bluuebunny/crossref_metadata_2025 huggingface dataset:
Benign or painful? The interpretation of pain and fear of progression in rheumatoid arthritis
Authors: Boyse Jack B. , Sharpe Louise , Richmond Bethany , Dear Blake , Dudeney Joanne , Sesel Amy-Lee , Menzies Rachel E.
Published: October 2023

People with chronic pain tend to interpret ambiguous information as health-related, more so than people without. In this study, we aimed to investigate whether people with rheumatoid arthritis (RA) exhibit this interpretation bias and whether it is associated with fear of disease progression (FoP). The interpretation biases of people with RA (n = 164) were compared with an age- and gender-matched control group. We hypothesized that (1) people with RA would have larger interpretation biases than people without; (2) those who scored in the clinical range for FoP would have larger interpretation bias than those who did not; (3) interpretation bias would moderate the relationship between pain severity and FoP; and (4) interpretation bias would explain variance in FoP above and beyond other established predictors. Our results confirmed that people with RA were more likely to interpret ambiguous information as health-related compared with people without RA. This effect was more pronounced for the RA subgroup with clinically significant FoP than those scoring in the normal range. We did not find evidence to suggest interpretation bias moderated the relationship between pain and FoP or that FoP added to the variance of other known predictors. Our results indicate that interpretation bias is common amongst people with RA and is associated with FoP. Further research is required to illuminate the exact nature of this relationship.
Measuring quality of life in patients with kidney stone disease: is it the future in endourology?
Authors: Vo Anh Khoi , Somani Bhaskar K. , Ulvik Øyvind , Beisland Christian , Seitz Christian , Juliebø-Jones Patrick
Published: October 2023

Purpose of review

Kidney stone disease is recognized to negatively impact quality of life. This pertains to acute episodes, surgical interventions and even during asymptomatic periods. Over time there has been increased attention towards assessing this subjective parameter, including as a determinant of treatment success. Our aim was to evaluate the current status and emerging trends in this field.

Recent findings

Patient groups most affected appear to be recurrent stone formers, cystine stone formers, women, younger populations, non-Caucasians and low-income populations. Several stone specific patient reported outcome measures are now available of which, WISQol has been implemented the most in clinical research studies. More invasive interventions such as percutaneous nephrolithotomy impede quality of life to greater extent than alternatives such as shockwave lithotripsy.

There are certain patient groups who are more vulnerable to the negative impact of kidney stone disease on their quality of life. Urologists can improve patient care by recognizing these particular populations as well as by implemented patient reported outcome measures in their routine clinical practice and when performing research.
Association of Long-Term, New-Onset, and Postsurgical Diabetes With Survival in Patients With Resectable Pancreatic Cancer
Authors: Kanbour Sarah , Yenokyan Gayane , Abusamaan Mohammed , Laheru Daniel , Alam Ayman , El Asmar Marie Line , Virk Zunaira , Hardenbergh Dylan , Mathioudakis Nestoras
Published: October 2023

Background

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Identifying modifiable risk factors, such as diabetes, is crucial. In the context of PDAC diagnosis, diabetes manifests as long-term (LTD), new-onset (NOD), or postsurgical (PSD) phenotypes. The link between these diabetes phenotypes and PDAC survival is debated.

Materials and Methods

We performed a retrospective study on patients with resectable PDAC who underwent pancreatectomy at Johns Hopkins Hospital from 2003 to 2017. We utilized the National Death Index and electronic medical records to determine vital status. We categorized diabetes as LTD, NOD, or PSD based on the timing of diagnosis relative to pancreatic resection. Using multivariable Cox models, we assessed hazard ratios (HRs) for survival times associated with each phenotype, considering known PDAC prognostic factors.

Results

Of 1556 patients, the 5-year survival was 19% (95% CI, 17–21). No significant survival differences were observed between diabetes phenotypes and non-diabetic patients. NOD and PSD presented nonsignificant increased risks of death (aHR: 1.14 [95% CI, 0.8–1.19] and 1.05 [95% CI, 0.89–1.25], respectively). LTD showed no survival difference (aHR, 0.98; 95% CI, 0.99–1.31).

Conclusions

No link was found between diabetes phenotypes and survival in resectable PDAC patients. Comprehensive prospective studies are required to validate these results.
Understanding the Impact of Mpox on Sexual Health Clinical Services: A National Knowledge, Attitudes, and Practices Survey – United States, 2022
Authors: Schubert Sara L. , Miele Kathryn , Quilter Laura , Agnew-Brune Christine , Coor Alexandra , Kachur Rachel , Lewis Felicia , Ard Kevin L. , Wendel Karen , Anderson Teri , Nagendra Gowri ,   National Network of STD Clinical Prevention Training Center Co-Authors, Tromble Erin
Published: October 2023

Background

During the 2022 mpox outbreak, most cases were associated with sexual contact and many people with mpox sought care from sexual health clinics and programs. The National Network of STD Clinical Prevention Training Centers (NNPTC), in partnership with Centers for Disease Control and Prevention, conducted a survey of United States sexual health clinics and programs to assess knowledge, practices, and experiences around mpox to inform a future public health response.

Methods

Between August 31–September 13, 2022, the NNPTC facilitated a web-based survey. Descriptive statistics were generated in R.

Results

Among 168 responses by clinicians (n = 131, 78%) and program staff (n = 37, 22%), more than half (51%) reported at least somewhat significant mpox-related clinical disruptions including burdensome paperwork requirements for mpox testing (40%) and tecovirimat use (88%). Long clinic visits (51%) added additional burden, the median mpox-related visit lasted one hour. Few clinicians felt comfortable with advanced pain management, and clinicians felt most uninformed about pre-exposure (19%) and post-exposure (24%) prophylaxis. Of 89 respondents involved in vaccination, 61% reported using equity strategies; however, accounts of these strategies revealed a focus on guideline or risk factor-based screenings instead of equity activities.

Conclusions

These findings highlight the substantial impact of the 2022 mpox outbreak on sexual health care in the United States. Critical gaps and barriers were identified that may inform additional mpox training and technical assistance, including challenges with testing, diagnosis, and management as well as a disconnect between programs’ stated goal of equity and operationalization of strategies to achieve equity.
Phycobacter azelaicus gen. nov. sp. nov., a diatom symbiont isolated from the phycosphere of Asterionellopsis glacialis
Authors: Coe Lisa S. Y. , Fei Cong , Weston James , Amin Shady A.
Published: October 2023

A diatom-associated bacterium, designated as strain F10T, was isolated from a pure culture of the pennate diatom Asterionellopsis glacialis A3 and has since been used to characterize molecular mechanisms of symbiosis between phytoplankton and bacteria, including interactions using diatom-derived azelaic acid. Its origin from a hypersaline environment, combined with its capacity for quorum sensing, biofilm formation, and potential for dimethylsulfoniopropionate methylation/cleavage, suggest it is within the family

Roseobacteraceae

. Initial phylogenetic analysis of the 16S rRNA gene sequence placed this isolate within the

Phaeobacter

genus, but recent genomic and phylogenomic analyses show strain F10T is a separate lineage diverging from the genus

Pseudophaeobacter

. The genomic DNA G+C content is 60.0 mol%. The predominant respiratory quinone is Q-10. The major fatty acids are C18 : 1 ω7c and C16 : 0. Strain F10T also contains C10 : 03-OH and the furan-containing fatty acid 10,13-epoxy-11-methyl-octadecadienoate (9-(3-methyl-5-pentylfuran-2-yl)nonanoic acid). The major polar lipids are diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. Based on genomic, phylogenomic, phenotypic and chemotaxonomic characterizations, strain F10T represents a novel genus and species with the proposed name, Phycobacter azelaicus gen. nov. sp. nov. The type strain is F10T (=NCMA B37T=NCIMB 15470T=NRIC 2002T).
Proposal for Acinetobacter higginsii sp. nov. to accommodate organisms of human clinical origin previously classified as Acinetobacter genomic species 16
Authors: Nemec Alexandr , Španělová Petra , Shestivska Violetta , Radolfová-Křížová Lenka , Maixnerová Martina , Feng Yu , Qin Jiayuan , Cevallos Miguel A. , Zong Zhiyong
Published: October 2023

In 1989, Bouvet and Jeanjean delineated five proteolytic genomic species (GS) of

Acinetobacter

, each with two to four human isolates. Three were later validly named, whereas the remaining two (GS15 and GS16) have been awaiting nomenclatural clarification. Here we present the results of the genus-wide taxonomic study of 13 human strains classified as GS16 (n=10) or GS15 (n=3). Based on core genome phylogenetic analysis, the strains formed two respective but closely related phylogroups within the

Acinetobacter

haemolytic clade. The intraspecies genomic average nucleotide identity based on blast (ANIb) values for GS16 and GS15 reached ≥94.9 % and ≥98.7, respectively, whereas ANIb values between them were 92.5–93.5% and those between them and the known species were ≤91.5 %. GS16 and GS15 could be differentiated from the other

Acinetobacter

species by their ability to lyse gelatin and sheep blood and to assimilate d,l-lactate, along with their inability to acidify d-glucose and assimilate glutarate. In contrast, GS16 and GS15 were indistinguishable from one another by metabolic/physiological features or whole-cell MALDI-TOF mass spectra. All the GS15/GS16 genomes contained genes encoding a class D β-lactamase,

Acinetobacter

-derived cephalosporinase and aminoglycoside 6′-N-acetyltransferase. Searching NCBI databases revealed genome sequences of three additional isolates of GS16, but none of GS15. We conclude that our data support GS16 as representing a novel species, but leave the question of the taxonomic status of GS15 open, given its close relatedness to GS16 and the small number of available strains. We propose the name Acinetobacter higginsii sp. nov. for GS16, with the type strain NIPH 1872T (CCM 9243T=CIP 70.18T=ATCC 17988T).
Investigating the neural effects of typicality and predictability for face and object stimuli
Authors: Ficco Linda , Li Chenglin , Kaufmann Jürgen M. , Schweinberger Stefan R. , Kovács Gyula Z.
Published: October 2023

The brain calibrates itself based on the past stimulus diet, which makes frequently observed stimuli appear as typical (as opposed to uncommon stimuli, which appear as distinctive). Based on predictive processing theory, the brain should be more “prepared” for typical exemplars, because these contain information that has been encountered frequently, and allow to economically represent items of that category. Thus, one could ask whether predictability and typicality of visual stimuli interact, or rather act in an additive manner. We adapted the design by Egner and colleagues (2010), who used cues to induce expectations about stimulus category (face vs. chair) occurrence during an orthogonal inversion detection task. We measured BOLD responses with fMRI in 35 participants. First, distinctive stimuli always elicited stronger responses than typical ones in all ROIs, and our whole-brain directional contrasts for the effects of typicality and distinctiveness converge with previous findings. Second and importantly, we could not replicate the interaction between category and predictability reported by Egner et al. (2010), which casts doubt on whether cueing designs are ideal to elicit reliable predictability effects. Third, likely as a consequence of the lack of predictability effects, we found no interaction between predictability and typicality in any of the four tested regions (bilateral fusiform face areas, lateral occipital complexes) when considering both categories, nor in the whole brain. We discuss the issue of replicability in neuroscience and sketch an agenda for how future studies might address the same question.
Effect of Human Infant Gut Microbiota on Mouse Behavior, Dendritic Complexity, and Myelination
Authors: Dubey Harikesh , Roychoudhury Rohon , Alex Ann , Best Charlotte , Liu Sheng , White Antonio , Carlson Alexander , Azcarate-Peril M. Andrea , Mansfield Linda S. , Knickmeyer Rebecca
Published: October 2023

The mammalian gut microbiome influences numerous developmental processes. In human infants it has been linked with cognition, social skills, hormonal responses to stress, and brain connectivity. Yet, these associations are not necessarily causal. The present study tested whether two microbial stool communities, common in human infants, affected behavior, myelination, dendritic morphology, and spine density when used to colonize mouse models. Humanized animals were more like specific-pathogen free mice than germ-free mice for most phenotypes, although in males, both humanized groups were less social. Both humanized groups had thinner myelin sheaths in the hippocampus, than did germ-free animals. Humanized animals were similar to each other except for dendritic morphology and spine density where one group had greater dendritic length in the prefrontal cortex, greater dendritic volume in the nucleus accumbens, and greater spine density in both regions, compared to the other. Results add to a body of literature suggesting the gut microbiome impacts brain development.

Teaser

Fecal transplants from human infants with highly abundantBifidobacterium, an important inhabitant of the intestinal tract of breastfed newborns, may promote brain connectivity in mice.
ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers
Authors: Xu Yaru , Wang Zhaoning , Sjöström Martin , Deng Su , Wang Choushi , Johnson Nickolas A , Gonzalez Julisa , Li Xiaoling , Metang Lauren A , Tirado Carla Rodriguez , Mukherji Atreyi , Wainwright Garrett , Yu Xinzhe , Yang Yuqiu , Barnes Spencer , Hofstad Mia , Zhu Hong , Hanker Ariella , He Housheng Hansen , Chen Yu , Wang Zhao , Raj Ganesh , Arteaga Carlos , Feng Felix , Wang Yunguan , Wang Tao , Mu Ping
Published: October 2023

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as abona fideco-activator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.

Statement of Significance

This study reveals a novel epigenetic mechanism regulating tumor lineage plasticity and therapy response, enhances understanding of drug resistance and unveils a new therapeutic strategy for prostate cancer and other malignancies. Our findings also illuminate TET2’s oncogenic role and mechanistically connect TET2-driven epigenetic rewiring to lineage plasticity and therapy resistance.
Multiple steps of prion strain adaptation to a new host
Authors: Bocharova Olga , Makarava Natallia , Pandit Narayan P. , Molesworth Kara , Baskakov Ilia V.
Published: October 2023

The transmission of prions across species is a critical aspect of their dissemination among mammalian hosts, including humans. This process often necessitates strain adaptation. In this study, we sought to investigate the mechanisms underlying prion adaptation while mitigating biases associated with the history of cross-species transmission of natural prion strains. To achieve this, we utilized the synthetic hamster prion strain S05. Propagation of S05 using mouse PrPCin Protein Misfolding Cyclic Amplification did not immediately overcome the species barrier. This finding underscores the involvement of factors beyond disparities in primary protein structures. Subsequently, we performed five serial passages to stabilize the incubation time to disease in mice. The levels of PrPScincreased with each passage, reaching a maximum at the third passage, and declining thereafter. This suggests that only the initial stage of adaptation is primarily driven by an acceleration in PrPScreplication. During the protracted adaptation to a new host, we observed significant alterations in the glycoform ratio and sialylation status of PrPScN-glycans. These changes support the notion that qualitative modifications in PrPSccontribute to a more rapid disease progression. Furthermore, consistent with the decline in sialylation, a cue for “eat me” signaling, the newly adapted strain exhibited preferential colocalization with microglia. In contrast to PrPScdynamics, the intensity of microglia activation continued to increase after the third passage in the new host. In summary, our study elucidates that the adaptation of a prion strain to a new host is a multi-step process driven by several factors.
Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization
Authors: Ben-Chetrit Nir , Niu Xiang , Sotelo Jesus , Swett Ariel D. , Rajasekhar Vinagolu K. , Jiao Maria S. , Stewart Caitlin M. , Bhardwaj Priya , Kottapalli Sanjay , Ganesan Saravanan , Loyher Pierre-Louis , Potenski Catherine , Hannuna Assaf , Brown Kristy A. , Iyengar Neil M. , Giri Dilip D. , Lowe Scott W. , Healey John H. , Geissmann Frederic , Sagi Irit , Joyce Johanna A. , Landau Dan A.
Published: October 2023

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novelex vivoorganotypic TME (oTME) model of breast cancer,in vivomurine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomasin vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.
A viral-specific CD4+T cell response protects female mice from Coxsackievirus B3 infection
Authors: Pattnaik Aryamav , Dhalech Adeeba H. , Condotta Stephanie A. , Corn Caleb , Richer Martin J. , Snell Laura M. , Robinson Christopher M.
Published: October 2023

Biological sex plays an integral role in the immune response to various pathogens. The underlying basis for these sex differences is still not well defined. Here, we show that Coxsackievirus B3 (CVB3) induces a viral-specific CD4+T cell response that can protect female mice from mortality. We found that CVB3 can induce expansion of CD62LloCD4+T cells in the mesenteric lymph node and spleen of female but not male mice as early as 5 days post-inoculation, indicative of activation. Using a recombinant CVB3 virus expressing a model CD4+T cell epitope, we found that this response is due to viral antigen and not bystander activation. Finally, the depletion of CD4+T cells before infection increased mortality in female mice, indicating that CD4+T cells play a protective role against CVB3 in our model. Overall, these data demonstrated that CVB3 can induce an early CD4 response in female but not male mice and further emphasize how sex differences in immune responses to pathogens affect disease outcomes.
A generalised method for experiment design and model selection in the Bayesian framework
Authors: Jagadeesan Prem , Raman Karthik , Tangirala Arun K
Published: October 2023

Computational modelling of dynamical systems often involves many free parameters estimated from experimental data. The information gained from an experiment plays a crucial role in the goodness of predictions and parameter estimates. Optimal Experiment Design (OED) is being used to choose an experiment containing maximum information from a set of possible experiments. This work presents a novel Bayesian Optimal Experiment Design principle for generalised parameter distributions. The generalization is archived by extending theβ-information gain to the discrete distributions. Theβ-information gain is based on what is known as the Bhattacharyya coefficient. We show that maximising theβ-information gain is equivalent to maximising the angle between the prior and posterior distributions, reducing the posterior’s uncertainty. Further, we apply the proposed BOED criteria for two realistic experiment designs in systems biology. Firstly, we use theβinformation gain to choose the best measurement method for parameter estimation in a Hes1 transcription model. The measurement method selected by theβ-information gain results in the minimum mean square error of the parameter estimates. In the second case, we employ the proposed information gained to select an optimal sampling schedule for HIV 1 2 LTR model. The sampling schedule chosen by the presented method reduces both prediction and parameter uncertainty. Finally, we propose a novel method for model selection usingβinformation gain and demonstrate the working of the proposed method in the model selection in compartmental models.
Pulsed stimuli entrain p53 to synchronize single cells and modulate cell-fate determination
Authors: Venkatachalapathy Harish , Yang Zhilin , Azarin Samira M. , Sarkar Casim A. , Batchelor Eric
Published: October 2023

Entrainment to an external stimulus enables a synchronized oscillatory response across a population of cells, increasing coherent responses by reducing cell-to-cell heterogeneity. It is unclear whether the property of entrainability extends to systems where responses are intrinsic to the individual cell, rather than dependent on coherence across a population of cells. Using a combination of mathematical modeling, time-lapse fluorescence microscopy, and single-cell tracking, we demonstrated that p53 oscillations triggered by DNA double-strand breaks (DSBs) can be entrained with a periodic damage stimulus, despite such synchrony not known to function in effective DNA damage responses. Surprisingly, p53 oscillations were experimentally entrained over a wider range of DSB frequencies than predicted by an established computational model for the system. We determined that recapitulating the increased range of entrainment frequencies required, non-intuitively, a less robust oscillator and wider steady-state valley on the energy landscape. Further, we show that p53 entrainment can lead to altered expression dynamics of downstream targets responsible for cell fate in a manner dependent on target mRNA stability. Overall, this study demonstrates that entrainment can occur in a biological oscillator despite the apparent lack of an evolutionary advantage conferred through synchronized responses and highlights the potential of externally entraining p53 dynamics to reduce cellular variability and synchronize cell-fate responses for therapeutic outcomes.
Sensitive detection of chloroplast movements through changes in leaf cross-polarized reflectance
Authors: Hermanowicz Paweł , Giza Aleksandra , Łabuz Justyna
Published: October 2023

We present a sensitive method for non-contact detection of chloroplast movements in leaves and other photosynthetic tissues, based on changes in the magnitude of cross-polarized reflectance of the leaf. We created a custom optical set-up and dedicated software for measurements of changes in red light reflectance during irradiation with blue light, known to trigger chloroplast relocations. Experiments onArabidopsis thalianawild type and several mutants with disrupted chloroplast movements showed that the chloroplast avoidance response, induced by high blue light, led to a substantial increase in diffuse reflectance of unpolarized red light. The effects of the accumulation response in low blue light were the opposite. The specular reflectance of the leaf was unaffected by the chloroplast positioning. To further improve the specificity of the detection, we examined the effects of chloroplast relocations on the leaf reflectance of a linearly polarized incident beam. The greatest relative change associated with chloroplast movements was observed when the planes of polarization of the incident and detected beams were perpendicular. This suggests that the chloroplast positioning affects the magnitude of depolarization of light. We applied the developed approach to examine chloroplast relocations in four angiosperm species collected in the field. In particular, the method allowed us to detect the chloroplast avoidance response in the green stems of bilberry before bud break. Such samples are not amenable to transmittance-based detection.

Significance statement

Despite the importance of chloroplast movements for the optimization of photosynthetic efficiency and biomass production, high throughput reflectance-based methods are not routinely used for their detection. Strong dependence of the amount of specularly reflected light reaching the detector on the leaf orientation may lead to a substantial error in chloroplast relocation measurements. We show that the assessment of chloroplast responses through polarized reflectance reduces systematic errors due to the leaf movements and improves the sensitivity of detection. This opens a possibility of non-invasive, non-contact detection of chloroplast relocations using existing instrumentation for remote sensing of agriculturally relevant crop traits.
Emerging role of oncogenic β-catenin in exosome biogenesis as a driver of immune escape in hepatocellular carcinoma
Authors: Dantzer Camille , Vaché Justine , Brunel Aude , Mahouche Isabelle , Raymond Anne-Aurélie , Dupuy Jean-William , Petrel Melina , Bioulac-Sage Paulette , Perrais David , Dugot-Senant Nathalie , Verdier Mireille , Bessette Barbara , Billottet Clotilde , Moreau Violaine
Published: October 2023

Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of β-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic β-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of β-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated β-catenin represses expression ofSDC4andRAB27A, two main actors in exosome biogenesis, in both liver cancer cell lines and HCC patient samples. Using nanoparticle tracking analysis and live-cell imaging, we further demonstrated that activated β-catenin represses exosome release. Then, we demonstrated in 3D spheroid models that activation of β-catenin promotes a decrease in immune cell infiltration through a defect in exosome secretion. Taken together, our results provide the first evidence that oncogenic β-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of β-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response.
Analysis of uveal melanoma scRNA sequencing data identifies neoplastic-immune hybrid cells that exhibit metastatic potential
Authors: Anderson Ashley N. , Conley Patrick , Klocke Christopher D. , Sengupta Sidharth K. , Robinson Trinity L. , Fan Yichen , Jones Jocelyn A. , Gibbs Summer L. , Skalet Alison H. , Wu Guanming , Wong Melissa H.
Published: October 2023

Uveal melanoma (UM) is the most common non-cutaneous melanoma and is an intraocular malignancy that affects nearly 7,000 individuals per year worldwide. Of these, nearly 50% will progress to metastatic disease for which there are currently no effective therapies. Despite advances in the molecular profiling and metastatic stratification of class 1 and 2 UM tumors, little is known regarding the underlying biology of UM metastasis. Our group has identified a disseminated tumor cell population characterized by co-expression of immune and melanoma proteins, (circulating hybrid cells (CHCs), in patients with UM. Compared to circulating tumor cells, CHCs are detected at an increased prevalence in peripheral blood and can be used as a non-invasive biomarker to predict metastatic progression. To identify mechanisms underlying enhanced hybrid cell dissemination we sought to identify hybrid cells within a primary UM single cell RNA-seq dataset. Using rigorous doublet discrimination approaches, we identified UM hybrids and evaluated their gene expression, predicted ligand-receptor status, and cell-cell communication state in relation to other melanoma and immune cells within the primary tumor. We identified several genes and pathways upregulated in hybrid cells, including those involved in enhancing cell motility and cytoskeleton rearrangement, evading immune detection, and altering cellular metabolism. In addition, we identified that hybrid cells express ligand-receptor signaling pathways implicated in promoting cancer metastasis including IGF1-IGFR1, GAS6-AXL, LGALS9-P4HB, APP-CD74 and CXCL12-CXCR4. These results contribute to our understanding of tumor progression and interactions between tumor cells and immune cells in the UM microenvironment that may promote metastasis.
Using deep-learning to obtain calibrated individual disease and ADL damage transition probabilities between successive ELSA waves
Authors: Dil Emre , Rutenberg Andrew
Published: October 2023

We predictively model damage transition probabilities for binary health outputs of 19 diseases and 25 activities of daily living states (ADLs) between successive waves of the English Longitudinal Study of Aging (ELSA). Model selection between deep neural networks (DNN), random forests, and logistic regression found that a simple one-hidden layer 128-node DNN was best able to predict future health states (AUC ≥ 0.91) and average damage probabilities (R2≥ 0.92). Feature selection from 134 explanatory variables found that 33 variables are sufficient to predict all disease and ADL states well. Deciles of predicted damage transition probabilities were well calibrated, but correlations between predicted health states were stronger than observed. The hazard ratios (HRs) between high-risk deciles and the average were between 3 and 10; high prevalence damage transitions typically had smaller HRs. Model predictions were good across all individual ages. A simple one-hidden layer DNN predicts multiple binary diseases and ADLs with well calibrated damage and repair transition probabilities.
Measuring mtDNA turnover, synthesis, and supercoiling via selective bromodeoxyuridine incorporation
Authors: Deng Jingti , Mohan Armaan , Shutt Timothy E
Published: October 2023

Increasing work on mitochondria is focused on the dynamic aspects of this organelle, a key part of which is regulation of the mitochondrial genome (mtDNA). Here we describe a protocol that selectively incorporates bromodeoxyuridine into mtDNA for the measurement of mtDNA turnover, synthesis or supercoiling via an adapted immunoblot and Southern blot protocol. For complete use and execution of this protocol see Al Khatib et al.1,2and Lei et al.3
Co-transcriptional translation amplifies mRNA noise inEscherichia coli
Authors: Yang Sora , Park Soojin , Son Jung Bae , Kim Seunghyeon , Yi Soojung , Bu Gayun , Lee Nam Ki
Published: October 2023

The variability in mRNA expression among isogenic cells exposed to identical environments is inherent. This variability originates from the inherent stochasticity of all processes underlying transcription. Although transcription and translation can occur simultaneously on the same mRNA molecule in bacteria, it is not well understood whether and how co-transcriptional translation contributes to variability in mRNA expression. Here, we studied the contribution of co-transcriptional translation to mRNA noise inE. colicells. Using a transcription system physically decoupled from translation, we investigated the effect of ribosome binding to mRNA transcripts on variability in mRNA expression. We found that the propagation of RNAP noise to the mRNA level was increased by ribosome binding, leading to larger variations in the mRNA levels. We further demonstrated that ribosome binding increased the transcription initiation rate, resulting in the promoter becoming susceptible to RNAP noise. Co-transcriptional translation amplified transcriptional noise and modulated transcriptional bursting kinetics in bacterial cells.
Development of neural circuits for social motion perception in schooling fish
Authors: Zada David , Schulze Lisanne , Yu Jo-Hsien , Tarabishi Princess , Napoli Julia L , Lovett-Barron Matthew
Published: October 2023

Many animals move in groups, where collective behavior emerges from the interactions amongst individuals. These social interactions produce the coordinated movements of bird flocks and fish schools, but little is known about their developmental emergence and neurobiological foundations. By characterizing the visually-based schooling behavior of the micro glassfishDanionella cerebrum, here we found that social development progresses sequentially, with animals first acquiring the ability to aggregate, followed by postural alignment with social partners. This social maturation was accompanied by the development of neural populations in the midbrain and forebrain that were preferentially driven by visual stimuli that resemble the shape and movements of schooling fish. The development of these neural circuits enables the social coordination required for collective movement.

One-Sentence Summary

The collective behavior of schooling fish emerges with the development of neural populations selective to social motion.
Analysis of the peptide helicity using an ensemble spectroscopic model with re-calibrated parameters
Authors: Zavrtanik Uroš , Lah Jurij , Hadži San
Published: October 2023

The α-helix is the fundamental building block of protein structure. Understanding the physical principles that determine how a specific amino acid sequence defines helicity is a key step towards elucidating the sequence-structure relationship. An established method for quantitation of helix content using circular dichroism (CD) relies on the linear spectroscopic model. In this model, the helix length-correction is not applied to each ensemble conformer individually, rather an average value is assumed for all conformers. Here we assess the validity of this approximation and introduce a more physically realistic ensemble-based analysis of the CD signal. We find that the linear model tends to underestimate peptide helicity, with the difference depending on the ensemble composition. Using a CD dataset covering a broad range of helicities, we re-calibrate spectroscopic parameters (helix and coil baselines) and determine helix-coil parameters for a set of alanine-rich peptides. Our results show that the ensemble model can leverage the small spectroscopic differences between peptide conformers, enabling it to extract more information from the experimental data. We show that some previously poorly-defined quantities, such as helix nucleation constant and heat capacity change associated with helix folding, can be reliably determined using ensemble model. Overall, the presented ensemble-based treatment of the CD signal, together with the re-calibrated values of the spectroscopic baseline parameters, provides a coherent framework for the analysis of the peptide helix content.

Abstract Figure
Discovery of a novel inhibitor of macropinocytosis with antiviral activity
Authors: Porebski Bartlomiej , Christ Wanda , Corman Alba , Haraldsson Martin , Barz Myriam , Lidemalm Louise , Häggblad Maria , Ilmain Juliana , Wright Shane C. , Murga Matilde , Shlegel Jan , Sezgin Erdinc , Bhabha Gira , Lauschke Volker M , Lafarga Miguel , Klingström Jonas , Huhn Daniela , Fernandez-Capetillo Oscar
Published: October 2023

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a new molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using High-Throughput Microscopy, where we identified new chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit infection by SARS-CoV-2, as well as by additional viruses, such as Monkeypox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present a new molecule that inhibits viral entry via the endocytic route, offering a new alternative to prevent viral infection.
Length-dependent Intramolecular Coil-to-Globule Transition in Poly(ADP-ribose) Induced by Cations
Authors: Wang Tong , Coshic Kush , Badiee Mohsen , Aksimentiev Aleksei , Pollack Lois , Leung Anthony K. L.
Published: October 2023

Poly(ADP-ribose) (PAR), as part of a post-translational modification, serves as a flexible scaffold for noncovalent protein binding. Such binding is influenced by PAR chain length through a mechanism yet to be elucidated. Structural insights have been elusive, partly due to the difficulties associated with synthesizing PAR chains of defined lengths. Here, we employ an integrated approach combining molecular dynamics (MD) simulations with small-angle X-ray scattering (SAXS) experiments, enabling us to identify highly heterogeneous ensembles of PAR conformers at two different, physiologically relevant lengths: PAR15and PAR22. Our findings reveal that numerous factors including backbone conformation, base stacking, and chain length contribute to determining the structural ensembles. We also observe length-dependent compaction of PAR upon the addition of small amounts of Mg2+ions, with the 22-mer exhibiting ADP-ribose bundles formed through local intramolecular coil-to-globule transitions. This study illuminates how such bundling could be instrumental in deciphering the length-dependent action of PAR.

GRAPHICAL ABSTRACT
A Phase 2 random, double-blind, placebo-controlled study of the safety and immunogenicity of a recombinant G protein-based respiratory syncytial virus vaccine in healthy older adults
Authors: Zhang Lunan , Zhao Gan , Cheng Xin , Wang Shuo , Wang Jiarong , Huai Xuefen , Xia Yu , Xiao Yanling , Ren Sulin , Zhang Shijie , Wang Bin
Published: October 2023

Background

Respiratory syncytial virus (RSV) is an important cause of disease in older adults. Vaccines against RSV infections and respiratory diseases are in large market demand. Although there are currently two licensed RSV-based pre-F antigen vaccines available for older adults, no G antigen-based RSV vaccine is authorized. This phase 2 study aimed to evaluate the safety and immunogenicity of a recombinant G protein-based RSV vaccine in this population.

Methods

A phase-2 randomized, double-blind, placebo-controlled, dose-ranging study was conducted to evaluate the safety, tolerability and immunogenicity of the BARS13 (rRSV G protein with CsA) when administered by an intramuscular (IM) injection to healthy participants 60 to 80 years old. A total of 125 eligible participants were randomized in a 3:1 ratio (vaccine versus placebo) for Cohorts 1 and 2 and randomized in a 2:1 ratio for Cohort 3 to receive one of the three treatment regimens or placebo.

Results

The average age was 65.3, and 50.4% (63/125) were men. Until the interim analysis (4 weeks following the last vaccination), no treatment-related SAE occurred. TEAEs did not increase with vaccination dosage or frequency. All adverse effects were mild or moderate, not severe or life-threatening. BARS13 vaccination increased IgG anti-RSV antibody levels in all cohorts, but higher doses and frequency boosted immune responses significantly. The high-dose thrice-administered recipients had serum-specific IgG antibody GMC of 881.0 IU/mL (95% CI: 794.5-1473.4) before the first dose (Week 0), 1116.3 IU/mL (95% CI:990.7-1772.5) 4 weeks after the first dose (Week 4), 1309.4IU/mL (95% CI: 1162.8-2041.5) 4 weeks after the second dose (Week 8), and1359.6 IU/mL (95% CI: 1197.9-2525.7) 4 weeks after the third dose (Week 12). For the low-dose twice-administered recipients, 84% responded at 4 weeks after the first immunization (Week 4) and 83.3% at 4 weeks after the second (Week 8). The high-dose twice-administered recipients had 95.5% response at 4 weeks after the first immunization (Week 4) and 72.2% at 4 weeks after the second (Week 8). At Week 4, 85.7% of high-dose thrice-administered recipients responded, 85.2% at Week 8, and 79.2% at Week 12.

Conclusions

The study demonstrates the safety and tolerability of BARS13 across different dose groups. Adverse reactions were not significantly different among participants receiving varying doses of BARS13. Levels of anti-G antibodies exhibited a dose- and frequency-dependent responses in the older population. The continuous upward trend in antibody concentration up to the interim analysis is promising for the effectiveness of BARS13.
Restoration of normal central pain processing following manual therapy in nonspecific chronic neck pain
Authors: Mata Josu Zabala , Azkue Jon Jatsu , Bialosky Joel E. , Saez Marc , López Estíbaliz Dominguez , Arrieta Maialen Araolaza , Lascurain-Aguirrebeña Ion
Published: October 2023

Objective

to determine if a 4-week manual therapy treatment restores normal functioning of central pain processing mechanisms in non-specific chronic neck pain (NSCNP), as well as the existence of a possible relationship between changes in pain processing mechanisms and clinical outcome.

Design

cohort study.

Methods

sixty-three patients with NSCNP received four treatment sessions (once a week) of manual therapy. Pressure pain thresholds (PPTs), conditioned pain modulation (CPM) and temporal summation of pain (TSP) were evaluated at baseline and after treatment completion. Therapy outcome was measured using the Global Rating of Change Scale, the Neck disability Index, intensity of pain during the last 24 hours, Tampa Scale of Kinesiophobia and Pain Catastrophizing Scale.

Results

Following treatment, an increased CPM response and attenuated TSP were found, along with amelioration of pain and improved clinical status. PPTs at trapezius muscle on the side of neck pain were increased after therapy, but not those on the contralateral trapezius and tibialis anterior muscles. Only minor associations were found between normalization of TSP/CPM and measures of clinical outcome.

Conclusion

Clinical improvement after manual therapy is accompanied by restoration of CPM and TSP responses to normal levels in NSCNP patients. The existence of only minor associations between changes in central pain processing and clinical outcome suggests multiple mechanisms of action of manual therapy in NSCNP.
Improving treatment precision in head and neck BNCT: delineation of oral and pharyngeal mucosa based on an MRI Atlas for standardized applications
Authors: Hirose Katsumi , Kato Ryohei , Sato Mariko , Ichise Koji , Tanaka Mitsuki , Fujioka Ichitaro , Kawaguchi Hideo , Hatayama Yoshiomi , Aoki Masahiko , Takai Yoshihiro
Published: October 2023

Background and purpose

Boron neutron capture therapy (BNCT) has been routinely practiced for treatment of head and neck cancer in Japan. However, differences in contouring the oral and pharyngeal mucosa can lead to discrepancies in treatment. This study aimed to introduce a standardized approach using an MRI-based atlas, aiming to minimize inter-observer error and improve dose precision.

Materials and Methods

An MRI atlas of the head and neck mucosa was developed using water/fat-separated images from a healthy man. Using CT images from three patients, seven radiation oncologists performed contouring of the head and neck mucosa twice over a 3-week period. Contouring was first performed using CT alone, then later using fused T2-weighted images with the mucosal atlas for guidance. Contouring errors were assessed and their impacts on tumor dose were evaluated.

Results

The introduction of the MRI-based mucosal atlas significantly reduced inter-observer variation in mucosal volume (the coefficient of variation, abbreviated with COV, decreased from 0.61 with CT alone to 0.21 with the MRI atlas; p=0.003). Moreover, the atlas resulted in improved contour homology among observers and reduced variations in tumor dose. For all cases, COVs for maximum, mean, and minimum tumor doses were all below 5%.

Conclusion

Utilizing an MRI-based mucosal atlas in BNCT contouring can significantly reduce inter-observer variation, improve contour homology, and decrease variations in tumor dose. These findings suggest strong potential for standardizing and enhancing the quality of BNCT for head and neck cancer.