bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of severe infections after the introduction of biologic DMARDs in people with newly diagnosed rheumatoid arthritis: a population-based interrupted time-series analysis
Authors: Zhou Vivienne Y , Lacaille Diane , Lu Na , Kopec Jacek A , Qian Yi , Nosyk Bohdan , Aviña-Zubieta J Antonio , Esdaile John M , Xie Hui
Published: April 2023

Objectives

To determine the impact of the introduction of biologic DMARDs (bDMARDs) on severe infections among people newly diagnosed with RA compared with non-RA individuals.

Methods

In this population-based retrospective cohort study using administrative data (from 1990–2015) for British Columbia, Canada, all incident RA patients diagnosed between 1995 and 2007 were identified. General population controls with no inflammatory arthritis were matched to RA patients based on age and gender, and were assigned the diagnosis date (i.e. index date) of the RA patients they were matched with. RA/controls were then divided into quarterly cohorts according to their index dates. The outcome of interest was all severe infections necessitating hospitalization or occurring during hospitalization after the index date. We calculated 8-year severe infection rates for each cohort and conducted interrupted time-series analyses to compare severe infection trends in RA/controls with index date during pre-bDMARDs (1995–2001) and post-bDMARDs (2003–2007) periods.

Results

A total of 60 226 and 588 499 incident RA/controls were identified. We identified 14 245 severe infections in RA, and 79 819 severe infections in controls. The 8-year severe infection rates decreased among RA/controls with increasing calendar year of index date in the pre-bDMARDs period, but increased over time only among RA, not controls, with index date in the post-bDMARDs period. The adjusted difference between the pre- and post-bDMARDs secular trends in 8-year severe infection rates was 1.85 (P = 0.001) in RA and 0.12 (P = 0.29) in non-RA.

Conclusion

RA onset after bDMARDs introduction was associated with an elevated severe infection risk in RA patients compared with matched non-RA individuals.
Emerging evidence for poxvirus‐mediated unfolded protein response: Lumpy skin disease virus maintains self‐replication by activating PERK and IRE1 signaling
Authors: Tan Jinlong , Liu Yinju , Yang Fan , Chen Guohua , Fang Yongxiang , He Xiaobing , Lou Zhongzi , Jia Huaijie , Jing Zhizhong , Li Weike
Published: April 2023

The monkeypox epidemic has attracted global attention to poxviruses. The cytoplasmic replication of poxviruses requires extensive protein synthesis, challenging the capacity of the endoplasmic reticulum (ER). However, the role of the ER in the life cycle of poxviruses is unclear. In this study, we demonstrate that infection with the lumpy skin disease virus (LSDV), a member of the poxvirus family, causes ER stress in vivo and in vitro, further facilitating the activation of the unfolded protein response (UPR). Although UPR activation aids in the restoration of the cellular environment, its significance in the LSDV life cycle remains unclear. Furthermore, the significance of ER imbalance for viral replication is also unknown. We show that LSDV replication is hampered by an unbalanced ER environment. In addition, we verify that the LSDV replication depends on the activation of PERK‐eIF2α and IRE1‐XBP1 signaling cascades rather than ATF6, implying that global translation and reduced XBP1 cleavage are deleterious to LSDV replication. Taken together, these findings indicate that LSDV is involved in the repression of global translational signaling, ER chaperone transcription, and ATF6 cleavage from the Golgi into the nucleus, thereby maintaining cell homeostasis; moreover, PERK and IRE1 activation contribute to LSDV replication. Our findings suggest that targeting UPR elements may be applied in response to infection from LSDV or even other poxviruses, such as monkeypox.
Surgical Correction of Posttraumatic Varus Deformity of the Distal Tibia Due to Medial Growth Arrest in Children and Adolescents: Surgical Technique
Authors: Schwartz Robert , Kotlarsky Pavel , Eidelman Mark
Published: April 2023

Background:

Varus deformity of the distal tibia secondary to epiphyseal fracture and partial growth arrest is relatively common. Growth arrest of the medial part of the epiphysis leads to varus deformity of the distal tibia and fibular overgrowth. If the deformity is left untreated, the malalignment may lead to irreversible damage and early ankle joint osteoarthritis in the long term.

Several surgical techniques have been described in the literature to achieve correction and prevent late complications. These include the closure of the remaining epiphysis and various osteotomies around the ankle, using internal and external fixation.

Materials and Methods:

We report a technique that includes medial open wedge supramalleolar osteotomy, insertion of a structural cortical allograft and fixation with an anatomically contoured locking plate, completion of closure of the distal tibial physis, and distal fibular epiphysiodesis to prevent tibiofibular relations distortion. Part of this protocol is osteotomy of the distal fibula to prevent excessive pressure on the talus, and at the end of the operation, fibular fixation should be performed as well. In children with open physis and potential for significant leg length discrepancy, we recommend closure of the contralateral physis of the distal tibia and fibula. To the best of our knowledge, precise details of this protocol have not been described.

Conclusion:

We believe that this protocol is a reliable, accurate, and relatively simple method that provides not only anatomic correction and restoration of the ankle joint to prevent early ankle and subtalar arthritis but also addresses late complications, such as ipsilateral fibular overgrowth and limb length discrepancy.
Eosinophilic gastroenteritis: Pathogenesis, diagnosis, and treatment
Authors: Li Kaiwen , Ruan Gechong , Liu Shuang , Xu Tianming , Guan Kai , Li Ji , Li Jingnan
Published: April 2023

Eosinophilic gastroenteritis (EGE) is a gastrointestinal disorder of unclear etiology that is characterized by eosinophilic infiltration of the stomach and small intestine, and consists of mucosal, muscular, and serosal subtypes. Eosinophilic infiltration of the gastrointestinal tract is a fundamental histopathological characteristic of EGE and is driven by several T-helper type 2 (Th2)-dependent cytokines and induced by food allergy. Due to the lack of a diagnostic gold standard, EGE has a high rate of delayed diagnosis or misdiagnosis. However, several new diagnostic strategies have been developed, such as novel genetic biomarkers and imaging tests. Although dietary therapy and corticosteroids remain the common choices for EGE treatment, recent decades have seen the emergence of novel treatment alternatives, such as biologics that target particular molecules involved in the pathogenic process. Preliminary investigations and clinical trials have demonstrated the efficacy of biologics and provided additional insights for the era of refractory or corticosteroid-dependent EGE biologics.
Hydatid cyst of the psoas: case report and review of literature
Authors: Mhand Mohammed , Ramdani Abdelbassir , Khomssi Nabil , Rhoul Chafik , Bouhout Tariq , Serji Badr , El Harroudi Tijani
Published: April 2023

Introduction:

Hydatid disease (HD) is a parasitic pathology that remains endemic in Morocco and poses a public health problem. Its location in the psoas muscle is a rare entity. We report this case highlighting the diagnostic challenges, therapeutic modalities as well as prognosis.

Case Presentation:

We report the case of a 40-year-old male patient without a notable pathological history, referred to our department for management of a paravertebral hydatid cyst mass with fluid density and scalloping on the verteral body on thoraco-abdomino-pelvic computed tomography scan. After a pretherapeutic assessment, the patient underwent an exploratory laparotomy which objective a deep right laterovertebral mass. The patient underwent a resection of the protruding dome, lavage using hydrogen peroxide and drainage of the residual cavity. The patient recovered well and was discharged 5 days later on albendazole 10 mg/kg/d. The anatomopathological analysis of the specimen confirmed the diagnosis of hydatid cyst. The evolution was satisfactory for the patient with a recall of 6 months.

Discussion:

Hydatidosis is an anthropozonosis caused by the larval form of Echinococcus granulosus. It can reach the psoas muscle by great circulation. The diagnosis of HD in the psoas is often difficult. Biology and imaging confirm the diagnosis and the standard treatment remains surgery.

Conclusion:

HD of the psoas is a rare entity. The diagnosis is based on biology and imaging, and radical treatment is surgery.
Antimicrobial resistance patterns in paediatric infections at Damascus Hospital, Syria: a retrospective cohort study
Authors: Kahal Fares , Helwani Ahmed , Torbey André , Alsaadi Aya , Mohsen Fatema , Al Bani Maher
Published: April 2023

Background:

Antimicrobial resistance is the third top-ranking global causative of death. Ninety per cent of babies with sepsis who were admitted to the ICU in the Middle East had antibiotic-resistant bacteria. We aim to describe the epidemiology, culture findings, bacterial antibiotic resistance, as well as the outcomes of children who present with nosocomial or community-acquired infections.

Methods:

A retrospective observational cohort study was conducted to analyze children with positive culture results presenting with nosocomial or community-acquired infections in Damascus Hospital, Damascus, Syria, which is considered one of the biggest hospitals in Syria.

Results:

In all, 116 patients with 177 positive culture results were included in the study. However, 54 (47%) were males, and 62 (53%) were females. Ages ranged between 3 h and 13 years. Cases of positive culture results peaked at the age or period of 0–11 months, that is 59(50%). The most prevalent bacteria were Staphylococcus aureus (33%), Enterobacter (21%), Pseudomonas aeruginosa (15%) and Escherichia coli (12%). The most used antibiotics were ceftriaxone (70%), vancomycin (60%) and amikacin (25%). The highest bacterial antibiotic resistance occurred with third-generation cephalosporins, and the most antibiotic-resistant bacterium was P. aeruginosa. Nosocomial infections occurred in 51% of the patients. Death was the outcome of 16% of the patients.

Conclusion:

The situation regarding bacterial resistance to antibiotics is critical, with the most notable examples of these resisted antibiotics being ceftriaxone, cefepime, cefotaxime, trimethoprim, gentamycin, levofloxacin and piperacillin with tazobactam, and there is no doubt that this is a major contributing factor to the high prevalence of nosocomial infections and death rates found in this study.
Universal early warning signals of phase transitions in climate systems
Authors: Dylewsky Daniel , Lenton Timothy M. , Scheffer Marten , Bury Thomas M. , Fletcher Christopher G. , Anand Madhur , Bauch Chris T.
Published: April 2023

The potential for complex systems to exhibit tipping points in which an equilibrium state undergoes a sudden and often irreversible shift is well established, but prediction of these events using standard forecast modelling techniques is quite difficult. This has led to the development of an alternative suite of methods that seek to identify signatures of critical phenomena in data, which are expected to occur in advance of many classes of dynamical bifurcation. Crucially, the manifestations of these critical phenomena are generic across a variety of systems, meaning that data-intensive deep learning methods can be trained on (abundant) synthetic data and plausibly prove effective when transferred to (more limited) empirical datasets. This paper provides a proof of concept for this approach as applied to lattice phase transitions: a deep neural network trained exclusively on two-dimensional Ising model phase transitions is tested on a number of real and simulated climate systems with considerable success. Its accuracy frequently surpasses that of conventional statistical indicators, with performance shown to be consistently improved by the inclusion of spatial indicators. Tools such as this may offer valuable insight into climate tipping events, as remote sensing measurements provide increasingly abundant data on complex geospatially resolved Earth systems.
Predicting 1-year in-stent restenosis in superficial femoral arteries through multiscale computational modelling
Authors: Corti Anna , Migliavacca Francesco , Berceli Scott A. , Chiastra Claudio
Published: April 2023

In-stent restenosis in superficial femoral arteries (SFAs) is a complex, multi-factorial and multiscale vascular adaptation process whose thorough understanding is still lacking. Multiscale computational agent-based modelling has recently emerged as a promising approach to decipher mechanobiological mechanisms driving the arterial response to the endovascular intervention. However, the long-term arterial response has never been investigated with this approach, although being of fundamental relevance. In this context, this study investigates the 1-year post-operative arterial wall remodelling in three patient-specific stented SFA lesions through a fully coupled multiscale agent-based modelling framework. The framework integrates the effects of local haemodynamics and monocyte gene expression data on cellular dynamics through a bi-directional coupling of computational fluid dynamics simulations with an agent-based model of cellular activities. The framework was calibrated on the follow-up data at 1 month and 6 months of one stented SFA lesion and then applied to the other two lesions. The calibrated framework successfully captured (i) the high lumen area reduction occurring within the first post-operative month and (ii) the stabilization of the median lumen area from 1-month to 1-year follow-ups in all the stented lesions, demonstrating the potentialities of the proposed approach for investigating patient-specific short- and long-term responses to endovascular interventions.
Experimental studies suggest differences in the distribution of thorax elasticity between insects with synchronous and asynchronous musculature
Authors: Casey Cailin , Heveran Chelsea , Jankauski Mark
Published: April 2023

Insects have developed diverse flight actuation mechanisms, including synchronous and asynchronous musculature. Indirect actuation, used by insects with both synchronous and asynchronous musculature, transforms thorax exoskeletal deformation into wing rotation. Though thorax deformation is often attributed exclusively to muscle tension, the inertial and aerodynamic forces generated by the flapping wings may also contribute. In this study, a tethered flight experiment was used to simultaneously measure thorax deformation and the inertial/aerodynamic forces acting on the thorax generated by the flapping wing. Compared to insects with synchronous musculature, insects with asynchronous muscle deformed their thorax 60% less relative to their thorax diameter and their wings generated 2.8 times greater forces relative to their body weight. In a second experiment, dorsalventral thorax stiffness was measured across species. Accounting for weight and size, the asynchronous thorax was on average 3.8 times stiffer than the synchronous thorax in the dorsalventral direction. Differences in thorax stiffness and forces acting at the wing hinge led us to hypothesize about differing roles of series and parallel elasticity in the thoraxes of insects with synchronous and asynchronous musculature. Specifically, wing hinge elasticity may contribute more to wing motion in insects with asynchronous musculature than in those with synchronous musculature.
Emendation of cellular fatty acid composition of gliding marine bacteria belonging to the genus Aureispira
Authors: Kawahara Kazuyoshi , Iriyama Fuka , Yokota Akira
Published: April 2023

Aureispira marina and Aureispira maritima are gliding marine bacteria with high content of arachidonic acid in cellular lipids isolated from southern coastline of Thailand. In the previous reports (Hosoya, et al., Int. J. Syst. Evol. Microbiol., 56, 2931-2935, 2006, Hosoya et al., Int. J. Syst. Evol. Microbiol., 57, 1948-1951, 2007) only small amounts (less than 5%) of 3-hydroxy fatty acids were detected as cellular hydroxy fatty acids, but recently we found that these bacteria were abundant in 2-hydroxy fatty acids as components of ceramides in their lipids. In the present study cellular fatty acids of these bacteria were reexamined, and the combined ratio of 2-hydroxy fatty acids, composed of iso-17:1 2-OH, iso-17:0 2-OH, and 16:1 2-OH, was shown to be more than 40% of total amount of fatty acids. As the high content of 2-hydroxy fatty acids is a characteristic chemotaxonomic feature of these bacteria, we propose the emendation of cellular fatty acid composition of the above species belonging to the genus Aureispira according to the results in this study.
Adjuvants influence the maturation of VRC01-like antibodies during immunization
Authors: Knudsen Maria L. , Agrawal Parul , MacCamy Anna , Parks K. Rachael , Gray Matthew D. , Takushi Brittany N. , Khechaduri Arineh , Coler Rhea N. , LaBranche Celia C. , Montefiori David , Stamatatos Leonidas
Published: April 2023

Once naïve B cells expressing germline VRC01-class B cell receptors become activated by germline-targeting immunogens, they enter germinal centers and undergo affinity maturation. Booster immunizations with heterologous Envs are required for the full maturation of VRC01-class antibodies. Here, we examined whether and how three adjuvants, Poly(I:C), GLA-LSQ, or Rehydragel, that activate different pathways of the innate immune system, influence the rate and type of somatic mutations accumulated by VRC01-class BCRs that become activated by the germline-targeting 426c.Mod.Core immunogen and the heterologous HxB2.WT.Core booster immunogen. We report that although the adjuvant used had no influence on the durability of plasma antibody responses after the prime, it influenced the plasma VRC01 antibody titers after the boost and the accumulation of somatic mutations on the elicited VRC01 antibodies.

ONE SENTENCE SUMMARY

VRC01-class BCRs with different somatic mutations are being selected depending on the adjuvant used during immunization
Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes
Authors: Yu Katharine , Basu Amrita , Yau Christina , Wolf Denise M , Goodarzi Hani , Bandyopadhyay Sourav , Korkola James E , Hirst Gillian L , Asare Smita ,   I-SPY 2 TRIAL investigators, Demichele Angela , Hylton Nola , Yee Douglas , Esserman Laura , van ’t Veer Laura , Sirota Marina
Published: April 2023

Drug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes. In this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival. We found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2-receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel-resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line.
ALDH2 dysfunction accelerates ESCC pathogenesis
Authors: Flashner Samuel , Shimonosono Masataka , Matsuura Norihiro , Ohashi Shinya , Klein-Szanto Andres J. , Diehl J. Alan , Chen Che-Hong , Mochly-Rosen Daria , Nakagawa Hiroshi
Published: April 2023

The alcohol metabolite acetaldehyde is a potent human carcinogen. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulates and causes genotoxic stress in cells expressing the dysfunctional ALDH2E487Kmutant protein linked toALDH2*2, the single nucleotide polymorphism highly prevalent amongst East Asians. Chronic alcohol users with heterozygousALDH2*2display an increased risk for the development of esophageal squamous cell carcinoma (ESCC) and other alcohol-related cancers. However, how ALDH2 influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three dimensional organoids, and xenograft models. We find that alcohol exposure results in increased organoid formation and tumor growth concurrent with increased reactive oxygen species (ROS), increased DNA damage, and the enrichment of putative cancer stem cells (CSCs) characterized by high CD44 expression. Pharmacological activation of ALDH2 function by Alda-1 inhibits this phenotype, indicating that acetaldehyde is the primary driver of these changes. ALDH2 dysfunction also affects response to a commonly used chemotherapy for the treatment of ESCC. We find that Aldh2 dysfunction facilitated enrichment of CSCs following cisplatin-induced cell death and oxidative stress in murine organoids. Together, these data provide evidence that alcohol exposure, results in more aggressive tumors through enrichment of CSCs, which is augmented by ALDH2 dysfunction.
Melanoma clonal subline analysis uncovers heterogeneity-driven immunotherapy resistance mechanisms
Authors: Gruen Charli , Yang Howard H. , Sassano Antonella , Wu Emily , Gopalan Vishaka , Marie Kerrie L. , Castro Andrea , Mehrabadi Farid Rashidi , Wu Chih Hao , Church Isabella , Needle Gabriel A. , Smith Cari , Chin Sung , Ebersole Jessica , Marcelus Christina , Fon Anyen , Liu Huaitian , Malikic Salem , Sahinalp Cenk , Carter Hanna , Hannenhalli Sridhar , Day Chi-Ping , Lee Maxwell P. , Merlino Glenn , Pérez-Guijarro Eva
Published: April 2023

Intratumoral heterogeneity (ITH) can promote cancer progression and treatment failure, but the complexity of the regulatory programs and contextual factors involved complicates its study. To understand the specific contribution of ITH to immune checkpoint blockade (ICB) response, we generated single cell-derived clonal sublines from an ICB-sensitive and genetically and phenotypically heterogeneous mouse melanoma model, M4. Genomic and single cell transcriptomic analyses uncovered the diversity of the sublines and evidenced their plasticity. Moreover, a wide range of tumor growth kinetics were observedin vivo, in part associated with mutational profiles and dependent on T cell-response. Further inquiry into melanoma differentiation states and tumor microenvironment (TME) subtypes of untreated tumors from the clonal sublines demonstrated correlations between highly inflamed and differentiated phenotypes with the response to anti-CTLA-4 treatment. Our results demonstrate that M4 sublines generate intratumoral heterogeneity at both levels of intrinsic differentiation status and extrinsic TME profiles, thereby impacting tumor evolution during therapeutic treatment. These clonal sublines proved to be a valuable resource to study the complex determinants of response to ICB, and specifically the role of melanoma plasticity in immune evasion mechanisms.
Genetic variation in promoter region of the bovine LAP3 gene associated with estimated breeding values of milk production traits and clinical mastitis in dairy cattle
Authors: Worku Destaw , Gowane Gopal , Verma Archana
Published: April 2023

The purpose of this study was to identify genetic variants in the promoter and 5’UTR regions of bovine leucine amino peptidase three (LAP3) gene and analysed their associations with estimated breeding values (EBVs) of milk production traits and clinical mastitis in Sahiwal and Karan Fries cattle. Eleven SNPs were identified within the region under study of the LAP3 gene, including seven promoter variants (rs717156555: C>G, rs720373055: T>C, rs715189731: A>G, rs516876447: A>G, rs4618572 69: C>T, rs136548163: C>T, and rs720349928: G>A) and four 5’UTR variants (rs717884982: C>T, rs722359733: C>T, rs481631804: C>T and rs462932574: T>G). Out of them, 10 SNPs variants were found in both Sahiwal and Karan Fries cattle, with one SNP variant (rs481631804: C>T) being unique to Karan Fries cattle. Seven of these identified SNPs were chosen for association analyses. Individual SNP based association analysis revealed that two SNPs (rs720373055: T>C and rs7203499 28: G>A) were significantly associated with EBVs of lactation milk yield (LMY), 305-day milk yield (305dMY), and one significant association of SNP rs722359733: C>T with lactation length (LL) was observed. Haplotype based association analysis indicated that diplotypes are significantly associated with EBVs of LMY, 305dMY, and LL, individuals with H1H3 (CTACGCT/GCGTACG) being linked to higher lactation performance than other diplotypes. Further logistic regression analysis revealed that, animals with diplotype H1H3 was less susceptible to the incidence of clinical mastitis than other cows, as the odds ratio for the non-incidence of clinical mastitis was found to be low. Altogether, variations in the LAP3 gene promoter could be used as a genetic marker, most notably diplotype H1H3, may greatly benefit the simultaneous improvement of mastitis resistance and milk yield traits in dairy cattle. Moreover, bioinformatics analysis predicted that the SNPs rs720373055: T>C, rs715189731:A>G and rs720349928: G>A is located in the core promoter region and in TFBs, play key role in regulation of studied phenotypes.
Acute irradiation alters the heterogeneity among medullary thymic epithelial cells
Authors: Horie Kenta , Namiki Kano , Miyauchi Maki , Ishikawa Tatsuya , Hayama Mio , Maruyama Yuya , Miyao Takahisa , Murata Shigeo , Akiyama Nobuko , Akiyama Taishin
Published: April 2023

The thymus has the ability to regenerate from acute injury caused by radiation, infection, and stressors. In addition to thymocytes, thymic epithelial cells in the medulla (mTECs), which are crucial for T cell self-tolerance by ectopically expressing and presenting thousands of tissue-specific antigens (TSAs), are damaged by these insults and recover thereafter. However, given recent discoveries on the high heterogeneity of mTECs, it remains to be determined whether the frequency and properties of mTEC subsets are restored during thymic recovery from radiation damage. Here we demonstrate that acute total body irradiation with a sublethal dose induces aftereffects on heterogeneity and gene expression of mTECs. Single-cell RNA-sequencing (scRNA-seq) analysis showed that irradiation reduces the frequency of mTECs expressing AIRE, which is a critical regulator of TSA expression, 15 days after irradiation. In contrast, transit-amplifying mTECs (TA-mTECs), which are progenitors of AIRE-expressing mTECs, and Ccl21a-expressing mTECs, were less affected. Interestingly, detailed analysis of scRNA-seq data suggested that the proportion of a unique mTEC cluster expressing Ccl25 and high level of TSAs was severely decreased by irradiation. Overall, we propose that acute irradiation disturbs the heterogeneity and properties of mTECs, and may thereby impair TSA expression for thymic T cell selection.
An mRNA-LNP-based Lassa virus vaccine induces protective immunity in mice
Authors: Hashizume Mei , Takashima Ayako , Iwasaki Masaharu
Published: April 2023

The mammarenavirus Lassa virus (LASV) causes the life-threatening hemorrhagic fever disease, Lassa fever. The lack of licensed medical countermeasures against LASV underscores the urgent need for the development of novel LASV vaccines, which has been hampered by the requirement for a biosafety level 4 facility to handle live LASV. Here, we investigated the efficacy of mRNA-lipid nanoparticle (mRNA-LNP)-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or the nucleoprotein (LCMnp) of the prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), in mice using recombinant (r) LCMV expressing a modified LASgpc and wild-type rLCMV. Two doses of LASgpc- or LCMnp-mRNA-LNP administered intravenously or intramuscularly protected mice from a lethal challenge with rLCMVs. Negligible levels of LASgpc-specific antibodies were induced in mRNA-LNP-immunized mice, but robust LASgpc- and LCMnp-specific CD8+T cell responses were detected. Our findings and surrogate mouse models of LASV infection provide a critical foundation for the rapid development of mRNA-LNP-based LASV vaccines.
Cell Painting-based bioactivity prediction boosts high-throughput screening hit-rates and compound diversity
Authors: Haslum Johan Fredin , Lardeau Charles , Karlsson Johan , Turkki Riku , Leuchowius Karl-Johan , Smith Kevin , Müllers Erik
Published: April 2023

Efficiently identifying bioactive compounds towards a target of interest remains a time- and resource-intensive task in early drug discovery. The ability to accurately predict bioactivity using morphological profiles has the potential to rationalize the process, enabling smaller screens of focused compound sets.

Towards this goal, we explored the application of deep learning with Cell Painting, a high-content image-based assay, for compound bioactivity prediction in early drug screening. Combining Cell Painting data and unrefined single-concentration activity readouts from high-throughput screening (HTS) assays, we investigated to what degree morphological profiles could predict compound activity across a set of 140 unique assays.

We evaluated the performance of our models across different target classes, assay technologies, and disease areas. The predictive performance of the models was high, with a tendency for better predictions on cell-based assays and kinase targets. The average ROC-AUC was 0.744 with 62% of assays reaching ≥0.7, 30% reaching ≥0.8 and 7% reaching ≥0.9 average ROC-AUC, outperforming commonly used structure-based predictions in terms of predictive performance and compound structure diversity. In many cases, bioactivity prediction from Cell Painting data could be matched using brightfield images rather than multichannel fluorescence images. Experimental validation of our predictions in follow-up assays confirmed enrichment of active compounds.

Our results suggest that models trained on Cell Painting data can predict compound activity in a range of high-throughput screening assays robustly, even with relatively noisy HTS assay data. With our approach, enriched screening sets with higher hit rates and higher hit diversity can be selected, which could reduce the size of HTS campaigns and enable primary screening with more complex assays.
Coordination of host and endosymbiont gene expression governs endosymbiont growth and elimination in the cereal weevilSitophilusspp
Authors: Ferrarini Mariana Galvão , Vallier Agnès , Vincent-Monégat Carole , Dell’Aglio Elisa , Gillet Benjamin , Hughes Sandrine , Hurtado Ophélie , Condemine Guy , Zaidman-Rémy Anna , Rebollo Rita , Parisot Nicolas , Heddi Abdelaziz
Published: April 2023

Background

Insects living in nutritionally poor environments often establish long-term relationships with intracellular bacteria that supplement their diets and improve their adaptive and invasive powers. Even though these symbiotic associations have been extensively studied on physiological, ecological and evolutionary levels, few studies have focused on the molecular dialogue between host and endosymbionts to identify genes and pathways involved in endosymbiosis control and dynamics throughout host development.

Results

We simultaneously analyzed host and endosymbiont gene expression during the life cycle of the cereal weevilSitophilus oryzae, from larval stages to adults, with a particular emphasis on emerging adults where the endosymbiontSodalis pierantoniusexperiences a contrasted growth-climax-elimination dynamics. We unraveled a constant arms race in which different biological functions are intertwined and coregulated across both partners. These include immunity, metabolism, metal control, apoptosis, and bacterial stress response.

Conclusions

The study of these tightly regulated functions, which are at the center of symbiotic regulations, provides evidence on how hosts and bacteria finely tune their gene expression and respond to different physiological challenges constrained by insect development in a nutritionally limited ecological niche.

Graphical Abstract
GENOME REPORT: Chromosome-scale genome assembly of the African spiny mouse (Acomys cahirinus)
Authors: Nguyen Elizabeth Dong , Fard Vahid Nikoonejad , Kim Bernard Y. , Collins Sarah , Galey Miranda , Nelson Branden R. , Wakenight Paul , Gable Simone M. , McKenna Aaron , Bammler Theo K. , MacDonald Jim , Okamura Daryl M. , Shendure Jay , Beier David R. , Ramirez Jan Marino , Majesky Mark W. , Millen Kathleen J. , Tollis Marc , Miller Danny E.
Published: April 2023

There is increasing interest in the African spiny mouse (Acomys cahirinus) as a model organism because of its ability for regeneration of tissue after injury in skin, muscle, and internal organs such as the kidneys. A high-quality reference genome is needed to better understand these regenerative properties at the molecular level. Here, we present an improved reference genome forA. cahirinusgenerated from long Nanopore sequencing reads. We confirm the quality of our annotations using RNA sequencing data from four different tissues. Our genome is of higher contiguity and quality than previously reported genomes from this species and will facilitate ongoing efforts to better understand the regenerative properties of this organism.
Melanin enhances metastatic melanoma colonization by inhibiting ferroptosis
Authors: Groenewoud Arwin , Zhao Gangyin , Gelmi Maria-Chiara , Yin Jie , Lamers Gerda E. M. , Doorn Remco van , Verdijk Rob. M. , Jager Martine J. , Engel Felix B. , Snaar-Jagalska B. Ewa
Published: April 2023

Melanoma associated death is mainly caused by metastatic disease. Increased melanin levels are associated with decreased melanoma patient survival, yet the contribution of melanin to this process is unknown. Here we show that melanin protects circulating melanoma cells from ferroptosis, enhancing their metastatic potential. We observed that melanin levels in patient-derived uveal melanoma cells as well as cutaneous and conjunctival melanoma cell lines correlate with their metastatic potential in zebrafish xenografts. We find strong associations of the melanin biosynthesis geneTYRP1, ferroptosis related enzymeGPX4and mitochondrial anion channel (VDAC1) with reduced melanoma-specific survival in TCGA data of cutaneous melanoma. Modulation of melanin levels significantly impacts melanoma metastatic potential, increasing or decreasing in concordance with melanin levels. Furthermore, melanin depletion significantly sensitized melanoma cells to ferroptosis leading to a decreased metastatic capacity and enhanced efficacy of ferroptosis induction based anti-cancer therapeutic strategies. Collectively, our results reveal that combined inhibition of melanin biosynthetic enzymes and induction of ferroptosis has potential as a treatment strategy of metastatic melanoma.

Graphical abstract
Biogeography and the evolution of acoustic communication in the polyploid North American gray treefrog complex
Authors: Booker William W. , Lemmon Emily Moriarty , Lemmon Alan R. , Ptacek Margaret B. , Hassinger Alyssa T. B. , Schul Johannes , Gerhardt H. Carl
Published: April 2023

After polyploid species are formed, interactions between diploid and polyploid lineages may generate additional diversity in novel cytotypes and phenotypes. In anurans, mate choice by acoustic communication is the primary method by which individuals identify their own species and assess suitable mates. As such, the evolution of acoustic signals is an important mechanism for contributing to reproductive isolation and diversification in this group. Here, we estimate the biogeographic history of the North American gray treefrog complex, consisting of the diploidHyla chrysoscelisand the tetraploidHyla versicolor, focusing specifically on the geographic origin of whole genome duplication and the expansion of lineages out of glacial refugia. We then test for lineage-specific differences in mating signals by applying comparative methods to a large acoustic data set collected over 52 years that includes>1500 individual frogs. Along with describing the overall biogeographic history and call diversity, we found evidence that the geographic origin ofH. versicolorand the formation of the midwestern polyploid lineage are both associated with glacial limits, and that the southwestern polyploid lineage is associated with a shift in acoustic phenotype relative to the diploid lineage with which they share a mitochondrial lineage. InH. chrysoscelis, we see that acoustic signals are largely split by Eastern and Western lineages, but that northward expansion along either side of the Appalachian Mountains is associated with further acoustic diversification. Overall, results of this study provide substantial clarity on the evolution of gray treefrogs as it relates to their biogeography and acoustic communication.
Role of DNA-DNA sliding friction and non-equilibrium dynamics in viral genome ejection and packaging
Authors: Fizari Mounir , Keller Nicholas , Jardine Paul J. , Smith Douglas E.
Published: April 2023

Many viruses eject their DNA via a nanochannel in the viral shell, driven by internal forces arising from the high-density genome packing. The speed of DNA exit is controlled by friction forces that limit the molecular mobility, but the nature of this friction is unknown. We introduce a method to probe the mobility of the tightly confined DNA by measuring DNA exit from phage phi29 capsids with optical tweezers. We measure extremely low initial exit velocity, a regime of exponentially increasing velocity, stochastic pausing that dominates the kinetics, and large dynamic heterogeneity. Measurements with variable applied force provide evidence that the initial velocity is controlled by DNA-DNA sliding friction, consistent with a Frenkel-Kontorova model for nanoscale friction. We confirm several aspects of the ejection dynamics predicted by theoretical models. Features of the pausing suggest it is connected to the phenomenon of “clogging” in soft-matter systems. Our results provide evidence that DNA-DNA friction and clogging control the DNA exit dynamics, but that this friction does not significantly affect DNA packaging.
Drug discovery for heart failure targeting myosin-binding protein C
Authors: Bunch Thomas A. , Guhathakurta Piyali , Thompson Andrew R. , Lepak Victoria C. , Carter Anna L , Thomas Jennifer J. , Thomas David D. , Colson Brett A.
Published: April 2023

Cardiac MyBP-C (cMyBP-C) interacts with actin-myosin to fine-tune cardiac muscle contractility. Phosphorylation of cMyBP-C, which reduces binding of cMyBP-C to actin or myosin, is often decreased in heart failure (HF) patients, and is cardioprotective in model systems for HF. Therefore, cMyBP-C is a potential target for HF drugs that mimic phosphorylation and/or perturb its interactions with actin or myosin. We labeled actin with fluorescein-5-maleimide (FMAL), and the C0-C2 fragment of cMyBP-C (cC0-C2) with tetramethyl rhodamine (TMR). We performed two complementary high-throughput screens (HTS) on an FDA-approved drug library, to discover small molecules that specifically bind to cMyBP-C and affect its interactions with actin or myosin, using fluorescence lifetime (FLT) detection. We first excited FMAL and detected its FLT, to measure changes in fluorescence resonance energy transfer (FRET) from FMAL (donor) to TMR (acceptor), indicating binding and/or structural changes in the protein complex. Using the same samples, we then excited TMR directly, using a longer wavelength laser, to detect the effects of compounds on the environmentally sensitive FLT of TMR, to identify compounds that bind directly to cC0-C2. Secondary assays, performed on selected modulators with the most promising effects in the primary HTS assays, characterized specificity of these compounds for phosphorylated versus unphosphorylated cC0-C2 and for cC0-C2 versus C1-C2 of fast skeletal muscle (fskC1-C2). A subset of identified compounds modulated ATPase activity in cardiac and/or skeletal myofibrils. These assays establish feasibility for discovery of small-molecule modulators of the cMyBP-C-actin/myosin interaction, with the ultimate goal of developing therapies for HF.
A comparison of the Netherlands, Norway and UK Familial Hypercholesterolemia screening programmes with implications for target setting and the UK’s NHS Long Term Plan
Authors: Page Christopher , Zheng Huiru , Wang Haiying , Rai Taranjit Singh , O’Kane Maurice , Hart Pádraig , McKee Shane , Watterson Steven
Published: April 2023

We sought to determine the most efficacious and cost-effective strategy to follow when developing a national screening programme by comparing and contrasting the national screening programmes of Norway, the Netherlands and the UK. Comparing the detection rates and screening profiles between the Netherlands, Norway, the UK and constituent nations (England, Northern Ireland, Scotland and Wales) it is clear that maximising the number of relatives screened per index case leads to identification of the greatest proportion of an FH population. The UK has stated targets to detect 25% of the population of England with FH across the 5 years to 2024 with the NHS Long Term Plan. However, this is grossly unrealistic and, based on pre-pandemic rates, will only be reached in the year 2096. We also modelled the efficacy and cost-effectiveness of two screening strategies: 1) Universal screening of 1-2-year-olds, 2) electronic healthcare record screening, in both cases coupled to reverse cascade screening. We found that index case detection from electronic healthcare records was 56% more efficacious than universal screening and, depending on the cascade screening rate of success, 36%-43% more cost-effective per FH case detected. The UK is currently trialling universal screening of 1–2-year-olds to contribute to national FH detection targets. Our modelling suggests that this is not the most efficacious or cost-effective strategy to follow. For countries looking to develop national FH programmes, screening of electronic healthcare records, coupled to successful cascade screening to blood relatives is likely to be a preferable strategy to follow.
Respiratory Syncytial Virus (RSV) Hospital Admission Rates and Patients’ Characteristics Before the Age of Two in England, 2015-2019
Authors: Fonseca Maria João , Hagenaars Saskia , Bangert Mathieu , Flach Clare , Hudson Richard
Published: April 2023

Background

A granular understanding of respiratory syncytial virus (RSV) burden in England is needed to prepare for new RSV prevention strategies. We estimated the rates of RSV hospital admissions in infants before age two in England and describe baseline characteristics.

Methods

A birth cohort of all infants born between 01/03/2015 and 28/02/2017 (n=449,591) was established using Clinical Practice Research Datalink-Hospital Episode Statistics. Case cohorts included infants with an admission for 1) RSV-coded, 2) bronchiolitis-coded, 3) any respiratory tract infection (RTI)-coded <24 months and 4) RSV-predicted by an algorithm <12 months. Baseline characteristics were described in case and comparative cohorts (infants without corresponding admission). Cumulative incidence and admission rates were calculated. Multiple linear regression was used to estimate the proportion of RTI healthcare visits attributable to RSV.

Results

The RSV-coded/RSV-predicted case cohorts were composed of 4,813/12,694 infants (cumulative incidence: 1.1%/2.8%). Case cohort infants were more likely to have low birth weight, comorbidities and to be born during RSV season than comparative cohort infants, yet >77% were term healthy infants and >54% born before the RSV season. During the first year of life, 11.6 RSV-coded and 34.4 RSV-predicted hospitalizations occurred per 1,000 person-years. Overall, >25% of unspecified lower RTI admissions were estimated to be due to RSV.

Conclusions

In England, one in 91 infants had an RSV-coded admission, likely underestimated by ∼3-fold. Most infants were term healthy infants born before the RSV season. To decrease the total burden of RSV at the population level, immunization programs need to protect all infants.
Self-organized intracellular twisters
Authors: Dutta Sayantan , Farhadifar Reza , Lu Wen , Kabacaoğlu Gokberk , Blackwell Robert , Stein David B. , Lakonishok Margot , Gelfand Vladimir I. , Shvartsman Stanislav Y. , Shelley Michael J.
Published: April 2023

Life in complex systems, such as cities and organisms, comes to a standstill when global coordination of mass, energy, and information flows is disrupted. Global coordination is no less important in single cells, especially in large oocytes and newly formed embryos, which commonly use fast fluid flows for dynamic reorganization of their cytoplasm. Here, we combine theory, computing, and imaging to investigate such flows in the Drosophila oocyte, where streaming has been proposed to spontaneously arise from hydrodynamic interactions among cortically anchored microtubules loaded with cargo-carrying molecular motors. We use a fast, accurate, and scalable numerical approach to investigate fluid-structure interactions of 1000s of flexible fibers and demonstrate the robust emergence and evolution of cell-spanning vortices, or twisters. Dominated by a rigid body rotation and secondary toroidal components, these flows are likely involved in rapid mixing and transport of ooplasmic components.