioritise likely causal variants.
Effective recognition of double-stranded RNA does not require activation of cellular inflammation
Authors: Drazkowska Karolina , Cieslicka Julia , Pastucha Anna , Markiewicz Lukasz , Goryca Krzysztof , Kowalczyk Tomasz , Cysewski Dominik , Bausch Andreas , Sikorski Pawel J.
Published: May 2024

Excess double-stranded RNA (dsRNA) is present in the cytoplasm of human cells, usually following viral infections. Recognition of dsRNAs activates innate immune pathways, leading to cellular inflammation and inhibition of cell growth. Here, we show that an effective dsRNA response may occur without the onset of inflammation. Interestingly, pro-inflammatory (RLR-dependent pathway) and cell growth inhibitory mechanisms (OAS/RNase L- and PKR-dependent pathways) can act independently. We found that the 5′ ends of dsRNA direct the onset of cellular inflammation, whereas RNA duplex activates the OAS/RNase L and PKR pathways. Unexpectedly, three of the most common human RNA epitranscriptomic markers –i.e. N6-methyladenosine, 5-methylcytosine, and pseudouridine – did not affect the immunogenicity of dsRNA; however, the presence ofN6-methyladenosine inhibited the OAS/RNase L pathway. Our observations demonstrate how precisely innate immunity is fine-tuned in cells to take appropriate countermeasures when a specific threat arises.
The genomic and epigenomic landscapes of hemizygous genes across crops with contrasting reproductive systems
Authors: Peng Yanling , Wang Yiwen , Liu Yuting , Fang Xinyue , Cheng Lin , Su Dalu , Zhang Tianhao , Shi Xiaoya , Xu Xiaodong , Long Qiming , Xu Qi , Wang Nan , Zhang Fan , Liu Zhongjie , Xiao Hua , Yao Jin , Tian Ling , Chen Songbi , Hu Wei , Huang Haibo , Huang Sanwen , Gaut Brandon , Zhou Yongfeng
Published: May 2024

Hemizygous genes, which present on only one of the two homologous chromosomes of diploid organisms, have been mainly studied in the context of sex chromosomes and sex-linked genes. However, structural variants (SVs), such as a deletion/insertion of one allele, can lead to hemizygous genes, a phenomenon largely unexplored in plants. Here, we investigated the genomic and epigenomic landscapes of hemizygous genes across 22 genomes with varying propagation histories: eleven clonal lineages, seven outcrossed samples and four inbred and putatively homozygous genomes. We identified SVs leading to genic hemizygosity. As expected, very few genes (0.01%-1.2%) were hemizygous in the homozygous genomes, representing negative controls. Hemizygosity was appreciable among outcrossed lineages, averaging 8.7% of genes, but consistently elevated for the clonal samples at 13.8% genes, likely reflecting heterozygous SVs accumulation during clonal propagation. Compared to diploid genes, hemizygous genes were more often situated in centromeric than telomeric regions and underlying weaker purifying selection. They also had reduced levels of expression, averaging ~20% of the expression levels of diploid genes, violating the evolutionary model of dosage compensation. We also detected higher DNA methylation levels, in hemizygous genes and transposable elements, which may contribute to the reduced expression of hemizygous genes. Finally, expression profiles showed that hemizygous genes were more specifically expressed in contexts related to fruit development, organ differentiation and stress responses. Overall, hemizygous genes accumulate in clonally propagated lineages and display distinct genetic, and epigenetic features compared to diploid genes, shedding new insights on genetic studies and breeding programs of clonal crops.
Dietary potassium and cold acclimation additively increase cold tolerance inDrosophila melanogaster
Authors: Helou Bassam , Ritchie Marshall W. , MacMillan Heath A. , Andersen Mads Kuhlmann
Published: May 2024

In the cold, chill susceptible insects lose the ability to regulate ionic and osmotic gradients. This leads to hemolymph hyperkalemia that drives a debilitating loss of cell membrane polarization, triggering cell death pathways and causing organismal injury. Biotic and abiotic factors can modulate insect cold tolerance by impacting the ability to mitigate or prevent this cascade of events. In the present study, we test the combined and isolated effects of dietary manipulations and thermal acclimation on cold tolerance in fruit flies. Specifically, we acclimated adultDrosophila melanogasterto 15 or 25°C and fed them either a K+-loaded diet or a control diet. We then tested the ability of these flies to recover from and survive a cold exposure, as well as their capacity to protect transmembrane K+gradients, and intracellular Na+concentration. As predicted, cold-exposed flies experienced hemolymph hyperkalemia and cold-acclimated flies had improved cold tolerance due to an improved maintenance of the hemolymph K+concentration at low temperature. Feeding on a high-K+diet improved cold tolerance additively, but paradoxically reduced the ability to maintain extracellular K+concentrations. Cold-acclimation and K+-feeding additively increased the intracellular K+concentration, aiding in maintenance of the transmembrane K+gradient during cold exposure despite cold-induced hemolymph hyperkalemia. There was no effect of acclimation of diet on intracellular Na+concentration. These findings suggest intracellular K+loading and reduced muscle membrane K+sensitivity as mechanisms through which cold-acclimated and K+-fed flies are able to tolerate hemolymph hyperkalemia.

Highlights

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Insect cold tolerance varies in relation to ionoregulatory capacity

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Cold acclimation improves cold tolerance and K+handling during cold exposure

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A high K+diet also improves cold tolerance, but reduces the K+-handling capacity

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We highlight a novel mechanism for preventing K+gradient disruption
Sequence alignment using large protein structure alphabets improves sensitivity to remote homologs
Authors: Edgar Robert C.
Published: May 2024

Recent breakthroughs in protein fold prediction from amino acid sequences have unleashed a deluge of new structures, raising new opportunities for expanding insights into the universe of proteins and pursuing practical applications in bio-engineering and therapeutics while also presenting new challenges to protein search and analysis algorithms. Here, I describe Reseek, a protein alignment algorithm which improves sensitivity in protein homolog detection compared to state-of-the-art methods including DALI, TM-align and Foldseek, with improved speed over Foldseek, the fastest previous method. Reseek is based on alignment of sequences where each residue in the protein backbone is represented by a letter in a novel “mega-alphabet” of 85,899,345,920 (∼1011) distinct states. Code is available athttps://github.com/rcedgar/reseek.
The hyperphosphorylation of SARS-CoV-2s nucleocapsid protein by GSK-3 involves a complex and redundant priming mechanism
Authors: Chen Song , He Zunyu , Kanyo Jean , Lam TuKiet , Ha Grace , Lindenbach Brett D. D. , Ha Ya
Published: May 2024

Upon entry into host cells, the nucleocapsid (N) protein of coronavirus becomes heavily phosphorylated within its central Ser-Arg domain by glycogen synthase kinase-3 (GSK-3). Most substrates for GSK-3 need to be phosphorylated, or primed, by another Ser/Thr kinase four residues downstream of the GSK-3 phosphorylation site. It was widely assumed that the hyperphosphorylation of SARS-CoV-2s N protein requires independent priming at Ser-188 and Ser-206, which initiates sequential phosphorylation by GSK-3. Here we present biochemical and mass spectrometry data that contradicts this simple model, revealing instead a much more complex and highly cooperative mechanism where redundant priming, as well as exosite docking, enables N proteins efficient phosphorylation by GSK-3. The R203M and R203K/G204R mutations, found in the recent delta and omicron variants of concern, both hinder N hyperphosphorylation by GSK-3. The mechanistic insights generated in this study suggest a novel approach to treat COVID-19 by combining multiple classes of pharmacological agents to inhibit N hyperphosphorylation.
Interpretable Protein-DNA Interactions Captured by Structure-Sequence Optimization
Authors: Zhang Yafan , Silvernail Irene , Lin Zhuyang , Lin Xingcheng
Published: May 2024

Abstract

Sequence-specific DNA recognition underlies essential processes in gene regulation, yet methods for simultaneous prediction of genomic DNA recognition sites and their binding affinity remain lacking. Here, we present the Interpretable protein-DNA Energy Associative (IDEA) model, a residue-level, interpretable biophysical model capable of predicting binding sites and affinities of DNA-binding proteins. By fusing structures and sequences of known protein-DNA complexes into an optimized energy model, IDEA enables direct interpretation of physicochemical interactions among individual amino acids and nucleotides. We demonstrate that this energy model can accurately predict DNA recognition sites and their binding strengths across various protein families. Additionally, the IDEA model is integrated into a coarse-grained simulation framework that quantitatively captures the absolute protein-DNA binding free energies. Overall, IDEA provides an integrated computational platform alleviating experimental costs and biases in assessing DNA recognition and can be utilized for mechanistic studies of various DNA-recognition processes.
Molecular Signatures for Microbe-Associated Colorectal Cancers
Authors: Sayed Ibrahim M , Vo Daniella T , Alcantara Joshua , Inouye Kaili M , Pranadinata Rama F , Luo Linda , Boland C Richard , Goyal Nidhi P. , Kuo Dennis John , Huang Sherry C. , Sahoo Debashis , Ghosh Pradipta , Das Soumita
Published: May 2024

Background

Genetic factors and microbial imbalances play crucial roles in colorectal cancers (CRCs), yet the impact of infections on cancer initiation remains poorly understood. While bioinformatic approaches offer valuable insights, the rising incidence of CRCs creates a pressing need to precisely identify early CRC events. We constructed a network model to identify continuum states during CRC initiation spanning normal colonic tissue to pre-cancer lesions (adenomatous polyps) and examined the influence of microbes and host genetics.

Methods

A Boolean network was built using a publicly available transcriptomic dataset from healthy and adenoma affected patients to identify an invariant Microbe-Associated Colorectal Cancer Signature (MACS). We focused onFusobacterium nucleatum(Fn), a CRC-associated microbe, as a model bacterium. MACS-associated genes and proteins were validated by RT-qPCR, RNA seq, ELISA, IF and IHCs in tissues and colon-derived organoids from genetically predisposed mice (CPC-APCMin+/-) and patients (FAP, Lynch Syndrome, PJS, and JPS).

Results

The MACS that is upregulated in adenomas consists of four core genes/proteins: CLDN2/Claudin-2 (leakiness), LGR5/leucine-rich repeat-containing receptor (stemness), CEMIP/cell migration-inducing and hyaluronan-binding protein (epithelial-mesenchymal transition) and IL8/Interleukin-8 (inflammation). MACS was induced uponFninfection, but not in response to infection with other enteric bacteria or probiotics. MACS induction uponFninfection was higher inCPC-APCMin+/-organoids compared to WT controls. The degree of MACS expression in the patient-derived organoids (PDOs) generally corresponded with the known lifetime risk of CRCs.

Conclusions

Computational prediction followed by validation in the organoid-based disease model identified the early events in CRC initiation. MACS reveals that the CRC-associated microbes induce a greater risk in the genetically predisposed hosts, suggesting its potential use for risk prediction and targeted cancer prevention.
Intersex/Differences of Sex Development (I/DSD) Traits: Exploring Their Association with 15% of Phenotypically Detailed Genetic Disorders
Authors: Ragno Leah , Pyle Louise C.
Published: May 2024

The study of Intersex traits or Differences of Sex Development (I/DSD) is an imperative area within medical genetics that confronts a long-standing problem: the prevalence of these conditions in the population is not fully clear, likely undercounted, and therefore no universally agreed upon numbers exist. Proportions among rare differences are not fully understood. While each specific I/DSD condition is individually rare, together they are estimated to affect about 0.7-1.7% of people worldwide (Fausto-Sterling, 1993). Over 10% of individuals with I/DSD traits exhibit comorbidities affecting other bodily systems, suggesting a broader, systemic impact of these conditions. The comprehensive phenotypic spectrum and systemic implications of I/DSD traits are not well-documented, likely due to social, cultural, and privacy concerns that may contribute to the under-phenotyping of genital variations. This research aims to delineate the disease landscape associated with I/DSD traits. By using the Online Mendelian Inherit ance in Man (OMIM) database, a comprehensive resource for human genes and genetic disorders, we compiled an expert list of 155 Human Phenotype Ontology (HPO) terms that encompass the entirety of the medically defined I/DSD space. These terms were cross-referenced with the OMIM database to pinpoint diseases annotated with these HPO terms. Out of 8,181 phenotypically detailed diseases listed in OMIM and included in the HPO database, we discovered that 1,264 (15.5%) have associations with I/DSD-related HPO terms, signifying their presence in I/DSD traits. This substantial overlap underscores the need to rethink I/DSD not just as isolated anomalies but as a continuum of conditions that are crucial for a broader understanding of health issues. It also highlights that I/DSD traits are relatively common within the realm of rare differences, emphasizing the necessity for specialists, such as clinical geneticists, to be well-versed in I/DSD. Our findings call for a shift in the medical community’s perception and approach to studying I/DSD traits. Further research is required to confirm these associations and to explore the relationship between I/DSD traits and overall health.
Adaptive loss of shortwave cone opsins during genomic evolution in cartilaginous fish
Authors: Zhang Bo , Feng Yidong , Lv Meiqi , Jia Lei , Liao Yongguan , Xu Xiaoyan , Meyer Axel , Sun Jinsheng , Li Yumin , Zhang Yaolei , Zhao Na , Li Yunkai , Bao Baolong
Published: May 2024

There is ample evidence of the loss of the shortwave visual protein gene in cartilaginous fish. However, the underlying logic and mechanisms by which organisms need to adapt to the environment behind the opsin loss are still unclear. Here, we report the assembly structure of the whole genome ofOkamejei kenojeiandPrionace glauca, identify TcMar difference between skates/rays and sharks/chimaeras, and analyze the distribution characteristics and intra group differentiation of opsin-related genes in cartilaginous fish. By establishing a zebrafish model with short wave opsin gene deletion, we find blue or violet lightviashort-wave sensitive opsins SWS1 or SWS2 can cause the photoreceptor layer thinning (the biomarker for age-related macular degeneration in human eye) through enactive the cell aging. The loss ofswsis helpful for alleviating the short-wave light damage on the eye. Since the tapetum lucidum in the eye is found broad existence in various cartilaginous fish, a logical hypothesis was creatively proposed that the existence of tapetum lucidum on the retina of cartilaginous fish is interdependent with the loss of shortwave visual protein gene, providing a new perspective and explanatory path for further understanding of the evolution of visual genes in cartilaginous fish.
Mitochondrial inner membrane remodeling as a driving force of organelle shaping
Authors: Preminger Noga , Zucker Ben , Hassdenteufel Sarah , Stephan Till , Jakobs Stefan , Kozlov Michael M , Schuldiner Maya
Published: May 2024

Mitochondria are dynamic organelles exhibiting diverse shapes. While the variation of shapes, ranging from spheres to elongated tubules, and the transition between them, are clearly seen in many cell types, the molecular mechanisms governing this morphological variability remain poorly understood. Here, we propose a novel shaping mechanism based on the interplay between the inner and outer mitochondrial membranes. Our biophysical model suggests that the difference in surface area, arising from the pulling of the inner membrane into cristae, correlates with mitochondrial elongation. Analysis of live cell super-resolution microscopy data supports this correlation, linking elongated shapes to the extent of cristae in the inner membrane. Knocking down cristae shaping proteins further confirms the impact on mitochondrial shape, demonstrating that defects in cristae formation correlate with mitochondrial sphericity. Our results suggest that the dynamics of the inner mitochondrial membrane are important not only for simply creating surface area required for respiratory capacity, but go beyond that to affect the whole organelle morphology. This work explores the biophysical foundations of individual mitochondrial shape, suggesting potential links between mitochondrial structure and function. This should be of profound significance, particularly in the context of disrupted cristae shaping proteins and their implications in mitochondrial diseases.
Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides
Authors: Hsiao Meng-Hsuan , Miao Yang , Liu Zixing , Schütze Konstantin , Limjunyawong Nathachit , Chien Daphne Chun-Che , Monteiro Wayne Denis , Chu Lee-Shin , Morgenlander William , Jayaraman Sahana , Jang Sung-eun , Gray Jeffrey J. , Zhu Heng , Dong Xinzhong , Steinegger Martin , Larman H. Benjamin
Published: May 2024

Animal venoms, distinguished by their unique structural features and potent bioactivities, represent a vast and relatively untapped reservoir of therapeutic molecules. However, limitations associated with extracting or expressing large numbers of individual venoms and venom-like molecules have precluded their therapeutic evaluation via high throughput screening. Here, we developed an innovative computational approach to design a highly diverse library of animal venoms and “metavenoms”. We employed programmable M13 hyperphage display to preserve critical disulfide-bonded structures for highly parallelized single-round biopanning with quantitation via high-throughput DNA sequencing. Our approach led to the discovery of Kunitz type domain containing proteins that target the human itch receptor Mas-related G protein-coupled receptor X4 (MRGPRX4), which plays a crucial role in itch perception. Deep learning-based structural homology mining identified two endogenous human homologs, tissue factor pathway inhibitor (TFPI) and serine peptidase inhibitor, Kunitz type 2 (SPINT2), which exhibit agonist-dependent potentiation of MRGPRX4. Highly multiplexed screening of animal venoms and metavenoms is therefore a promising approach to uncover new drug candidates.
Detection of a reassortant swine- and human-origin H3N2 influenza A virus in farmed mink in British Columbia, Canada
Authors: Kuchinski Kevin S. , Tyson John , Lee Tracy , Detmer Susan , Berhane Yohannes , Burns Theresa , Prystajecky Natalie A. , Himsworth Chelsea G.
Published: May 2024

In December 2021, influenza A viruses (IAV) were detected in a population of farmed mink in British Columbia, Canada. Based on genomic sequencing and phylogenetic analysis, these IAVs were subtyped as H3N2s that originated from reassortment of swine H3N2 (clade 1990.4h), human seasonal H1N1 (pdm09), and swine H1N2 (clade 1A.1.1.3). This reassortant has been subsequently observed in swine in several Midwest American states, as well as in swine and turkeys in Ontario, suggesting its spillover into farmed mink in British Columbia was incidental to its broader dissemination in North American swine populations. These detections reaffirm the need for extensive genomic surveillance of IAVs in swine populations to monitor reassortments that might become public health concerns. They also highlight the need for closer surveillance of IAVs in mink to preserve animal health, protect agricultural interests, and monitor potential zoonotic threats.
International medical graduates’ experiences of clinical competency assessment in postgraduate and licensing examinations: a scoping review protocol
Authors: Hynes Helen , Wiese Anél , McCarthy Nora , Sweeney Catherine , Foley Tony , Bennett Deirdre
Published: May 2024

An international medical graduate (IMG) is a doctor who has received their basic medical qualification from a medical school located in a different country from that in which they practice or intend to practice. IMGs are known to face difficulties in their working lives, including differential attainment in assessment.

The objective of this review is to map key concepts and types of evidence in academic and gray literature relating to international medical graduates’ experiences of clinical competency assessment and to identify knowledge gaps on this topic by systematically searching, selecting, and synthesizing existing knowledge.

All studies will relate to IMGs. The concept of interest will be IMGs’ experiences of assessment. The context will be postgraduate, licensing or credentialing medical assessments of clinical competence.

This review will be conducted in accordance with the Joanna Briggs Institute (JBI) methodology for scoping reviews. Seven electronic databases will be searched for literature published between 2009 and 2024: the Australian Education Index, British Education Index, ERIC, PubMed, PsycINFO, Scopus, and SocINDEX. Gray literature will be searched using Google, Google Scholar, and published reports from postgraduate training bodies and medical licensing organizations. Documents will be independently screened, selected, and extracted by two researchers using a piloted data-extraction tool. Data will be analyzed and presented in tables and in a narrative format.

Scoping review registration

Open Science Framework:https://osf.io/8gdm7
Converting dose-area product to effective dose in dental cone-beam computed tomography using organ-specific deep learning
Authors: Pauwels Ruben
Published: May 2024

Objective

To develop an accurate method for converting dose-area product (DAP) to patient dose for dental cone-beam computed tomography (CBCT) using deep learning.

Methods

24,384 CBCT exposures of an adult phantom were simulated with PCXMC 2.0, using permutations of tube voltage, filtration, source-isocenter distance, beam width/height and isocenter position. Equivalent organ doses as well as DAP values were recorded. Next, using the aforementioned scan parameters as inputs, neural networks (NN) were trained using Keras for estimating the equivalent dose per DAP for each organ. Two methods were explored for positional input features: (1) ‘Coordinate’ mode, which uses the (continuous) XYZ-coordinates of the isocenter, and (2) ‘AP/JAW’ mode, which uses the (categorical) anteroposterior and craniocaudal position. Each network was trained, validated and tested using a 3/1/1 data split. Effective dose (ED) was calculated from the combination of NN outputs using ICRP 103 tissue weighting factors. The performance of the resulting NN models for estimating ED/DAP was compared with that of a multiple linear regression (MLR) model as well as direct conversion coefficients (CC).

Results

The mean absolute error (MAE) for organ dose / DAP on the test data ranged from 0.18% (bone surface) to 2.90% (oesophagus) in ‘Coordinate’ mode and from 2.74% (red bone-marrow) to 14.13% (brain) in ‘AP/JAW’ mode. The MAE for ED was 0.23% and 4.30%, respectively, for the two modes, vs. 5.70% for the MLR model and 20.19%-32.67% for the CCs.

Conclusion

NNs allow for an accurate estimation of patient dose based on DAP in dental CBCT.
Beam loss detection based on generation of Cherenkov light in optical fibers in the CERN Linear Electron Accelerator for Research
Authors: Benítez S. , Salvachúa B. , Chen M.
Published: May 2024

Cherenkov optical beam loss monitors (oBLMs) based on optical fibers are a revolutionary achievement among the monitoring systems in particle accelerators. Due to the nature of the Cherenkov phenomenon and the intrinsic characteristics of optical fibers, the photon production and fiber light transmission need to be studied to deduce the total amount of Cherenkov photons detected by the photosensors attached at the end of the system. Simulations of the Cherenkov oBLM detector system have been implemented using the software with postprocessing considering the light attenuation and capture factors in the optical fiber. In addition, the study includes the longitudinal beam loss localization of the controlled beam losses produced along the CERN Linear Electron Accelerator for Research (CLEAR) test facility line. In this paper, the Cherenkov photon detection by an oBLM installed in the CLEAR facility is simulated, analyzed, and compared with experimental data.

Published by the American Physical Society
2024
Prospect study for the measurement of the
Hbb¯
coupling at the LHC and FCC-hh
Authors: Abdy Zahra , Mohammadi Najafabadi Mojtaba
Published: May 2024

This paper employs the H+b+jets signature in proton-proton collisions to explore the structure of the Hbb¯ couplings. The focus of the analysis lies in the decay of the Higgs boson into a photon pair, taking into account both reducible and irreducible backgrounds and a realistic simulation of the detector effects. To enhance the discrimination between signal and background, a multivariate analysis is employed to analyze the kinematic variables and optimise the signal-to-background ratio. The results indicate that the H+b+jets process can significantly contribute to the precise measurement of CP-even and CP-odd couplings between the bottom quark and the Higgs boson at the LHC and FCC-hh. Finally, a novel asymmetry is introduced for the purpose of probing CP violation within the Hbb¯ coupling, formulated exclusively based on lab-frame momenta.

Published by the American Physical Society
2024
Can Supercooled Phase Transitions Explain the Gravitational Wave Background Observed by Pulsar Timing Arrays?
Authors: Athron Peter , Fowlie Andrew , Lu Chih-Ting , Morris Lachlan , Wu Lei , Wu Yongcheng , Xu Zhongxiu
Published: May 2024

Several pulsar timing array collaborations recently reported evidence of a stochastic gravitational wave background (SGWB) at nHz frequencies. While the SGWB could originate from the merger of supermassive black holes, it could be a signature of new physics near the 100 MeV scale. Supercooled first-order phase transitions (FOPTs) that end at the 100 MeV scale are intriguing explanations, because they could connect the nHz signal to new physics at the electroweak scale or beyond. Here, however, we provide a clear demonstration that it is not simple to create a nHz signal from a supercooled phase transition, due to two crucial issues that could rule out many proposed supercooled explanations and should be checked. As an example, we use a model based on nonlinearly realized electroweak symmetry that has been cited as evidence for a supercooled explanation. First, we show that a FOPT cannot complete for the required transition temperature of around 100 MeV. Such supercooling implies a period of vacuum domination that hinders bubble percolation and transition completion. Second, we show that even if completion is not required or if this constraint is evaded, the Universe typically reheats to the scale of any physics driving the FOPT. The hierarchy between the transition and reheating temperature makes it challenging to compute the spectrum of the SGWB.

Published by the American Physical Society
2024
Field Theory Expansions of String Theory Amplitudes
Authors: Saha Arnab Priya , Sinha Aninda
Published: May 2024

Motivated by quantum field theory (QFT) considerations, we present new representations of the Euler-Beta function and tree-level string theory amplitudes using a new two-channel, local, crossing symmetric dispersion relation. Unlike standard series representations, the new ones are analytic everywhere except at the poles, sum over poles in all channels, and include contact interactions, in the spirit of QFT. This enables us to consider mass-level truncation, which preserves all the features of the original amplitudes. By starting with such expansions for generalized Euler-Beta functions and demanding QFT-like features, we single out the open superstring amplitude. We demonstrate the difficulty in deforming away from the string amplitude and show that a class of such deformations can be potentially interesting when there is level truncation. Our considerations also lead to new QFT-inspired, parametric representations of the Zeta function and π, which show fast convergence.

Published by the American Physical Society
2024
Direct observation of entangled electronic-nuclear wave packets
Authors: Moğol Gönenç , Kaufman Brian , Weinacht Thomas , Cheng Chuan , Ben-Itzhak Itzik
Published: May 2024

We present momentum resolved covariance measurements of entangled electronic-nuclear wave packets created and probed with octave spanning phaselocked ultrafast pulses. We launch vibrational wave packets on multiple electronic states via multiphoton absorption, and probe these wave packets via strong field double ionization using a second phaselocked pulse. Momentum resolved covariance mapping of the fragment ions highlights the nuclear motion, while measurements of the yield as a function of the relative phase between pump and probe pulses highlight the electronic coherence. The combined measurements allow us to directly visualize the entanglement between the electronic and nuclear degrees of freedom and follow the evolution of the complete wavefunction.

Published by the American Physical Society
2024
Surface Magnetization in Antiferromagnets: Classification, Example Materials, and Relation to Magnetoelectric Responses
Authors: Weber Sophie F. , Urru Andrea , Bhowal Sayantika , Ederer Claude , Spaldin Nicola A.
Published: May 2024

We use symmetry analysis and density-functional theory to determine and characterize surface terminations that have a finite equilibrium magnetization density in antiferromagnetic materials. A nonzero magnetic dipole moment per unit area or “surface magnetization” can arise on particular surfaces of many antiferromagnets due to the bulk magnetic symmetries. Such surface magnetization underlies intriguing physical phenomena like interfacial magnetic coupling and can be used as a readout method of antiferromagnetic domains. However, a universal description of antiferromagnetic surface magnetization is lacking. We first introduce a classification system based on whether the surface magnetization is either sensitive or robust to roughness and on whether the magnetic dipoles at surface of interest are compensated or uncompensated when the bulk magnetic order is retained at the surface. We show that roughness-sensitive categories can be identified by a simple extension of a previously established group-theory formalism for identifying roughness-robust surface magnetization. We then map the group-theory method of identifying surface magnetization to a novel description in terms of bulk magnetic multipoles, which are already established as symmetry indicators for bulk magnetoelectric responses at both linear and higher orders. We use density-functional calculations to illustrate that nominally compensated surfaces in magnetoelectric Cr2O3 and centrosymmetric altermagnetic FeF2 develop a finite magnetization density at the surface, in agreement with our predictions based on both group theory and the ordering of the bulk multipoles. Our analysis provides a comprehensive basis for understanding the surface magnetic properties and their intimate correspondence to bulk magnetoelectric effects in antiferromagnets and has important implications for technologically relevant phenomena such as exchange-bias coupling.

Published by the American Physical Society
2024
Who is a Leader in the Leading Eight? Indirect Reciprocity under Private Assessment
Authors: Fujimoto Yuma , Ohtsuki Hisashi
Published: May 2024

Indirect reciprocity is a mechanism that explains large-scale cooperation in human societies. In indirect reciprocity, an individual chooses whether to cooperate with another based on reputation information, and others evaluate the action as good or bad. Under what evaluation rule (called “social norm”) cooperation evolves has long been of central interest in the literature. It has been reported that if individuals can share their evaluations (i.e., public reputation), social norms called “leading eight” can be evolutionarily stable. On the other hand, when they cannot share their evaluations (i.e., private assessment), the evolutionary stability of cooperation is still in question. To tackle this question, we create a novel method to analyze the reputation structure in the population under private assessment. Specifically, we characterize each individual by two variables, “goodness” (what proportion of the population considers the individual as good) and “self-reputation” (whether an individual thinks of him or herself as good or bad), and analyze the stochastic process of how these two variables change over time. We discuss the evolutionary stability of each of the leading-eight social norms by studying the robustness against invasions of unconditional cooperators and defectors. We identify key pivots in those social norms for establishing a high level of cooperation or stable cooperation against mutants. Our finding gives an insight into how human cooperation is established in a real-world society.

Published by the American Physical Society
2024
Unleashing the mechanism to promote psychological ownership: a comparative study of generation X, Y, and Z
Authors: Bhushan Balram
Published: May 2024

Purpose

With the increasing turnover intention worldwide, psychological ownership is gaining traction. Considering the significance of the same for the development and growth of an organization, this paper explores the mechanism to promote psychological ownership and how generational differences contribute to the same.

Design/methodology/approach

A questionnaire was designed and circulated to 1450 employees covering Generation X, Y, and Z. A total of 378 usable responses were received and subjected to Process Macro Model 7 to test seven hypotheses. SPSS was used to test the reliability and validity of the dataset, and RStudio was used for the Confirmatory Factor Analysis.

Findings

The findings supported the moderated mediation model between psychological ownership (PO) and psychological availability (PA). Here, meaningfulness (MN) was the mediator, and age was the moderator. The paper suggests that Generation Z experiences significantly lower psychological ownership (PO) and psychological availability (PA) compared to their elder colleagues. The indirect effect of PA on PO through meaningfulness was significant for all generations, and the generational transition also introduced significant changes.

Originality/value

This is the first study to examine the generational differences in psychological ownership among employees. Accordingly, this research adds to the organizational development literature and suggests that human resource managers design customized interventions for promoting psychological availability. Also, the organization needs to maintain demographic diversity to facilitate learning and development.