bluuebunny/crossref_metadata_2025 huggingface dataset:
The lateral habenula integrates age and experience to promote social transitions in developing rats
Authors: Cobb-Lewis Dana , George Anne , Hu Shannon , Packard Katherine , Song Mingyuan , Nguyen-Lopez Oliver , Tesone Emily , Rowden Jhanay , Wang Julie , Opendak Maya
Published: January 2024

Social behavior deficits are an early-emerging marker of psychopathology and are linked with early caregiving quality. However, the infant neural substrates linking early care to social development are poorly understood. Here, we focused on the infant lateral habenula (LHb), a highly-conserved brain region at the nexus between forebrain and monoaminergic circuits. Despite its consistent links to adult psychopathology, this brain region has been understudied in development when the brain is most vulnerable to environmental impacts. In a task combining social and threat cues, suppressing LHb principal neurons had opposing effects in infants versus juveniles, suggesting the LHb promotes a developmental switch in social approach behavior under threat. We observed that early caregiving adversity (ECA) disrupts typical growth curves of LHb baseline structure and function, including volume, firing patterns, neuromodulatory receptor expression, and functional connectivity with cortical regions. Further, we observed that suppressing cortical projections to the LHb rescued social approach deficits following ECA, identifying this microcircuit as a substrate for disrupted social behavior. Together, these results identify immediate biomarkers of ECA in the LHb and highlight this region as a site of early social processing and behavior control.
Identification of extracellular membrane protein ENPP3 as a major cGAMP hydrolase, cementing cGAMP’s role as an immunotransmitter
Authors: Mardjuki Rachel , Wang Songnan , Carozza Jacqueline A. , Abhiraman Gita C. , Lyu Xuchao , Li Lingyin
Published: January 2024

cGAMP is a second messenger that is synthesized in the cytosol upon detection of cytosolic dsDNA and passed between cells to facilitate downstream immune signaling. ENPP1, an extracellular enzyme, was the only metazoan cGAMP hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from that of ENPP1 and accounts for all remaining cGAMP hydrolysis activity in mice lacking ENPP1. Importantly, we also show that as with ENPP1, selectively abolishing ENPP3’s cGAMP hydrolase activity results in diminished cancer growth and metastasis of certain tumor types. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work clearly shows that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a new target for cancer immunotherapy.
Transformation of human chondrocytes with copper-containing metal-organic biohybrids (MOBs)
Authors: Khasru Tasneem , McKenzie Katie , Rugg Kyle , Boudreaux Shaylee , McMahen Kelly , Uppu Navya , DeCoster Mark A.
Published: January 2024

Copper is involved in the biosynthesis of collagen, however soluble copper salts dissipate quickly and copper nanoparticles are cytotoxic. Here we added a novel copper-containing nanomaterial (CuHARS) to assess human chondrocyte function in the presence of copper. Human dermal fibroblasts (HDFs) were also treated as a control. Chondrocyte response to CuHARS was assessed by chronic nanomaterial treatment (30 µg/ml) followed by digital microscopy and image analysis of cellular features compared to normal chondrocytes. Unexpectedly, chronic CuHARS treatment of human chondrocytes transformed cells over time to cells with extremely elongated and variegated processes and lower proliferation rates compared to normal chondrocytes. In these transformed cells, which we named 3G, shedding of fine processes was observed over time and collected supernatants demonstrated elevated collagen levels compared to normal cell culture media. In contrast to chondrocytes, HDFs treated with CuHARS showed attenuated changes in morphology, and notably retained a prominent ability for continued proliferation. These results demonstrate that a copper-containing biohybrid material (CuHARS) can stably transform human chondrocytes with highly altered morphology, lower proliferation rates, and altered membrane dynamics compared to normal chondrocytes. In contrast, human dermal fibroblasts demonstrated attenuated changes in morphology, and retained an enhanced ability for proliferation.
Investigating the molecular basis of cleptobiosis in eusocial stingless bees (Apidae: Hymenoptera)
Authors: Ricardo Paulo Cseri , Araujo Natalia De Souza , Arias Maria Cristina
Published: January 2024

Cleptobiosis is a widespread strategy among animals in which members of one species raid for food or other valuable resources that were obtained by another species. Obligate cleptobiotic species are however rare, and the eusocial stingless beeLestrimelitta limaofeatures amongst these rare species. This bee pillages other stingless bee colonies. To provide some insights into the molecular basis and evolution of cleptobiosis in eusocial bees, here we compare transcriptomic data of foraging workers of the robber beeL. limaoand three non-robber stingless bees:Nannotrigona testaceicornis, Scaptotrigona depilis, andTetragonisca angustula. Our findings demonstrate that most of the orthologs identified as differentially expressed (DE) among the robber and the non-robber bees are downregulated inL. limaoworkers, showing a reduced expression activity in the cleptobiont during foraging. Several DE orthologs potentially regulate neuronal and synaptic activities in addition to other critical cellular functions. Additionally, differentially expressed orthologs associated with floral resource exploration and energetic metabolism were identified. These genes warrant further investigation to enhance our understanding of the specific molecular adaptations associated with cleptobiosis in eusocial terms.
Forget and Forgive: A Neurocognitive Mechanism for Increased Cooperation During Group Formation
Authors: Zajkowski Wojciech , Badman Ryan P. , Haruno Masahiko , Akaishi Rei
Published: January 2024

How do group size changes influence cooperation within groups? To examine this question, we performed a dynamic, network-based prisoner’s dilemma experiment with fMRI. Across 83 human subjects, we observed increased cooperation as group size increased. However, our computational modeling analysis of behavior and fMRI revealed that group size itself did not increase cooperation. Rather, interaction between (1) subjects’ stable prosocial tendencies, and (2) dynamic reciprocal strategy weighted by memory confidence, underlies the group size-modulated increase in cooperation because the balance between them shifts toward the prosocial tendency with higher memory demands in the larger groups. We found that memory confidence was encoded in fusiform gyrus and precuneus, whereas its integration with prosocial tendencies was reflected in the left DLPFC and dACC. Therefore, interaction between recall uncertainty during reciprocal interaction (i.e., forgetting) and one’s individual prosocial preference is a core pillar of emergent cooperation in more naturalistic and dynamic group formation.
Discovering Root Causal Genes with High Throughput Perturbations
Authors: Strobl Eric V , Gamazon Eric R
Published: January 2024

Root causal gene expression levels – orroot causal genesfor short – correspond to the initial changes to gene expression that generate patient symptoms as a downstream effect. Identifying root causal genes is critical towards developing treatments that modify disease near its onset, but no existing algorithms attempt to identify root causal genes from data. RNA-sequencing (RNA-seq) data introduces challenges such as measurement error, high dimensionality and non-linearity that compromise accurate estimation of root causal effects even with state-of-the-art approaches. We therefore instead leverage Perturb-seq, or high throughput perturbations with single cell RNA-seq readout, to learn the causal order between the genes. We then transfer the causal order to bulk RNA-seq and identify root causal genes specific to a given patient for the first time using a novel statistic. Experiments demonstrate large improvements in performance. Applications to macular degeneration and multiple sclerosis also reveal root causal genes that lie on known pathogenic pathways, delineate patient subgroups and implicate a newly defined omnigenic root causal model.
Genome sequence resources from three isolates of the apple canker pathogenNeonectria ditissimainfecting forest trees
Authors: Bourras Salim , Vélëz Heriberto , Ihrmark Katarina , Corrales Gutiérrez Miguel Ángel , Elfstrand Malin , Garkava-Gustavsson Larisa , Dalman Falk Kerstin
Published: January 2024

Neonectria ditissimais a generalist ascomycete plant pathogen causing canker diseases on a variety of hardwood tree species and can cross-infect many of them. The fungus enters the plants through wounds throughout the year.N. ditissimais considered a major threat to apple production responsible for the fruit tree canker disease which damages trees and causes rotting of fruits in storage. Nearby forests and shelter belts can serve as source of inoculum for well-managed apple orchards. Thus, knowledge about theN. ditissimaisolates infecting different host species is essential for designing integrated pest management strategies. Here, we describe the genomes of threeN. ditissimaisolates, Nd_iso34, Nd_iso35, and Nd_iso36, infecting European beech, American tulip tree, and American beech, respectively. We obtained genome assemblies of ca. 45 megabases for all isolates, covering 94% of theN. ditissimareference annotation, and 97% of the universal single-copy orthologs (BUSCOs). We conclude that these genome assemblies are a highly relevant resource considering the scarcity of genomic data available forN. ditissima.
Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis
Authors: Li Yang , Li Chuhan , Sun Qiang , Chen Fengyuan , Cheung Yeelo , Zhao Yu , Xie Ting , Chazaud Bénédicte , Sun Hao , Wang Huating
Published: January 2024

Stem cell activity is known to be tightly regulated by both intrinsic and extrinsic pathways but less is known about whether and how stem cells modulate their niche microenvironment. Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and also tightly regulated by macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in the niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophic muscle. Here in this study we demonstrate that intrinsic deletion of transcription factor YY1 in MuSCs exacerbates dystrophic pathologies by altering the cellular composition and heterogeneity of MPs and FAPs. Further analysis reveals that the YY1 loss induces the expression of immune genes in MuSCs, includingCcl5. Augmented secretion of CCL5 from MuSCs promotes the recruitment of MPs via CCL5/CCR5 mediated crosstalk, which subsequently hinders the apoptosis and clearance of FAPs through elevated TGFβ1 accumulation. Maraviroc mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we further demonstrate that YY1 repressesCcl5transcription in MuSCs by directly binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study has demonstrated the previously unappreciated role of MuSCs in actively shaping their niche microenvironment through secreting immunomodulatory cytokines, and has also provided novel insight into the therapeutic intervention of muscle dystrophy.
Dyrk1a is required for craniofacial development inXenopus laevis
Authors: Johnson H. Katherine , Wahl Stacy E , Sesay Fatmata , Litovchick Larisa , Dickinson Amanda JG
Published: January 2024

Loss of function mutations in the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model,Xenopus laevis.Dyrk1amRNA and protein was expressed throughout the developing head and was enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, usingdyrk1amorpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators,sox9andpax3are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with DYRK1A mutations.
Excess dietary sodium partially restores salt and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron
Authors: Porter Aidan , Vorndran Hannah E. , Marciszyn Allison , Mutchler Stephanie M. , Subramanya Arohan R. , Kleyman Thomas R. , Hendershot Linda M. , Brodsky Jeffrey L. , Buck Teresa M.
Published: January 2024

The maintenance of fluid and electrolyte homeostasis by the kidney requires proper folding and trafficking of ion channels and transporters in kidney epithelia. Each of these processes requires a specific subset of a diverse class of proteins termed molecular chaperones. One such chaperone is GRP170, which is an Hsp70-like, endoplasmic reticulum (ER)-localized chaperone that plays roles in protein quality control and protein folding in the ER. We previously determined that loss of GRP170 in the mouse nephron leads to hypovolemia, electrolyte imbalance, and rapid weight loss. In addition, GRP170-deficient mice develop an AKI-like phenotype, typified by tubular injury, elevation of clinical kidney injury markers, and induction of the unfolded protein response (UPR). By using an inducible GRP170 knockout cellular model, we confirmed that GRP170 depletion induces the UPR, triggers an apoptotic response, and disrupts protein homeostasis. Based on these data, we hypothesized that UPR induction underlies hyponatremia and volume depletion in rodents, but that these and other phenotypes might be rectified by supplementation with high salt. To test this hypothesis, control and GRP170 tubule-specific knockout mice were provided with a diet containing 8% sodium chloride. We discovered that sodium supplementation improved electrolyte imbalance and reduced clinical kidney injury markers, but was unable to restore weight or tubule integrity. These results are consistent with UPR induction contributing to the kidney injury phenotype in the nephron-specific GR170 knockout model, and that the role of GRP170 in kidney epithelia is essential to both maintain electrolyte balance and cellular protein homeostasis.
Modeling the impact of neuromorphological alterations in Down syndrome on fast neural oscillations
Authors: Clusella Pau , Manubens-Gil Linus , Garcia-Ojalvo Jordi , Dierssen Mara
Published: January 2024

Cognitive disorders, including Down syndrome (DS), present significant morphological alterations in neuron architectural complexity. However, the relationship between neuromorphological alterations and impaired brain function is not fully understood. To address this gap, we propose a novel computational model that accounts for the observed cell deformations in DS. The model consists of a cross-sectional layer of the mouse motor cortex, composed of 3000 neurons. The network connectivity is obtained by accounting explicitly for two single-neuron morphological parameters: the mean dendritic tree radius and the spine density in excitatory pyramidal cells. We obtained these values by fitting reconstructed neuron data corresponding to three mouse models: wild-type (WT), transgenic (TgDyrk1A), and trisomic (Ts65Dn). Our findings reveal a dynamic interplay between pyramidal and fast-spiking interneurons leading to the emergence of gamma activity (∼40 Hz). In the DS models this gamma activity is diminished, corroborating experimental observations and validating our computational methodology. We further explore the impact of disrupted excitation-inhibition balance by mimicking the reduction recurrent inhibition present in DS. In this case, gamma power exhibits variable responses as a function of the external input to the network. Finally, we perform a numerical exploration of the morphological parameter space, unveiling the direct influence of each structural parameter on gamma frequency and power. Our research demonstrates a clear link between changes in morphology and the disruption of gamma oscillations in DS. This work underscores the potential of computational modeling to elucidate the relationship between neuron architecture and brain function, and ultimately improve our understanding of cognitive disorders.

Author summary

The structural integrity of individual brain neurons and the intricate networks they form are fundamental to all brain functions, with structural anomalies directly linked to neurological disorders. Deciphering these links is a leading question in developmental disorders such as Down syndrome. Our work sheds light on the pivotal role that the structure of complex neural systems plays in shaping emergent network activity. In particular, our anatomically informed network modeling enables determining the extent to which specific deficits in neuronal architecture and connectivity perturb oscillatory patterns of activity.
FoxO transcription factors actuate the formative pluripotency specific gene expression programme
Authors: Santini Laura , Kowald Saskia , Sestini Giovanni , Rivron Nicolas , Leeb Martin
Published: January 2024

Naïve pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naïve pluripotency-specific transcription factors (TFs). Upon exiting naïve pluripotency, ES cells transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage-choice. However, the mechanisms underlying disengagement from the naïve GRN and initiation of the formative GRN are unclear. Here, we demonstrate that phosphorylated AKT acts as a gatekeeper that prevents nuclear localization of FoxO TFs in naïve ESCs. PTEN-mediated reduction of AKT activity upon exit from naïve pluripotency allows nuclear entry of FoxO TFs, enforcing a cell fate transition by binding and activating formative pluripotency-specific enhancers. Indeed, FoxO TFs are necessary and sufficient for transition from the naïve to the formative pluripotent state. Our work uncovers a pivotal role for FoxO TFs and AKT signalling in mechanisms establishing formative post-implantation pluripotency, a critical early embryonic cell fate transition.
Pivotal roles ofPlasmodium falciparumlysophospholipid acyltransferase 1 in cell cycle progression and cytostome internalization
Authors: Fukumoto Junpei , Yoshida Minako , Tokuoka Suzumi M. , Hayakawa Eri Saki H. , Miyazaki Shinya , Sakura Takaya , Inaoka Daniel Ken , Kita Kiyoshi , Usukura Jiro , Shindou Hideo , Tokumasu Fuyuki
Published: January 2024

The rapid intraerythrocytic replication ofPlasmodium falciparum, a deadly species of malaria parasite, requires a quick but constant supply of phospholipids to support marked cell membrane expansion. In the malarial parasite, many enzymes functioning in phospholipid synthesis pathway have not been identified or characterized. Here, we identifiedP. falciparumlysophospholipid acyltransferase 1 (PfLPLAT1) and showed that PfLPLAT1 is vital for asexual parasite cell cycle progression and cytostome internalization. Deficiency in PfLPLAT1 resulted in decreased parasitemia and prevented transition to the schizont stage. Parasites lacking PfLPLAT1 also exhibited distinctive omega-shaped vacuoles, indicating disrupted cytostome function. Transcriptomic analyses suggested that this deficiency impacted DNA replication and cell cycle regulation. Mass spectrometry-based enzyme assay and lipidomic analysis demonstrated that recombinant PfLPLAT1 exhibited lysophospholipid acyltransferase activity with a preference for unsaturated fatty acids as its acyl donors and lysophosphatidic acids as an acceptor, with its conditional knockout leading to abnormal lipid composition and marked morphological and developmental changes including stage arrest. These findings highlight PfLPLAT1 as a potential target for antimalarial therapy, particularly due to its unique role and divergence from human orthologs.
The PCM scaffold enables RNA localization to centrosomes
Authors: Fang Junnan , Tian Weiyi , Quintanilla Melissa A. , Beach Jordan R. , Lerit Dorothy A.
Published: January 2024

As microtubule-organizing centers, centrosomes direct assembly of the bipolar mitotic spindle required for chromosome segregation and genome stability. Centrosome activity requires the dynamic assembly of pericentriolar material (PCM), the composition and organization of which changes throughout the cell cycle. Recent studies highlight the conserved localization of several mRNAs encoded from centrosome-associated genes enriched at centrosomes, includingPericentrin-like protein(Plp) mRNA. However, relatively little is known about how RNAs localize to centrosomes and influence centrosome function. Here, we examine mechanisms underlying the subcellular localization ofPlpmRNA. We find thatPlpmRNA localization is puromycin-sensitive, and thePlpcoding sequence is both necessary and sufficient for RNA localization, consistent with a co-translational transport mechanism. We identify regions within thePlpcoding sequence that regulatePlpmRNA localization. Finally, we show that protein-protein interactions critical for elaboration of the PCM scaffold permit RNA localization to centrosomes. Taken together, these findings inform the mechanistic basis ofPlpmRNA localization and lend insight into the oscillatory enrichment of RNA at centrosomes.
Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma
Authors: Arnold Moriah R. , Cohn Gabriel M. , Oxe Kezia Catharina , Elliott Somarr N. , Moore Cynthia , Laraia Peter V. , Shekoohi Sahar , Brownell Dillon , Meshul Charles K. , Witt Stephan N. , Larsen Dorthe H. , Unni Vivek K.
Published: January 2024

Although an increased risk of the skin cancer melanoma in people with Parkinson’s Disease (PD) has been shown in multiple studies, the mechanisms involved are poorly understood, but increased expression of the PD-associated protein alpha-synuclein (αSyn) in melanoma cells may be important. Our previous work suggests that αSyn can facilitate DNA double-strand break (DSB) repair, promoting genomic stability. We now show that αSyn is preferentially enriched within the nucleolus in the SK-MEL28 melanoma cell line, where it colocalizes with DNA damage markers and DSBs. Inducing DSBs specifically within nucleolar ribosomal DNA (rDNA) increases αSyn levels near sites of damage. αSyn knockout increases DNA damage within the nucleolus at baseline, after specific rDNA DSB induction, and prolongs the rate of recovery from this induced damage. αSyn is important downstream of ATM signaling to facilitate 53BP1 recruitment to DSBs, reducing micronuclei formation and promoting cellular proliferation, migration, and invasion.
Genome-aware annotation of CRISPR guides validates targets in variant cell lines and enhances discovery in screens
Authors: Lam Simon , Thomas John C. , Jackson Stephen P.
Published: January 2024

Pooled CRISPR-Cas9 genetic knockout screens are powerful high-throughput tools for identifying chemo-genetic, synthetic-lethal and synthetic-viability interactions and are used as a key step towards identifying disease-modifying knockout candidates and informing drug design and therapeutic regimens. CRISPR guide libraries are commercially available for purchase and have been widely applied in different cell lines. However, discrepancies between the genomes used to design CRISPR libraries and the genomes of the cells subjected to CRISPR screens lead to loss of signal or introduction of bias towards the most conserved genes. Here, we present an algorithm, EXOme-guided Reannotation of nuCleotIde SEquences (Exorcise), which uses sequence search and CRISPR target annotation to adapt existing CRISPR libraries to user-defined genomes and exomes. Applying Exorcise on 55 commercially available CRISPR-spCas9 knockout libraries for human and mouse, we found that all libraries have mis-annotations, and that design strategy affects off-target effects and targeting accuracy relative to a standard reference sequence. In simulations on synthetic data, we modelled common mis-annotations in CRISPR libraries and found that they adversely affected recovery of the ground truth for all genes except for those with the strongest signals. Finally, we reanalysed DepMap and DDRcs CRISPR screens with Exorcise annotations and found that strong hits were retained, and lower-confidence hits were strengthened. Use of Exorcise on DepMap with exomes inferred from transcriptomic expression data demonstrated that cell-line–aware reannotation is possible without whole-genome sequencing. Taken together, our results show that Exorcise is a powerful reannotation tool that focuses existing CRISPR libraries towards the cell line genome under investigation and allows post-hoc reanalysis of completed CRISPR screens. Exorcise is open-source software licenced under a Creative Commons Zero Universal 1.0 licence and is available at .
NRX-101 (D-Cycloserine + Lurasidone), a Qualified Infectious Disease Product, is Active Against Drug-Resistant Urinary PathogensIn Vitro
Authors: Sapko Michael T. , Manyak Michael , Panicucci Riccardo , Javitt Jonathan C.
Published: January 2024

Background

D-Cycloserine (DCS) is a broad-spectrum antibiotic that is currently FDA-approved to treat tuberculosis (TB) disease and urinary tract infection. Despite numerous reports showing good clinical efficacy, DCS fell out of favor as a UTI treatment because of its propensity to cause side effects. NRX-101, a fixed dose combination of DCS and lurasidone, has been awarded Qualified Infectious Disease Product and Fast Track Designation by the US Food and Drug Administration and is being developed for various CNS indications because of its unique synergistic effect; each component mitigates side effects of the other.

Methods

In this study, we tested NRX-101 against the urinary tract pathogensE. coli, P. aeruginosa, K. pneumoniae, andA. baumanniiin Mueller Hinton broth (caMHB) and artificial urine media (AUM). Several strains were multidrug resistant. Test compounds were serially diluted in broth/media. Minimum inhibitory concentration (MIC) was defined as the lowest concentration of test compound at which no bacterial growth was observed.

Results

DCS exhibited antibacterial efficacy against all strains tested while lurasidone did not appreciably affect the antibacterial action of DCSin vitro. In AUM, the MICs ranged from 128 to 512 mcg/ml for both DCS and NRX-101. In caMHB, MICs ranged from 8 to 1024 mcg/ml for NRX-101 and 32 to 512 mcg/ml for DCS alone.

Conclusions

Our data confirm that DCS as antibacterial activity against reference and drug-resistant urinary pathogens. Furthermore, lurasidone does not interfere with DCS’s anti-microbial actionin vitro. These results support the clinical development of NRX-101 as a treatment for complicated urinary tract infection.
TheStreptococcusphage protein paratox is an intrinsically disordered protein
Authors: Asakereh Iman , Rutbeek Nicole R. , Singh Manvir , Davidson David , Prehna Gerd , Khajehpour Mazdak
Published: January 2024

The bacteriophage protein paratox blocks quorum sensing in its streptococcal host by directly binding the signal receptor and transcription factor ComR. This reduces ability ofStreptococcusto uptake environmental DNA and protects phage DNA from damage by recombination. Past work characterizing the paratox:ComR molecular interaction revealed that paratox adopts a well-ordered globular fold when bound to ComR. However, solution-state biophysical measurements suggested that paratox may be conformationally dynamic. To address this discrepancy, we investigated the stability and dynamic properties of paratox in solution using circular dichroism, nuclear magnetic resonance, and several fluorescence-based protein folding assays. Our work shows that under dilute buffer conditions paratox is intrinsically disordered. We also show that the addition of kosmotropic salts or protein stabilizing osmolytes induces paratox folding. However, only the addition of ComR was able to induce paratox to adopt its previously characterized globular fold. Furthermore, as we can induce different paratox folding-states we characterize Prx folding thermodynamics and folding kinetics using stopped flow measurements. Based upon the kinetic results, paratox is a highly dynamic protein in dilute solution, folding and refolding within the 10 ms timescale. Overall, our results demonstrate that the streptococcal phage protein paratox is an intrinsically disordered protein in a two-state equilibrium with a solute-stabilized folded form. Furthermore, the solute-stabilized paratox fold is likely the predominant form of paratox in a solute-crowded bacterial cell. Finally, our work suggests that Prx binds and inhibits ComR, and thus quorum sensing inStreptococcus, by a combination of conformational selection and induced-fit binding mechanisms.
Stopping the Vicious Cycle: Equitable Enforcement Strategies to Achieve Safe, Stable, and Accessible Housing for People with Disabilities
Authors: MICHEL KATIE HANNON , WATTS MAYA HAZARIKA , BRESLIN JESSICA , TOBIN‐TYLER ELIZABETH
Published: January 2024

Policy Points

People with disabilities experience a vicious cycle of poverty, poor health, and marginalization partly because of the inequitable implementation and enforcement of laws, including underenforcement of civil rights and housing laws and overenforcement of punitive nuisance and criminal laws.

Inequitable enforcement reflects policy choices that prioritize powerful entities (e.g., landlords, developers) to the detriment of people who experience intersectional structural discrimination based on, for example, race, disability, and income.

Equitable enforcement, a process of ensuring compliance with the law while considering and minimizing harms to marginalized people, can promote health and disability justice by increasing access to safe, stable, and accessible housing.
Mapping the Lobbying Footprint of Harmful Industries: 23 Years of Data From OpenSecrets
Authors: CHUNG HOLLY , CULLERTON KATHERINE , LACY‐NICHOLS JENNIFER
Published: January 2024

Policy Points

Our research reveals the similarities and differences among the lobbying activities of tobacco, alcohol, gambling, and ultraprocessed food industries, which are often a barrier to the implementation of public health policies.

Over 23 years, we found that just six organizations dominated lobbying expenses in the tobacco and alcohol sectors, whereas the gambling sector outsourced most of their lobbying to professional firms.

Databases like OpenSecrets are a useful resource to monitor the commercial determinants of health.

Context

Commercial lobbying is often a barrier to the development and implementation of public health policies. Yet, little is known about the similarities and differences in the lobbying practices of different industry sectors or types of commercial actors. This study compares the lobbying practices of four industry sectors that have been the focus of much public health research and advocacy: tobacco, alcohol, gambling, and ultraprocessed foods.

Methods

Data on lobbying expenditures and lobbyist backgrounds were sourced from the OpenSecrets database, which monitors lobbying in the United States. Lobbying expenditure data were analyzed for the 1998–2020 period. We classified commercial actors as companies or trade associations. We used Power BI software to link, analyze, and visualize data sets.

Findings

We found that the ultraprocessed food industry spent the most on lobbying ($1.15 billion), followed by gambling ($817 million), tobacco ($755 million), and alcohol ($541 million). Overall, companies were more active than trade associations, with associations being least active in the tobacco industry. Spending was often highly concentrated, with two organizations accounting for almost 60% of tobacco spending and four organizations accounting for more than half of alcohol spending. Lobbyists that had formerly worked in government were mainly employed by third‐party lobby firms.

Conclusions

Our study shows how comparing the lobbying practices of different industry sectors offers a deeper appreciation of the diversity and similarities of commercial actors. Understanding these patterns can help public health actors to develop effective counterstrategies.
C v D: A Missed Opportunity to Clarify the Distinction Between Jurisdiction and Admissibility
Authors: Matos Shaun
Published: January 2024

The distinction between issues of jurisdiction and admissibility is at the heart of arbitration law due to the role it plays in defining the relationship between tribunals and the courts of the seat. Nevertheless, there has long been controversy as to the foundation of the distinction and on which side of the line the issue of alleged non‐compliance with pre‐arbitration steps falls. C v D offered a rare opportunity for an apex court to consider the distinction between issues of jurisdiction and admissibility, and to resolve these controversies. Whilst the judgment provides certainty on some matters, the reasoning adopted creates more confusion than it resolves and is unlikely to be the final word on the matter.
Here to stay? Challenges to liberal environmentalism in regional climate governance
Authors: Krogmann David
Published: January 2024

While regionalism is highly relevant in many policy fields today, regional idiosyncrasies have been poorly understood in the literature on multilateral climate governance. This article explores regional ideas in climate governance by comparing the Caribbean Community (CARICOM) and the Council of Baltic Sea States (CBSS). As international climate governance has institutionalised a normative compromise of liberal environmentalism since the 1990s, the article further assesses ideational challenges to this compromise. It examines how these ideas have evolved over time and explains variation between the organisations through the advent of new knowledge. Relying on qualitative content analysis, the article finds that both CARICOM and CBSS have supported and reproduced liberal environmentalism in the past. More recently, CARICOM has started to connect climate change with notions of survival and justice, implicitly challenging liberal environmentalism, while CBSS remains situated within established discourses of sustainable development. The article then argues that the availability of new knowledge from both scientific as well as experiential sources explains the evolution of ideas in regional organisations. Problem definitions of climate change evolve within regional organisations when officials gain access to new scientific data and are able to combine or confirm them with experience from their day‐to‐day work.
Supply chain divergence challenges a ‘Brussels effect’ from Europe's human rights and environmental due diligence laws
Authors: Bastos Lima Mairon G. , Schilling‐Vacaflor Almut
Published: January 2024

Human rights violations and pressing environmental issues have tainted agricultural trade. The role of international market demand for commodities such as soy in causing those problems is clear, yet they remain mostly unaddressed. Therefore, European countries have led a new global trend on mandatory human rights and environmental due diligence (HREDD), advancing the EU's growing global regulatory ambitions. Here, we analyse the prospects for successful externalisation of Europe's sustainability standards – a ‘Brussels Effect’ – using Brazilian soy as a case. Our analysis exposes how the practice of supply chain divergence (i.e., the segmentation of exports tailored to different consumer requirements) can easily evade policy impacts and negate their additionality where Europe commands a minor market share. To avoid becoming just a niche market in these cases, the EU would need to expand on its actions, (i) engaging with other major consumer countries to export its standards, (ii) doubling down on HREDD's coverage to include financial actors and companies trading with other markets, or (iii) moving beyond ‘do no harm’ policies to adopt more strategically targeted ‘do good’ instruments to counter drivers of deforestation on the landscape level.
Non‐negligible levels of implicit skin tone bias among Australian healthcare workers between 2007 and 2022: Analysis of subgroups and trends over time based on Project Implicit data
Authors: Ejova Anastasia , van Antwerpen Natasha R. , Semmler Carolyn , Bean Christopher G. , Green Deanne M.
Published: January 2024

Implicit (i.e. unconscious) racial biases held by health professionals negatively affect patient–practitioner communication and health outcomes. Implicit biases are typically assessed through implicit association tests (IATs). We extracted cross‐sectional IAT data originating in Australia from two large publicly available data sets hosted by Project Implicit. In total, IATs were available from 1956 healthcare workers (1249 of European ethnicity; 829 professionals/technicians as opposed to support workers). All had participated between 2006 and 2022. Levels of implicit skin tone bias were found to be moderate according to Project Implicit guidelines and substantially greater than zero (d = 0.87). Participants of European ethnicity and older age scored higher, but there were no differences across occupation types (professional vs. support worker) or over years. Consistent with findings around the world, the findings highlight a need for interventions that could reduce implicit bias and thereby improve the healthcare experiences of people from minority groups.
SOEs' commitment to transparency: Voluntary disclosure as a driver of mandatory disclosure
Authors: Biedma López Estíbaliz , Larrán Jorge Manuel , Gómez Aguilar Nieves , Conesa Carril María C.
Published: January 2024

Non‐compliance with transparency obligations among publicly owned enterprises has revealed the lack of coercive capacity of the legislation. In this context, literature suggests that mandatory disclosure becomes a matter of company willingness, but this has not been empirically tested so far. Drawing on Oliver's (1991) typology of organizational strategies and studies on normativity production, this study analyzes whether voluntary disclosure levels of financial and non‐financial information determine compliance with transparency legal requirements for the case of Andalusian state‐owned enterprises (SOEs) owned by local and regional governments. We have verified this question using linear regression analysis. The analysis proves that when transparency legislation lacks enforcement power, the level of voluntary disclosure determines the level of legal compliance. Both voluntary and mandatory disclosure levels are explained by the same determinants, suggesting that disclosure is determined by reasons of legitimacy and commitment to transparency. This contributes to the research lines on normativity and transparency in SOEs, being also relevant for lawmakers. This study provides evidence for Oliver's (1991) theoretical arguments about firms' strategies in the face of institutional pressures. It offers policy‐makers and SOE managers an insight into how prepared SOEs are to respond to the demands for greater transparency.
The equine umbilical cord in clinically healthy pregnancies
Authors: Lawson Jessica M. , Verheyen Kristien , Smith Ken C. , Bryan Jill S. , Foote Alastair K. , de Mestre Amanda M.
Published: January 2024

Background

Excessive umbilical cord length (UCL) is associated with equine pregnancy loss. However, a lack of UCL reference values makes it difficult to define excessive UCL. Further, factors associated with differences in UCL are poorly understood.

Objectives

To (i) report the total, allantoic and amniotic UCL in healthy term pregnancies in Thoroughbreds, (ii) describe the relationship between gestational age and UCL, fetal weight and crown rump length (CRL) using clinically normal pregnancies (CNPs) from mares dying during gestation, and (iii) identify associations between UCL and maternal age and parity, paternal age, and fetal sex.

Study design

Cross‐sectional.

Methods

Data including UCLs, fetal weight, CRL and maternal age, parity, paternal age and fetal sex were taken from CNPs from Thoroughbred mares dying during gestation (n = 32), and placentas from HTPs (n = 34) in England. Correlations were assessed using Spearman's rank with significant correlations estimated by locally weighted scatter plot smoothing (LOWESS). Regression plots were fitted to highly correlated variables to further assess and quantify relationships. Differences in UCL between categorical variables were assessed using Kruskall Wallis and Mann–Whitney U tests.

Results

The median total, amniotic and allantoic HTP UCLs were 53.5 cm (interquartile range [IQR] 16), 29.5 cm (IQR 7) and 25.0 cm (IQR 8) respectively. Gestational age and amniotic UCL were moderately correlated (rho = 0.53, p = 0.04), with LOWESS estimating an exponential increase followed by plateauing at around Day 200. Nonlinear associations were observed between fetal weight and gestational age and CRL (adjusted r2 = 0.98 and 0.95 respectively). A linear association was observed between gestational age and CRL: predicted CRL = −17.60 + 0.38 × gestational age, p < 0.001.

Main limitations

Limited availability of CNPs from mares dying during gestation. Estimated relationships can only approximate growth.

Conclusions

This study provides important UCL and fetal size reference values, which may aid in assessing abnormalities. For the first time, associations between UCL and gestational age have been described.
Inflammatory markers for differentiation of endometritis in the mare
Authors: Lection Jennine , Wagner Bettina , Byron Michael , Miller Andrew , Rollins Alicia , Chenier Tracey , Cheong Soon Hon , Diel de Amorim Mariana
Published: January 2024

Background

Endometrial biopsy is required to diagnose mares with chronic endometritis and endometrial degenerative fibrosis. An increase in understanding of equine reproductive immunology could be utilised to create less‐invasive, time‐efficient diagnostic tools especially when evaluating mares for chronic endometritis.

Objectives

To evaluate inflammatory cytokine and chemokine concentrations in uterine fluid samples collected by low‐volume lavage (LVL) as a potential screening diagnostic biomarker for endometritis.

Study design

Prospective cross‐sectional clinical study.

Methods

Forty‐six mares underwent a LVL and subsequently endometrial biopsy. Mares were split in three groups: healthy, acute endometritis, and chronic endometrial fibrosis (CEF) based on cytological and histological evaluation. A fluorescent bead‐based multiplex assay for IFN‐γ, IFN‐α, IL‐1β, IL‐4, IL‐10, IL‐17, sCD14, TNF‐α, CCL2, CCL3, CCL5 and CCL11 were carried out on the LVL fluid. The endometrial biopsy was utilised for histology and qPCR of IFN‐γ, IL‐1β, IL‐6, IL‐8, IL‐17, TNF‐α, CCL2 and CCL3 genes. Statistical analyses examined differences in inflammatory markers and predictive modelling for diseased endometrium.

Results

Secreted concentrations of IFN‐γ were lower in LVL fluid from reproductively healthy mares compared with acute endometritis (p = 0.04) and CEF (p = 0.006). Additionally, IL‐17, IL‐10, IL‐1β, TNF‐α, CCL2, CCL3, CCL5 and CCL11 were significantly increased (p ≤ 0.04) in LVL from CEF mares compared with healthy mares. Mares with CCL2 concentrations ≥550 pg/mL (14/14) had 100% probability of having CEF and/or acute endometritis. Healthy mares had lower relative abundance of IL‐17 mRNA compared with mares in CEF group [median (interquartile rage) = 14.76 (13.3, 15.3) and 12.4 (10.54, 13.81)], respectively (p = 0.02).

Main limitations

Limited sample size: larger numbers of mares with and without endometritis are required and reference intervals in LVL samples have to be established.

Conclusions

Inflammatory chemokines and cytokines concentrations differed between healthy mares and mares with acute endometritis or CEF in LVL.
Phase transition and thermal stability of ceramics from Na‐based geopolymers
Authors: Gao Binghuan , Li Yangyang , Son Hyeonjin , Jang Seongwan , Lee Hee‐Soo , Bae Chang‐Jun
Published: January 2024

Geopolymer ceramics undergo a series of thermal phase transitions, progressing from an amorphous geopolymer gel to a crystalline phase, and eventually to an amorphous glass phase as the temperature increases. However, there is a lack of mechanism understanding regarding to the crystallization process and the subsequent thermal degradation. Here, we fundamentally investigated the kinetics of nepheline formation in Na‐based geopolymer systems and its thermal stability up to 1400°C. Nepheline crystallization is controlled by bulk nucleation and three‐dimensional crystal growth based on the Avrami factor of 4.64, where the activation energy of nepheline formation is 350.59 kJ/mol. High thermal stability of geopolymer ceramics is achieved due to the appearance of nepheline up to 1400°C with the Si/Al ratio ranging from 1.40 to 1.94, while melting and amorphous structure are formed above a higher Si/Al ratio of 2.22. The nature of sintering for geopolymer ceramics consists of shrinkage, expansion and shrinkage corresponding to dehydroxylation, crystallization, and densification, leading to a thermal shrinkage of 21% at 1400°C.
Exploring the relationship between allergic contact dermatitis and atopic dermatitis in children: insights from a retrospective patch testing analysis
Authors: Andre Nicolas , Usher Alisa , Ofri Mai , Horev Amir
Published: January 2024

Background

Recent years have seen significant exploration into the potential link between allergic contact dermatitis and atopic dermatitis, yielding contradictory findings.

Methods

A retrospective cohort analysis of children aged 2 to 18 who underwent patch testing at the pediatric dermatology clinic at a tertiary medical center in Israel was conducted.

Results

Overall, 367 patients were included in the study, 31.6% of whom were diagnosed with atopic dermatitis. 160 children (43.6%) exhibited a positive reaction to at least one compound in the European baseline series. There was no statistically significant difference in reactivity between children with atopic dermatitis and those without (P = 0.848). Sub‐analyses based on ethnicity, gender, and age did not reveal significant differences in overall European baseline series reactivity (P = 0.612, P = 0.446, P = 0.488, respectively). Sensitivity was notably higher when patch readings were conducted 72 h after application compared to 48 h [0.95 (CI: 0.91–0.97) vs. 0.60 (CI: 0.55–0.66)].

Conclusions

Patch testing is imperative for suspected cases of allergic contact dermatitis in all children, regardless of their atopic background. Further research is warranted to potentially replace the traditional 48‐h reading with a single 72‐h reading in future guidelines, contributing to enhanced efficiency and cost‐effectiveness in clinical practice.