bluuebunny/crossref_metadata_2025 huggingface dataset:
A Worksheet to Quantify Social and Digital Media Content as Scholarly Products for Academic Promotion
Authors: Fitzgerald Jocelyn J. , Losee Joseph E. , Roth Ronald N. , Pettigrew Chentis , Thamman Ritu
Published: February 2024

Problem

Social and digital media contributions are a timely way of adding to the public discourse, serve as an online footprint of public contributions that a faculty member has made on behalf of their institution, can increase community trust, and serve as a public commitment to diversity, equity, and inclusion (DEI) work. Thus, such contributions should be considered significant and meritorious in a promotion package.

Approach

A diverse group of 6 University of Pittsburgh School of Medicine academics from varying specialties, training pathways, and academic ranks was assembled to create a consensus worksheet for the inclusion of social and digital media contributions in a promotion package. They reviewed existing literature on the quantification of social and digital media impact and current promotion practices within their institution. This review, combined with expert opinion, was used to pilot and vet the social and digital media worksheet, January 2022–March 2023.

Outcomes

The worksheet is comprised of 4 sections: Scholarship Philosophy; Reputation, Influence, and Leadership; Digital Content; and Media Appearances, Quotes, and Other (i.e., content or notable digital contributions not otherwise listed). It helps to clearly document for the faculty promotions and appointments committee that the faculty member is contributing to patient education, advocacy, epidemiology, research, health care professions education, or DEI via their social and digital media presence. The strengths of the metrics in the worksheet are that they are based on existing evidence, they include objective third-party metrics, and the benchmarks used for them skew conservative in their capture of the effort, quality, and influence of contributions.

Next Steps

The social and digital media worksheet is designed to be adaptable to a rapidly changing social and digital media landscape, and the metrics used in it are likely to be iterative and ever evolving. Transparency will be imperative when assessing candidates’ promotion portfolios.
Assessing Meaningful Improvement: Focus on the Tinnitus Functional Index
Authors: Henry J. A. , Thielman E. J. , Zaugg T. , Griest S. , Stewart B. J.
Published: February 2024

Many studies have attempted to determine methodology for interpreting change on outcome instruments that result from an intervention. The objective of these studies has been to devise methods to identify the minimal level of change that would be consistent with actual benefit perceived by the patient, and not just statistically significant change. With respect to intervention for bothersome tinnitus, the authors of the original study to develop and validate the Tinnitus Functional Index (TFI) suggested that a minimum 13-point reduction in the TFI score was likely to reflect a change perceived as meaningful to an individual. The 13-point estimation of meaningful change for an individual is appropriate for use with any adult seeking care for tinnitus. However, it cannot be relied upon in isolation to determine if an individual believes that there has been a noticeable, or meaningful improvement in their quality of life. It is important to use subjective impressions elicited from the patient to assist in interpreting the meaning of TFI data for an individual. For clinicians engaging in care for tinnitus, we recommend using the TFI and pairing it with the patient’s belief/impression as to whether they are doing better than they were before care for tinnitus was provided. Ideally, the outcome assessment would be conducted by someone other than the clinician who provided the intervention.
Validation of M-CHARTS for Quantitative Assessment of Metamorphopsia Following Rhegmatogenous Retinal Detachment Repair
Authors: Oquendo Paola L. , Figueiredo Natalia , Francisconi Carolina L. M. , Juncal Verena , Marafon Samara , Naidu Sumana C. , Pecaku Aurora , Demian Sueellen , Melo Isabela Martins , Longwell Jack , Muni Rajeev H.
Published: February 2024

Purpose:

To validate the quantitative assessment of metamorphopsia in rhegmatogenous retinal detachment(RRD) using M-CHARTS by determining its correlation with subjective reporting of metamorphopsia with a validated metamorphopsia questionnaire(modified MeMoQ).

Methods:

Research Ethics Board approved, prospective observational study carried out at St. Michael’s Hospital, Toronto, Canada. Patients with primary, unilateral RRD and healthy controls were included. Metamorphopsia at 3-months was assessed with modified MeMoQ and M-CHARTS.

Results:

100 patients(50 with RRD,50 controls) were included. 70%(35/50) of the RRD group had metamorphopsia with M-CHARTS and 80%(40/50) with MeMoQ. The modified MeMoQ and total M-CHARTS scores were significantly higher in patients with RRD compared to controls(p<0.0001). Cronbach’s alpha reliability coefficient was 0.934 in the RRD group. Horizontal, vertical, and total M-CHARTS scores were significantly correlated with MeMoQ scores(rs=0.465,p=0.0007;rs=0.405,p=0.004;rs=0.475,p=0.0005,respectively). M-CHARTS was 72.7% sensitive and 94.6% specific for detection of metamorphopsia(positive score≥0.2), with an area under the ROC curve=0.801. A stronger correlation was found in patients who scored ≥0.2 on the M-CHARTS and reported metamorphopsia with the MeMoQ(rs=0.454,p=0.001).

Conclusion:

We have validated M-CHARTS as a tool to quantitatively assess metamorphopsia in patients with RRD, which is significantly correlated with patient-reported outcomes using the metamorphopsia questionnaire(MeMoQ). A total score of ≥0.2 with M-CHARTS was more strongly correlated with MeMoQ.
Idiopathic terminal ileitis: myth or true entity?
Authors: Nandi Nicoletta , Tai Foong Way David , McAlindon Mark , Sidhu Reena
Published: February 2024

Purpose of review

Isolated terminal ileitis is an increasing phenomenon identified during colonoscopy. Idiopathic terminal ileitis (IDTI) is a diagnosis of exclusion, representing a significant challenge from a diagnostic and management point of view. This review provides an overview of the most recent and relevant evidence on idiopathic IDTI, focusing on its evolution, the natural history and the management strategies proposed in the literature.

Recent findings

IDTI is uncommon, with a reported prevalence between 0.5 and 7%. The main differential is with Crohn's disease and intestinal tuberculosis in endemic countries. A proportion of patients (0–50%) can progress and develop Crohn's disease; however, there are no reliable predictive factors to stratify IDTI patients.

IDTI is a challenging entity, with a small proportion of patients progressing to Crohn's disease over time thus requiring follow-up. Noninvasive modalities such as capsule endoscopy are useful for follow-up, but further research is required to better understand this entity.
Advancing ecological networks: moving beyond binary classification to probabilistic interactions
Authors: Philippe-Lesaffre Martin
Published: February 2024

Leveraging trophic interactions to deduce macro-ecological patterns has become a prevalent method, taking advantage of the extensive databases on binary trophic interactions (i.e., prey-predator relationships). However, this binary approach oversimplifies complex ecological dynamics and fails to capture the nuanced structure of food webs. The challenge lies in the scarcity and limited availability of data on non-binary interactions, which are crucial for a more comprehensive understanding of ecological networks. This study explores the use of binary classifiers, particularly the XGBOOST algorithm to address the limitations of traditional binary approaches to prey-predator relationships. By predicting predation probabilities among nine mammalian predators using species traits, my findings demonstrate the classifiers’ robust predictive capabilities to binary predictions but also a good correlation between probabilistic predation derived from binary classifiers and observed prey preferences. It also highlighted the importance of selecting informative species traits for predicting interaction, with performance contrastingly superior to null models. Despite a small sample size, this work provides insightful results and sets a foundation for future research to expand these models to broader ecological networks, emphasizing the need for comprehensive prey preference data.
The ultrastructure of the starfish skeleton is correlated with mechanical stress
Authors: Raman  , Labisch Susanna , Dirks Jan-Henning
Published: February 2024

Echinoderms and vertebrates both possess mesodermal endoskeletons. In vertebrates, the response to mechanical loads and the capacity to remodel the ultrastructure of the skeletal system are fundamental attributes of their endoskeleton. To determine whether these characteristics are also inherent in Echinoderms, we conducted a comprehensive biomechanical and morphological study on the endoskeleton ofAsterias rubens, a representative model organism for Echinoderm skeletons. Our analysis involved high-resolution X-ray CT scans of entire individual ossicles, covering the full stereom distribution along with the attached muscles. Leveraging this data, we conducted finite element analysis to explore the correlation between mechanical loads acting on an ossicle and its corresponding stereom structure. To understand the effects of localized stress concentration, we examined stereom regions subjected to high mechanical stress and compared them to areas with lower mechanical stress. Additionally, by comparing the stereom structures of ossicles in various developmental stages, we assessed the general remodeling capacity of these ossicles. Our findings suggest that the ability to adapt to mechanical loads is a common feature of mesoderm endoskeletons within the Deuterostomia taxonomic group. However, the material remodelling may be a specific trait unique to vertebrate endoskeletons.
The Primate-Specific Presence of Interferon Regulatory Factor-5 Pseudogene 1
Authors: Marquis Avery , Hubing Vanessa , Ziemann Chanasei , Moriyama Etsuko N. , Zhang Luwen
Published: February 2024

Interferon regulatory factor 5 (IRF5) is a critical transcription factor, regulating the production of inflammatory cytokines and interferons. Dysregulation of IRF5 has been linked to various autoimmune and inflammatory diseases. Pseudogenes may exhibit gene regulatory functions in various mechanisms. In this study, we find the human IRF5 pseudogene 1 (IRF5P1) is a chimeric processed pseudogene containing sequences derived from multiple sources. Remarkably, IRF5P1 is specific to higher primates such as apes and humans. We propose that IRF5P1 may have originated through the ancient integration of a retroviral sequence containing IRF5 mRNA from other animals. Interestingly, IRF5P1 overlaps with another gene, triple QxxK/R motif containing (TRIQK), and the antisense strand of IRF5P1 is predominantly expressed, likely as part of the TRIQK pre-mRNA. The antisense IRF5P1 RNA may regulate IRF5 expression through complementary binding to the IRF5 mRNA, and variants in the IRF5 gene may modulate this interaction. Our analysis suggests that IRF5P1 likely had positive effects on primate evolution, making IRF5P1 a favored component to maintain in the primate lineage, and rendering the pseudogene primate specific. Further studies are essential to elucidate the potential for IRF5P1 to participate in regulatory networks governing IRF5 activity and inflammation and innate immunity.
Waiting for the Perfect Vaccine
Authors: Röst Gergely , Wang Zhen , Moghadas Seyed M.
Published: February 2024

Vaccination has proven to be the most effective public health measure in the fight against various infectious diseases. For emerging or re-emerging diseases, a highly efficacious vaccine may not be available at the start of an outbreak. Timelines for availability of a safe and effective vaccine may significantly affect disease dynamics, its burden, and the healthcare resource utilization. Mitigating this impact may then rely on low-efficacy vaccines that may be rapidly produced and distributed to at-risk populations at the early stages of an outbreak. With the expectation for arrival of a more effective vaccine at a later stage of the outbreak, the optimal vaccination coverage with the existing, low-efficacy vaccines is elusive. While flattening the outbreak if a significant proportion of the susceptible population is vaccinated with a low-efficacy vaccine, the overall infections may not be minimized if a small proportion of the population left unvaccinated when a highly efficacious vaccine becomes available. The optimal coverage for early vaccination could thus depend on several parameters including the efficacy of the currently available vaccines, arrival timing of a more effective vaccine and its efficacy, and the transmissbility of the disease. Here, we develop a deterministic system of differential equations to investigate the optimal vaccination coverage with a low-efficacy vaccine within the aforementioned parameter space. Despite simplifying assumptions, we illustrate that minimizing the overall infections does not necessarily correspond to the highest coverage of early vaccination. However, a high vaccination coverage, even with a low-efficacy vaccine, may still contribute to alleviating severe disease outcomes and reducing healthcare resource utilization.
Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model
Authors: Simon Samson Eugin , Simmons Boston W. , Kim Minjeong , Joseph Sydney C. , Korba Emily , Marathe Sandesh J. , Bohm Margaret S , Mahajan Sidharth S. , Bohl Casey J. , Read Robert , Holt Jeremiah R. , Hayes D. Neil , Lu Lu , Williams Robert W. , Sipe Laura M. , Ashbrook David G. , Makowski Liza
Published: February 2024

Breast cancer (BC) is the most common cancer and the second cause of death in US women. Our lack of understanding of how genetic variants affect molecular mechanisms that mediate BC aggression poses a substantial obstacle to advancements in cancer diagnosis and therapy. To examine genetic variants on BC traits, a novel murine model was created with robust phenotypic and genomic variation. The FVB C3(1)-T-antigen (“C3Tag”) mouse develops spontaneous tumors in the mammary glands of female mice with a mean latency of 4-5 months of age. This genetically engineered mouse model (GEMM) is well established to resemble human basal-like TNBC. TNBC is an aggressive subtype with few clinical approaches and poor patient outcomes. Thus, to model human heterogeneity in BC outcomes, we systematically crossed the C3Tag GEMM into the BXD recombinant inbred family – the largest and best characterized genetic reference population. The new model is termed “BXD-BC” and F1 hybrids of the cross have isogenic genomes that are reproducible. BXD-BCs are a potent tool to determine the impact of genetic modifiers on BC tumor traits. We hypothesized that examination of BXD-BC GEMMs will enable the identification of susceptibility loci, candidate genes, and molecular networks that underlie variation of multiple BC phenotypes. Using N=29 BXD-BC strains, we demonstrated significant heritable variations in the severity of TNBC characteristics such as tumor latency, multiplicity, and survival. Interestingly, 2 BXD-BC strains never developed tumors out to 1 year of age. Thus, BXD-BC strains demonstrate variance in cancer susceptibility and progression compared to the parent C3Tag GEMM, indicating the presence of genetic modifiers. Through an unbiased systematic quantification of breast cancer severity across BXD-BC hybrids, we identified several significant quantitative trait loci (QTL) and candidate genes for specific tumor traits. In combination with public human GWAS datasets, we defined syntenic regions, candidate genes, and underlying networks through cross-species systems genetics analyses to demonstrate the translational validity of conserved, biologically relevant, and targetable candidates. Our findings suggest conserved candidates predicting TNBC patient survival. In sum, the BXD-BC resource is an innovative, reliable, and robust preclinical model that reflects robust genetic heterogeneity. Using cutting edge systems genetics, we have identified genetic modifiers of BC phenotypic variation that could be targeted to advance therapeutic limitations or as biomarkers of risk or response to therapy.
Protective function and differentiation cues of brain-resident CD8+ T cells during immune surveillance of chronic latentToxoplasma gondiiinfection
Authors: Porte Rémi , Belloy Marcy , Audibert Alexis , Bassot Emilie , Aïda Amel , Alis Marine , Miranda-Capet Romain , Jourdes Aurélie , van Gisbergen Klaas , Masson Frédérick , Blanchard Nicolas
Published: February 2024

ChronicT. gondiiinfection induces brain-resident CD8+ T cells (bTr) but their protective functions and differentiation cues remain undefined. Here, we used a mouse model of latent infection byT. gondiileading to effective CD8+ T cell-mediated parasite control. Thanks to antibody depletion approaches, we found that peripheral circulating CD8+ T cells are dispensable for brain parasite control during chronic stage, indicating that CD8+ bTr are sufficient to prevent brain parasite reactivation. We observed that the retention markers CD69, CD49a and CD103 are sequentially acquired by brain parasite-specific CD8+ T cells throughout infection, and that a majority of CD69/CD49a/CD103 triple-positive (TP) CD8+ T cells also express Hobit, a transcription factor associated with tissue residency. This TP subset develops in a CD4+ T cell-dependent manner, and is associated with effective parasite control during chronic stage. Conditional invalidation of TAP-mediated MHC class I presentation showed that presentation of parasite antigens by glutamatergic neurons and microglia regulate the differentiation of CD8+ bTr into TP cells. Single-cell transcriptomic analyses uponT. gondiilatency vs. encephalitis revealed that resistance to encephalitis is associated with the expansion of stem-like subsets of CD8+ bTr.

In summary, parasite-specific brain-resident CD8+ T cells are functionally heterogeneous and autonomously ensure parasite control duringT. gondiilatent infection. Their differentiation is shaped by neuronal and microglial MHC I presentation. A more detailed understanding of local T cell-mediated immune surveillance of this common parasite is needed for harnessing brain-resident CD8+ T cells in order to enhance control of chronic brain infections.
scSpatialSIM: a simulator of spatial single-cell molecular data
Authors: Soupir Alex C , Wrobel Julia , Creed Jordan H. , Ospina Oscar E , Wilson Christopher M , Manley Brandon J , Peres Lauren C. , Fridley Brooke L
Published: February 2024

Background

Spatial molecular data is increasingly being generated in biological tissue studies to increase our understanding of cell infiltration and spatial architecture of tissues. Examples of technologies used to study the spatial contexture of tissues are single-cell protein expression assays and spatial transcriptomics. The increased use of spatial biology technologies has also resulted in an increase in the development of statistical methods to describe the spatial landscape in tissues. Due to the lack of consensus on “gold standard” statistical approaches for assessing the spatial contexture of tissues, we created an R package,scSpatialSIM, to assess different statistical and bioinformatic methods.scSpatialSIMallows users to simulate single-cell molecular data to mimic real tissues at scale, clustering of cell types, and co-clustering / co-localization of two or more cell types.scSpatialSIMalso contains functions that give users the ability to simulate quantitative distributions for positive and negative cells (e.g., gene expression, fluorescence intensity).

Results

We demonstrate thatscSpatialSIMallows users to easily simulate various kernel densities of probability distributions used to create the marked point pattern – points distributed in space with either numeric or categorical features. UsingscSpatialSIM, we used four univariate spatial simulation scenarios to compare three different measures for spatial clustering (Ripley’s K(r), nearest neighbor G(r), and pair correlation g(r)). We found that Ripley’s K(r) identifies the most radii with significant clustering in all four scenarios. Nearest neighbor G(r) only identified all samples as significantly clustered at one radius (r= 0.07) in one simulation scenario (high abundance large cluster size). Pair correlation g(r) was better able to detect significant clustering at low radii when abundance was low.

Conclusions

Vignettes developed forscSpatialSIMcover the creation of single-type and multi-type spatial single-cell molecular data, as well as how these simulated data can be used with other R packages, such asspatialTIME, to derive spatial statistics. Development of this package is crucial for furthering our understanding of the power of existing methods and the development of novel applications to assess the spatial contexture of tissues by providing an objective platform for simulating spatial single-cell molecular data.
Vitreous fluid-isolated DNA for the genetic analysis of primary uveal melanoma: a proof-of-concept study
Authors: Nell R.J. , Versluis M. , Menger N.V. , Gelmi M.C. , Vu T.H.K. , Verdijk R.M. , Luyten G.P.M. , Jager M.J. , van der Velden P.A.
Published: February 2024

Background

Uveal melanoma is an aggressive ocular malignancy. Early molecular characterisation of primary tumours is crucial to identify those at risk of metastatic dissemination. Although tumour biopsies are being taken, liquid biopsies of ocular fluids may form a less invasive but relatively unexplored alternative. In this study, we aim to evaluate the DNA content of vitreous fluid from eyes with a uveal melanoma to obtain molecular information from the tumour.

Methods

DNA was isolated from 65 vitreous fluid samples from enucleated eyes with a uveal melanoma and studied using digital PCR. Primary and additional driver mutations (inGNAQ,GNA11,PLCB4,CYSLTR2,BAP1,SF3B1andEIF1AX) were investigated using accustomed targeted and drop-off assays. The copy numbers of chromosome 3p and 8q were measured using multiplex and single-nucleotide polymorphism-based assays. Our findings were compared to the molecular profile of matched primary tumours and to the clinicopathological tumour characteristics.

Results

Almost all (63/65) vitreous fluids had measurable levels of DNA, but melanoma-cell derived DNA (containing the primary driver mutation) was detected in 39/65 samples (median proportion 18%, range 0.2%-94%) and was associated with a larger tumour prominence, but not with any of the molecular tumour subtypes. Among the vitreous fluids with melanoma-cell derived DNA, not all samples harboured (analysable) other mutations or had sufficient statistical power to measure copy numbers. Still, additional mutations inBAP1,SF3B1andEIF1AXwere detected in 13/15 samples and chromosome 3p and 8q copy numbers matched the primary tumour in 19/21 and 18/20 samples, respectively. Collectively, a clinically-relevant molecular classification of the primary tumour could be inferred from 27/65 vitreous fluids.

Discussion

This proof-of-concept study shows that substantial amounts of DNA could be detected in vitreous fluids from uveal melanoma patients, including melanoma-cell derived DNA in 60% of the samples. Prognostically-relevant genetic alterations of the primary tumour could be identified in 42% of the patients. A follow-up study is needed to evaluate our approach in a prospective clinical context.
Comparative efficacy and safety of anti-cryptosporidial agents: Anin vitrostudy on Nitazoxanide, HFL, KDU731, and Paromomycin againstCryptosporidium parvum
Authors: Whitta Saffron T.G. , Lamont Bridget , Suwanarusk Rossarin , Russell Bruce M. , Muhsin-Sharafaldine Morad-Rémy
Published: February 2024

This study evaluates thein vitroeffectiveness of the anti-cryptosporidial agents Nitazoxanide, Halofuginone, the pyrazolopyridine analogue KDU731, and Paromomycin in combating the significant zoonotic pathogenCryptosporidium parvum. The study utilizes HCT-8 host cells to cultureC. parvumand fluorescent microscopy and qPCR for detecting parasitic growth. The efficacy of the compounds was assessed by calculating their inhibitory concentrations against the total growth ofC. parvumat 48 hours post-infection. The study further investigates the impact of these compounds on early parasitophorous vacuole formation, merozoite egress, host cell viability, and cell growth cycle. KDU731 displayed the most promising profile, with low nanomolar (102 nM ± 2.28) activity and negligible host cell toxicity. This study offers new insights into the relative efficacy and safety of various anti-cryptosporidial compounds, highlighting their stage-specific effects onC. parvumand the consequential impacts on host cells. Identifying safe and effective anti-cryptosporidial agents contributes significantly to the One Health approach, emphasizing the importance of integrated strategies in controlling zoonotic diseases.
Experimental assessment of marine microbial interactions: from predatory protists promoting bacterial survival to bacterial lysis of the protists
Authors: Axelsson-Olsson Diana , Gubonin Nikolaj , Israelsson Stina , Pinhassi Jarone
Published: February 2024

Bacteria in aquatic environments are a principal food source for predatory protists. Whereas interactions between bacteria and protists are recognized to play important roles in determining the pathogenesis and epidemiology of several human pathogens, few studies have systematically characterized the interactions between specific aquatic bacteria and protists beyond the prey-predator relation. We therefore surveyed the outcome of individual co-cultures between 18 different genome-sequenced marine bacteria with known virulence gene repertoires and three model protist species widely used for assessing bacteria-protist interactions. Strikingly, ten, five, and three bacterial isolates were capable of lysing the protistsAcanthamoeba polyphaga, Tetrahymena pyriformisandEuglena gracilis, respectively. A majority of the bacteria were able to grow and/or maintain viable populations in the presence of viable protists. Some bacteria survived longer in the presence of viable protists but not heat-killed protists, and were observed in protist vacuoles. In this respect, thus, marine bacteria are similar to several protist-dependent human pathogens, includingLegionella. Analyses of growth patterns in low-nutrient media showed that co-cultivation withA polyphagaallowed one bacterial strain to overcome nutritional stress and obtain active growth. Five isolates depended on viable amoebae to grow, notwithstanding nutrient media status. The remarkable capability of surviving encounters with, and even actively killing, bacterivorous protists, indicates that diverse (and possibly novel) bacterial defense strategies and virulence mechanisms to access nutrients are widespread among marine bacteria. The diversity of interactions uncovered here has important implications for understanding ecological and evolutionary consequences of population dynamics in bacteria and protists.

IMPORTANCE

The microbiome constitutes the base of food webs in marine waters. Its composition partly reflects biotic interactions, where bacteria primarily are considered as prey of predatory protists. However, studies that focus on one or a few species have shown that some bacteria have abilities to escape grazing and may even be capable of lysing their protist predators. In this study, we substantially extend these findings by systematically investigating interactions among multiple taxa of both bacteria and protists. Our results show that marine bacteria display a wider and more complex range of interactions with their predators than generally recognized - from growth dependency to protist lysis. Given that such interactions play key roles in the pathogenesis and epidemiology of several human pathogens, our findings imply that bacterial virulence traits can contribute to defining the structure and ecology of the marine microbiome.
Structural insights into CXCR4 modulation and oligomerization
Authors: Saotome Kei , McGoldrick Luke L. , Ho Jo-Hao , Ramlall Trudy F. , Shah Sweta , Moore Michael J. , Kim Jee Hae , Leidich Raymond , Olson William C. , Franklin Matthew C.
Published: February 2024

Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. CXCR4 also serves as a key target for diseases such as cancer and HIV. Previously reported crystal structures of CXCR4 bound to antagonists revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood, including its activation by CXCL12, as well as its assembly into higher-order oligomers. Here, we use cryoelectron microscopy (cryoEM) to investigate various modes of CXCR4 regulation in the presence and absence of Giprotein. CXCL12 activates CXCR4 by inserting its N-terminus deep into the CXCR4 orthosteric pocket. The binding of FDA-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the 7 transmembrane helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its CDR-H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal, to our knowledge, previously undescribed modes of GPCR oligomerization. Remarkably, CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.
Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications
Authors: Cookis Trinity , Lydecker Alexandria , Sauer Paul , Kasinath Vignesh , Nogales Eva
Published: February 2024

Polycomb repressive complex 2 (PRC2) is an epigenetic regulator essential for embryonic development and maintenance of cell identity that trimethylates histone H3 at lysine 27 (H3K27me3) leading to gene silencing. PRC2 is regulated by association with protein cofactors and crosstalk with histone posttranslational modifications. Trimethylated histone H3 K4 (H3K4me3) and K36 (H3K36me3) localize to sites of active transcription where H3K27me3 is absent and inhibit PRC2 activity through unknown mechanisms. Using cryo-electron microscopy we reveal that histone H3 tails modified with H3K36me3 engage poorly with the PRC2 active site and preclude its effective interaction with chromatin, while the H3K4me3 modification binds to the allosteric site in the EED subunit, acting as an antagonist that competes with allosteric activators required for the spreading of the H3K27me3 repressive mark. Thus, the location along the H3 tail of the H3K4me3 and H3K36me3 modifications allow them to target two essential requirements for efficient trimethylation of histone H3K27. We further show that the JARID2 cofactor modulates PRC2 activity in the presence of these histone modifications.
Comparative genomics illuminates adaptive evolution of DVNP with lifestyle and with loss of histone H1 in dinoflagellates
Authors: Wang Jingtian , Li Hongfei , Li Ling , Wang Yujie , Lin Senjie
Published: February 2024

About ten years ago dinoflagellate/viral nucleoprotein (DVNP) was discovered in dinoflagellates, an ecologically important and evolutionarily enigmatic group of aquatic protists. Apparently acquired from a viral origin, the appearance of DVNP coincided with the loss of nucleosome, a rare event in eukaryote evolution. Despite the potential importance of DVNP as the substitute of histones, its evolutionary trajectory and adaptive significance remain elusive. Here, we conducted comparative analyses using existing dinoflagellate genomes and transcriptomes from 26 species ranging from ancestral to later-diverging lineages to investigate the pattern of sequence and structural divergence. Results showed that the functional domestication of DVNP in ancestral dinoflagellates coincided with the loss of histone H1, while subsequent DVNP differentiation was accompanied by the yet another genomic innovation: acquisition of bacterial-originated histone-like protein. Furthermore, our data split DVNP into two major groups: the core DVNP that resembles histone H1 and shows consistently high levels of expression and the non-core DVNP with higher sequence variability and showing lower yet variable levels of expression. In addition, we observed a trend in DVNP evolution tracing that in lifestyle differentiation. This work offers insights into the adaptive evolution of DVNP, laying the foundation for further inquiries of evolutionary drivers and functional innovation of DVNP to enhance our understanding of dinoflagellate evolution and ecological success.
Preferred left-handed conformations of glycyls with pathogenic variants protect against aggregation
Authors: Mishra Purva , Potlia Rajesh , Sandhu Kuljeet Singh
Published: February 2024

Due to the lack of Cβatom, the glycyl residues can exhibit left-handed Ramachandran conformations that are mostly disallowed for L-amino acids. The structural and functional significance of distinct glycyl conformations remains under-appreciated. Through systematic analyses of various datasets, we show that: i) the left-handed glycyl residues are over-represented at disease-associated sites and are evolutionarily conserved. ii) The mutations of L-disallowed Gly tend to destabilize the native folding as assessed through the change in free energies. An independent analysis of folding nuclei further corroborates the findings. iii) L-disallowed Gly are enriched at the aggregation gatekeepers, more significantly so in thermophiles, and the mutations thereof reduce the protein solubility. (iv) The positiveΦdihedral angle of L-disallowed Gly disorients its Cαatom out of the phase of alternating pleats ofβ-strand, conforming a crescent that is incompatible to further pair with otherβ-strands, and thus discourages the inter-molecular aggregation of β-strands during protein folding. v) L-disallowed conformation of Gly holds predictive power to identify sites having pathogenic variants. Altogether, our observations highlight that the L-disallowed conformations of glycyls are evolutionarily selected to endow protein stability and protection against aggregation. Apart from enhancing the existing knowledge, the findings have implications in prioritizing the genetic lesions implicated in diseases, and in designing proteins with greater stability and solubility.
Androgens at the skin surface regulateS. aureuspathogenesis through the activation ofagrquorum sensing
Authors: John Maria Sindhura , Chinnappan Mahendran , Artami Methinee , Bhattacharya Mohini , Keogh Rebecca A. , Kavanaugh Jeffrey , Sharma Tripti , Horswill Alexander R. , Harris-Tryon Tamia A.
Published: February 2024

Staphylococcus aureus,the most frequent cause of skin infections, is more common in men than women and selectively colonizes the skin during inflammation. Yet, the specific cues that drive infection in these settings remain unclear. Here we show that the host androgens testosterone and dihydrotestosterone promoteS. aureuspathogenesis and skin infection. Without the secretion of these hormones, skin infectionin vivois limited. Testosterone activatesS. aureusvirulence in a concentration dependent manner through stimulation of theagrquorum sensing system, with the capacity to circumvent other inhibitory signals in the environment. Taken together, our work defines a previously uncharacterized inter-kingdom signal between the skin and the opportunistic pathogenS. aureusand identifies the mechanism of sex-dependent differences inS. aureusskin infection.

One-Sentence Summary

Testosterone promotesS. aureuspathogenesis through activation of theagrquorum sensing system.
Do light eaters live shorter lives? The case of ultralightCaenorhabditis elegans
Authors: Zhang Xuepei , Gharibi Hassan , Beusch Christian M. , Meng Zhaowei , Saei Amir A. , Gaetani Massimiliano , Zubarev Roman A.
Published: February 2024

The idea that ingesting heavy stable isotopes can increase longevity emerged shortly after the discovery of deuterium in the early 1930s and has been extensively tested since then on animals. Here we present the first experimental evidence for the opposite. GrowingC. eleganson bacteriaE. colithat are in turn fed on a diet depleted of heavy isotopes of C, H, N and O produced ultralight worms that grow and mature faster but have a shorter lifespan. Based on the differences in expression and solubility of proteins, we established an aging pseudo-time scale. Notably, the newly born ultralight worms appear to be significantly “younger” than their normal counterparts, while at day 10 they are significantly “older”. Pathway analysis revealed involvement of mitochondria; analysis of reactive oxygen species (ROS) confirmed significant ROS overproduction in ultralight worms that increases further with age. These findings provide a new modality of affecting the lifespan in this important animal model of human diseases and aging.
Coexistence of asynchronous and clustered dynamics in noisy inhibitory neural networks
Authors: Feld Yannick , Hartmann Alexander K. , Torcini Alessandro
Published: February 2024

A regime of coexistence of asynchronous and clustered dynamics is analyzed for globally coupled homogeneous and heterogeneous inhibitory networks of quadratic integrate-and-fire (QIF) neurons subject to Gaussian noise. The analysis is based on accurate extensive simulations and complemented by a mean-field description in terms of low-dimensionalnext generationneural mass models for heterogeneously distributed synaptic couplings. The asynchronous regime is observable at low noise and becomes unstable via a sub-critical Hopf bifurcation at sufficiently large noise. This gives rise to a coexistence region between the asynchronous and the clustered regime. The clustered phase is characterized by population bursts in theγ-range (30-120 Hz), where neurons are split in two equally populated clusters firing in alternation. This clustering behaviour is quite peculiar: despite the global activity being essentially periodic, single neurons display switching between the two clusters due to heterogeneity and/or noise.
Characterization of relativistic electron bunch duration and traveling wave structure phase velocity based on momentum spectra measurements
Authors: Vinatier T. , Assmann R. W. , Burkart F. , Dinter H. , Jaster-Merz S. M. , Kellermeier M. , Kuropka W. , Mayet F. , Stacey B. , Bruni C.
Published: February 2024

The Accelerator Research Experiment at Sinbad (ARES) linac at DESY aims to generate and characterize ultrashort electron bunches (fs to sub-fs duration) with high momentum and arrival time stability for the purpose of applications related to accelerator research and development, e.g., development of advanced and compact diagnostics and accelerating structures, test of new accelerator components, medical applications studies, machine learning, etc. During its commissioning phase, the bunch duration characterization of the electron bunches generated at ARES has been performed with an rf-phasing technique relying on momentum spectra measurements, using only common accelerator elements (rf accelerating structures and magnetic spectrometers). The sensitivity of the method allowed highlighting different response times for Mo and Cs2Te cathodes. The measured electron bunch duration in a wide range of machine parameters shows excellent agreement overall with the simulation predictions, thus demonstrating a very good understanding of the ARES operation on the bunch duration aspect. The importance of a precise experimental determination of the phase velocity of the first traveling wave accelerating structure after the electron source, for which we propose a simple new beam-based method precise down to a variation of one part per ten thousand respective to the speed of light in vacuum, is emphasized for this purpose. A minimum bunch duration of 20 fs rms, resolution-limited by the space charge forces, is reported. This is, to the best of our knowledge, around 4 times shorter than what has been previously experimentally demonstrated based on rf-phasing techniques with a single rf structure. The present study constitutes a strong basis for future time characterization down to the sub-fs level at ARES, using dedicated X-band transverse deflecting structures.

Published by the American Physical Society
2024
Quantifying the Properties of Nonproductive Attempts at Thermally Activated Energy-Barrier Crossing through Direct Observation
Authors: Lyons Aaron , Devi Anita , Hoffer Noel Q. , Woodside Michael T.
Published: February 2024

Thermally activated energy-barrier crossing is ubiquitous in physical, chemical, and biological processes. Most barrier-crossing attempts have insufficient energy to overcome the barrier; hence, productive transition paths that successfully cross the barrier are very rare compared to nonproductive fluctuations that enter the barrier region but return without crossing it. Recent experimental advances have yielded important insights into transition paths, but nonproductive attempts remain little studied experimentally or theoretically, even though they can reveal information about parts of the reaction energy landscape not visited during transition paths. Observing the diffusive dynamics of a bead hopping between bistable optical traps as a model system, we measured the duration, maximum position along the reaction coordinate, and occupancy statistics of unsuccessful crossing attempts. Experimental results agreed quantitatively with expectations of an analytical framework we derived from committor theory. Applying these analyses to a more complex example, DNA hairpin folding under tension, we found that some properties differed from those of transition paths, such as the asymmetric occupancies for folding and unfolding attempts, whereas others were similar, such as the diffusion coefficient reflecting landscape roughness. These results show how nonproductive crossing attempts can be detected and analyzed rigorously, enabling characterization of the full dynamics within the transition region.

Published by the American Physical Society
2024
A failure of accountancy professionalisation: corporate financial reporting and accounting knowledge
Authors: Lee Thomas A.
Published: February 2024

Purpose

The purpose of this study is to analyse historical events to argue the improbable prospect of radical accounting reform in corporate financial reporting (CFR) due to the absence of abstract accounting knowledge as part of accountancy professionalisation (AP).

Design/methodology/approach

A historical database of CFR and AP events in the UK is categorised and analysed to observe the evolution of accounting in CFR from the perspective of the sociology of professions relating to abstract knowledge in professionalisation.

Findings

CFR has always been a statutory function in the UK dependent on arbitrary accounting rules rather than expert measurements based on abstract accounting knowledge. Accounting rules have evolved as part of AP and currently form part of the statutory regulation of CFR. The accountancy profession has eschewed abstract accounting knowledge in a mutually beneficial and uncompetitive relationship with the law profession in CFR.

Research limitations/implications

The study is limited to the history of CFR and AP in the UK and its findings are contrary to the sociology of professions regarding abstract knowledge, consistent with the accountancy profession’s 19th-century experience of court-related services, and indicative of normative accounting research’s redundancy.

Practical implications

Regarding CFR and AP in the UK, the accountancy profession is an expert subordinate branch of the law profession and has no incentive to alter the status quo of statutory accounting rule compliance prevailing over abstract accounting knowledge-based expertise in CFR.

Originality/value

The study questions the optimism of prior research of accounting in CFR that suggests the possibility of radical reform using abstract knowledge.
Effect of organisational culture on employer branding and resultant employee brand equity in the private banking sector
Authors: Kaur Rajwinder , Pingle Sameer , Jaiswal Anand Kumar
Published: February 2024

Purpose

This research aims to investigate the relationship between employer branding and its antecedent organisational culture within the context of the private banking sector. The study also investigates the relationship between employer branding and employee brand equity as a consequential construct. Additionally, the mediating role of trust and the moderating role of gender in the relationship between employer branding and employee brand equity has been examined.

Design/methodology/approach

The present study’s findings result from data analysis collected from a sample of 454 employees working in private banks in India. The data analysis was conducted utilising the structural equation modelling technique with the assistance of analysis of moment structures (AMOS) software.

Findings

The study’s findings indicate that supportive and bureaucratic (formal) culture in private banks exhibit a significant relationship with employer branding. However, the relationship between innovative culture and employer branding was found to be insignificant. The research also reveals a significant positive association between employer branding and employee brand equity variables: brand consistent behaviour, brand endorsement and brand allegiance. Further, the study highlights the mediating role of employee trust in management in the relationship between employer branding and employee brand equity. Examining demographic variables suggests that gender moderates the relationship between employer branding and employee brand equity.

Originality/value

The originality of this study lies in its exploration of the critical role of organisational culture variables in shaping employer branding within the context of private banks. The findings highlight that cultivating supportive and bureaucratic cultures can effectively enhance the employer branding of private banks. The study emphasises the outcomes of employer branding initiatives, signifying that they contribute to developing brand equity among employees. This leads to long-term employee commitment and advocacy towards the organisation, as employees become brand advocates for the bank with which they are affiliated. The study contributes to a better understanding of the relationship between organisational culture, employer branding and employee brand equity, providing valuable implications for the private banking sector aiming to reinforce their employer brand and increase employee engagement.