tbuckley/cabot-search huggingface dataset:
Unexpected vulnerability of <i>Enterococcus faecium</i> to polymyxin B under anaerobic condition
Authors: Yongjun Son, Bitnara Kim, Pureun Kim, Jihyeon Min, Yerim Park, Jihye Yang, Wonjae Kim, Masanori Toyofuku, Woojun Park
Journal: Gut Microbes (2024)

Gram-positive Enterococcus faecium exhibited higher susceptibility (>4-fold) to polymyxin B (PMB), the canonical antimicrobial peptide against Gram-negative bacteria, under anaerobic condition than aerobic condition. Anaerobically grown E. faecium exhibited high vulnerability to PMB, leading to alteration of cell surface and morphology, as observed based on their high dansyl-PMB affinity (>2.9-fold), a proportion (>8.5-fold) of propidium iodide-stained cells, and observation of scanning electron microscopy results. Interestingly, our transcriptomic and chemical analyses revealed that enterocin B, produced anaerobically, imposes a burden on the cellular envelope when cells are exposed to PMB. This scenario was also supported by PMB susceptibility tests and killing curves, which showed that ΔentB knockout mutant cells were more resistant to PMB (32 µg/mL) compared to wild-type cells (4 µg/mL) under anaerobic condition. Fluorescent D-amino acid and BOCILLIN™-fluorescent profiling of transpeptidase activities in ΔentB mutant cells under anaerobic condition revealed similar levels of activity to those observed in WT cells under aerobic condition. The high level of secreted bacteriocins in WT under anaerobic condition likely led to significant membrane depolarization and loosening of the peptidoglycan layer, making the cells more permeable to PMB. Overall, our findings suggest that anaerobically produced bacteriocins, in conjunction with PMB, contribute to the killing of E. faecium by destabilizing its cell envelope.
Inequalities in uptake of childhood vaccination in England, 2019-23: longitudinal study
Authors: Aidan Flatt, Roberto Vivancos, Neil French, Sophie Quinn, Matthew Ashton, Valérie Decraene, Daniel Hungerford, David Taylor-Robinson
Journal: BMJ (2024)

Abstract Objective To quantify changes in inequalities in uptake of childhood vaccination during a period of steadily declining overall childhood vaccination rates in England. Design Longitudinal study. Setting General practice data for five vaccines administered to children (first and second doses of the measles, mumps, and rubella vaccine (MMR1 and MMR2, respectively), rotavirus vaccine, pneumococcal conjugate vaccine (PCV) booster, and six-in-one (DTaP/IPV/Hib/HepB) vaccine covering diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, and hepatitis B) from the Cover of Vaccination Uptake Evaluated Rapidly dataset in England. Participants Children aged &lt;5 years eligible for vaccinations between April 2019 and March 2023 registered at primary care practices in England. 2 386 317 (2 309 674 for rotavirus vaccine) children included in the study were eligible at age 1 year, 2 456 020 at 2 years, and 2 689 304 at 5 years. Main outcome measures Changes in quarterly vaccine uptake over time and compared by deprivation level. Regression analyses were used to quantify the change in inequalities in vaccine uptake over time—expressed as changes in the slope index of inequality (SII). Cumulative susceptibility to measles and rotavirus disease at age 5 years was estimated. Analyses were repeated at regional level. Results The absolute inequality in vaccine uptake at baseline (2019-20) was largest for MMR2 in children at age 5 years (SII −9.6%, 95% confidence interval (CI) −10.2% to −9.0%). For all vaccinations studied, the SII for uptake increased over the study period: from −5.1% to −7.7% for the six-in-one vaccine, −7.4% to −10.2% for rotavirus, −7.9% to −9.7% for PCV booster, −8.0% to −10.0% for MMR1 at age 2 years, −3.1% to −5.6% for MMR1 at age 5 years, and −9.6% to −13.4% for MMR2 at age 5 years. The number of children susceptible to measles by the end of the study period increased 15-fold in the least deprived group (from 1364 to 20 958) and 20-fold in the most deprived group (from 1296 to 25 345). For rotavirus, a 14-fold increase was observed in the least deprived group (from 2292 to 32 981) and a 16-fold increase in the most deprived group (from 2815 to 45 201). Regional analysis showed greatest inequalities in uptake in London and the northern regions. Conclusion The findings of this study suggest that inequalities in childhood vaccination are increasing in England, as uptake rates for five key childhood vaccinations decreased between 2019 and 2023, below the World Health Organization’s recommended 95% uptake target, and with noticeable regional differences. Urgent action is needed to strengthen systems for childhood vaccination, with a key focus on reducing inequalities.
Antiviral therapy for chronic hepatitis delta: new insights from clinical trials and real-life studies
Authors: Pietro Lampertico, Maria Paola Anolli, Dominique Roulot, Heiner Wedemeyer
Journal: Gut (2024)

Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, carrying a greater risk of developing cirrhosis and its complications. For decades, pegylated interferon alpha (PegIFN-α) has represented the only therapeutic option, with limited virological response rates and poor tolerability. In 2020, the European Medicines Agency approved bulevirtide (BLV) at 2 mg/day, an entry inhibitor of hepatitis B virus (HBV)/hepatitis delta virus (HDV), which proved to be safe and effective as a monotherapy for up to 144 weeks in clinical trials and real-life studies, including patients with cirrhosis. Long-term BLV monotherapy may reduce decompensating events in patients with cirrhosis. The combination of BLV 2 mg with PegIFN-α increased the HDV RNA undetectability rates on-therapy but not off-therapy, compared with PegIFN monotherapy. However, combination therapy, but not BLV monotherapy, may induce hepatitis B surface antigen (HBsAg) loss in some patients. The PegIFN lambda study has been discontinued due to liver toxicity issues, while lonafarnib boosted with ritonavir showed limited off-therapy efficacy in a phase 3 study. Nucleic acid polymer-based therapy is promising but large studies are still lacking. New controlled trial data come from molecules, such as monoclonal antibodies and/or small interfering RNA, that target HBsAg or HBV RNAs, which demonstrated not only profound HDV suppression, but also HBsAg decline. While waiting for new compounds to be approved as monotherapy or in combination, BLV monotherapy 2 mg/day remains the only approved therapy for CHD, at least in the European Union region.
Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis
Authors: Yong Du, Bérénice Faz-Lopez, Marie Dominique Ah Kioon, Claire Cenac, Michael Pierides, Kimberly S. Lakin, Robert F. Spiera, Julie Chaumeil, Marie-Elise Truchetet, Jessica K. Gordon, Jean-Charles Guéry, Franck J. Barrat
Journal: The Journal of Experimental Medicine (2024)

Systemic sclerosis (SSc) is an autoimmune disease that has a strong female predominance. Both the X-linked TLR7 and TLR8 can induce type I IFN (IFN-I) by plasmacytoid DCs (pDCs), which can promote fibrosis. We identified five subclusters of pDCs, including ISGhigh clusters that were over-represented in SSc patients. We observed that both TLR7 and TLR8 genes escape from X chromosome inactivation (XCI) at higher frequency in pDCs of SSc patients, which was associated with changes in TLR7 protein profile. Combined DNA/RNA FISH analysis revealed that the TLR7/8 locus is preferentially located outside of the inactive X (Xi) territory when TLR7 is expressed, suggesting that higher-order loop formation is linked to TLR7/8 expression from the Xi. Furthermore, the expression levels of XIST and the transcriptional repressor SPEN were reduced in SSc pDCs. Hence, our data revealed the heterogeneity of pDCs in SSc and suggested that altered XCI at the TLR7/8 locus may contribute to the chronic IFN-I activity of pDCs in female SSc patients.
Epidemiology of Dengue — Puerto Rico, 2010–2024
Authors: Dania M. Rodriguez, Zachary J. Madewell, Jomil M. Torres, Aidsa Rivera, Joshua M. Wong, Gilberto A. Santiago, Vanessa Rivera-Amill, Gabriela Paz-Bailey, Melissa Marzan-Rodriguez, Laura E. Adams
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Dengue is a mosquitoborne viral illness that can cause acute febrile illness, severe disease, or death.Worldwide, the number of dengue cases is increasing.During the last dengue outbreaks in Puerto Rico throughout 2010-2013, dengue virus (DENV) serotype 1 (DENV-1) predominated, and the largest proportion of cases occurred among adolescents and young adults aged 10-19 years.Dengue case data from January 1, 2010-November 4, 2024, were obtained from the Puerto Rico Department of Health.Bivariate analyses were conducted to evaluate the distribution of cases by patient age, DENV serotype, and hospitalization status during three periods: 2010 -2019 , 2020 -2022, and 2023-2024 .During 2023-2024, the median age of dengue cases increased to 26 years (95% CI = 25-27 years) compared with that during 2020-2022 (17 years; 95% CI = 17-18 years) and 2010-2019 (19 years; 95% CI = 19-19 years).After >10 years of DENV-1 predominance, the proportions of DENV serotypes 2 (DENV-2) and 3 (DENV-3) increased significantly during 2023-2024, with DENV-3 replacing DENV-1 as the predominant serotype.In addition, the proportion of dengue patients who were hospitalized increased from 35.7% (2010-2019) to 53.5% (2023-2024).The current dengue outbreak in Puerto Rico marks a shift in serotype predominance to DENV-3 and increasing percentages of cases in older age groups (61.7% in adults aged ≥20 years), although a high proportion of cases still occur among adolescents aged 10-19 years (29.5%).The current dengue outbreak also has a higher rate of hospitalizations than those in previous years.Understanding the changing epidemiology of dengue is crucial to guiding public health strategies for dengue control, including clinical management, surveillance and health care system resilience, and public outreach and education.
Mechanosensing regulates pDC activation in the skin through NRF2 activation
Authors: Vidyanath Chaudhary, Bikash Mishra, Marie Dominique Ah Kioon, Yong Du, Lionel B. Ivashkiv, Mary K. Crow, Franck J. Barrat
Journal: The Journal of Experimental Medicine (2024)

Plasmacytoid DCs (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I), and promote skin lesions and fibrosis in autoimmune patients. However, what controls their activation in the skin is unknown. Here, we report that increased stiffness inhibits the production of IFN-I by pDCs. Mechanistically, mechanosensing activates stress pathways including NRF2, which induces the pentose phosphate pathway and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 activity in vivo controlled the pDC response, leading to resolution or chronic induction of IFN-I in the skin. In systemic sclerosis (SSc) patients, although NRF2 was induced in skin-infiltrating pDCs, as compared with blood pDCs, the IFN response was maintained. We observed that CXCL4, a profibrotic chemokine elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.
Autopsy of a Hemodialysis Machine
Authors: Carole Bonnet, Massimo Torreggiani, Lavinia Bianco, Frédéric Amiard, Zeyad Elsalhy, Ajla Grozdanic, Hana Grozdanic, Anastasia Vladimira Sizov, Makrem Kayel, Michaël Saulnier, Gaëlle Vayssieres, Hafedh Fessi, Nicolas Delorme, Giorgina Barbara Piccoli
Journal: Journal of the American Society of Nephrology (2024)

Background Hemodialysis (HD) contributes significantly to healthcare’s carbon footprint. Worldwide about 100,000 dialysis machines end their life cycle each year. Our aim was to analyze the composition and the potential for recyclability of two dialysis machines, from the two companies with the largest market share, which had met their end-of-use terms (10-12 years of use according to French regulations). Methods One 5008 CorDiax (Fresenius Medical Care AG) and one Artis/Evosys (Gambro AB) were dismantled and each piece was analyzed in terms of weight and principal components (plastic, metal, mixed materials and electronic components). The time needed to disassemble the machine was recorded. Samples of 15 plastic elements were further studied using Fourier-Transform Infrared Spectroscopy (FTIR spectroscopy). The results were compared with the data provided by the manufacturers. Results The dismantled HD machines weighed 125.0 kg and 141.4 kg; plastic, metal, mixed materials and electronic components accounted for 28%, 15%, 51% and 6% of the first machine’s weight, and 28%, 19%, 40% and 13% of the second’s. The time needed to manually disassemble a dialysis machine into macro elements was around 12 hours. Dismantling into single materials was evaluated as needing at least one workweek (35 hours). The plastic elements were mostly a mixture of resins (petroleum-based material used to manufacture plastics), which makes their recycling potential negligible. Conclusions This study demonstrates that hemodialysis machines contribute to waste production at the end of their life cycle, with low recycling potential, and underlines the need to rethink their design in a cradle-to-cradle perspective.
Contributions from the Implementation Science Field to Clinical Trial Design for Kidney Research
Authors: Lilia Cervantes, Monica Perez Jolles, Katherine Rizzolo, Ladan Golestaneh, Russell E. Glasgow
Journal: Journal of the American Society of Nephrology (2024)

Cervantes, Lilia; Jolles, Monica Perez; Rizzolo, Katherine; Golastenah, Ladan; Glasgow, Russell E. Author Information
Exploring patient and public participation in the STANDING Together initiative for AI in healthcare
Authors: Jacqui Gath, Cassandra Leung, Adewale O. Adebajo, Jude Beng, Anmol Arora, Joseph E. Alderman, Joanne Palmer, Elinor Laws, Jaspret Gill, Melissa McCradden, Francis McKay, Alastair Denniston, Xiaoxuan Liu
Journal: Nature Medicine (2024)
Author Correction: Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain
Authors: Samuel E. Marsh, Alec J. Walker, Tushar Kamath, Lasse Dissing-Olesen, Timothy R. Hammond, T. Yvanka de Soysa, Adam M. H. Young, Sarah Murphy, Abdulraouf Abdulraouf, Naeem Nadaf, Connor Dufort, Alicia C. Walker, Liliana E. Lucca, Velina Kozareva, Charles Vanderburg, Soyon Hong, Harry Bulstrode, Peter J. Hutchinson, Daniel J. Gaffney, David A. Hafler, Robin J. M. Franklin, Evan Z. Macosko, Beth Stevens
Journal: Nature Neuroscience (2024)
Neoadjuvant Camrelizumab for Triple-Negative Breast Cancer
Authors: Heikki Joensuu
Journal: JAMA (2024)

Li Chen, MD; Hui Li, MD; Hao Zhang, MD; Huawei Yang, MD; Jun Qian, MD; Zhihua Li, MD; Yu Ren, MD; Shu Wang, MD; Peifen Fu, MD; Hongjian Yang, MD; Yunjiang Liu, MD; Jing Sun, MD; Jianyun Nie, MD; Ruiwen Lei, MD; Yongzhong Yao, MD; Anqin Zhang, MD; Shouman Wang, MD; Xiaopeng Ma, MD; Zhong Ouyang, MD; Hongwei Yang, MD; Song-Yang Wu, MD; Shuo-Wen Cao, MD; Kun Wang, MD; Aimei Jiang, MD; Quchang Ouyang, MD; Da Pang, MD; Limin Wei, MD; Xiaoming Zha, MD; Yu Shen, PhD; Xiangwen Qu, MD; Fei Wu, MD; Xiaoyu Zhu, PhD; Zhonghua Wang, MD; Lei Fan, MD; Zhi-Ming Shao, MD
Asparagine availability controls germinal center B cell homeostasis
Authors: Yavuz F. Yazicioglu, Eros Marin, Hana F. Andrew, Karolina Bentkowska, Julia C. Johnstone, Robert Mitchell, Zhi Yi Wong, Kristina Zec, Joannah Fergusson, Mariana Borsa, Iwan G. A. Raza, Moustafa Attar, Mohammad Ali, Barbara Kronsteiner, Izadora L. Furlani, James I. MacRae, Michael J. Devine, Mark Coles, Christopher D. Buckley, Susanna J. Dunachie, Alexander J. Clarke
Journal: Science Immunology (2024)

The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of
Crystal structure of the human LAG-3–HLA-DR1–peptide complex
Authors: Jan Petersen, Carmen Llerena, Bagher Golzarroshan, Camilla Faoro, Frederic Triebel, Jamie Rossjohn
Journal: Science Immunology (2024)

T cell activity is governed by T cell receptor (TCR) signaling and constrained by immune checkpoint molecules, including programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3). The basis for how LAG-3 binds to human leukocyte antigen class II molecules (HLA-II) remains unknown. Here, we present the 3.4-angstrom crystal structure of a LAG-3-peptide-HLA-II complex and probe the energetics of the complex interface. Coincident with the HLA-II binding site of the ancestrally related, monomeric CD4 receptor, the LAG-3 homodimer laterally engages two HLA-II molecules via distal D1 domain surfaces, imposing a 38° angular offset. The LAG-3-HLA-II interface is discontinuous and lacks involvement of the D1 extra loop, a binding site for anti-LAG-3 therapeutic monoclonal antibodies. Upon HLA-II binding, intrinsically mobile loops of the LAG-3 molecule become ordered, with contact residues highly conserved across HLA-DR, DQ, and DP allomorphs. Our data provide a structural foundation for development of immunomodulatory approaches targeting LAG-3.
O-GlcNAcylation stabilized WTAP promotes GBM malignant progression in an N6-methyladenosine-dependent manner
Authors: Jiawei Qiu, Rongrong Zhao, Caizhi Ma, Qingtong Wang, Boyan Li, Yanhua Qi, Ziwen Pan, Shulin Zhao, Shaobo Wang, Zijie Gao, Xiaofan Guo, Wei Qiu, Weijie Tang, Xing Guo, Lin Deng, Hao Xue, Gang Li
Journal: Neuro-Oncology (2024)

Interactions between mesenchymal glioblastoma stem cells (MES GSCs) and myeloid-derived macrophages (MDMs) shape the tumor-immunosuppressive microenvironment (TIME), promoting the progression of glioblastoma (GBM). N6-methyladenosine (m6A) plays important roles in the tumor progression. However, the mechanism of m6A in shaping the TIME of GBM remains elusive.
SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers
Authors: Rachna T. Shroff, Gentry King, Sarah Colby, Aaron J. Scott, Mitesh J. Borad, Laura Goff, Khalid Matin, Amit Mahipal, Aparna Kalyan, Milind M. Javle, Imane El Dika, Benjamin Tan, Puneet Cheema, Anuj Patel, Renuka Iyer, R. Katie Kelley, Jaykumar Thumar, Anthony El-Khoueiry, Katherine A. Guthrie, E. Gabriela Chiorean, Howard Hochster, Philip A. Philip
Journal: Journal of Clinical Oncology (2024)

PURPOSE SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs). METHODS Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m 2 , cisplatin 25 mg/m 2 , and nab-paclitaxel 100 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m 2 and cisplatin 25 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle). RESULTS Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28). CONCLUSION The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.
Three-dimensional Assessment of Ascending Aortic Stiffness, Motion and Growth in Ascending Thoracic Aortic Aneurysm
Authors: Nicasius S Tjahjadi, Taeouk Kim, Prabhvir S Marway, Carlos Alberto Campello Jorge, Timothy J Baker, Constantijn Hazenberg, Joost A van Herwaarden, Himanshu J Patel, C Alberto Figueroa, Nicholas S Burris
Journal:  (2024)

Abstract Aims Aortic wall stiffening in ascending thoracic aortic aneurysm (aTAA) is common. However, the spatial and temporal relationships between stiffness, aortic size, and growth in aTAA remain unclear. Methods and results In this single-centre retrospective study, we utilized vascular deformation mapping to extract multi-directional aortic motion, aortic distensibility, and aortic growth in a multi-planar fashion from multi-phasic ECG-gated computed tomography angiograms. Aortic displacement and stiffness metrics were compared between patients with sporadic ascending aortic dilation (Dilated), individuals without thoracic aortic dilation, and patients with Marfan syndrome. A total of 96 patients were included. Total and axial aortic root motion was significantly decreased in the Dilated group (n = 49) compared with the Non-dilated group (n = 38) and Marfan group (n = 16). Aortic distensibility was significantly lower in the Dilated group compared with the Non-dilated group and exhibited a more diffuse pattern of stiffening compared with the Marfan group in which stiffening was localized to the root. In Dilated group, aortic distensibility was moderately and positively associated with aortic growth rate (R = 0.34, P = 0.02). The moderate-to-strong association between age and aortic stiffness in non-dilated segments was either significantly blunted or absent in dilated segments. Conclusion Vascular deformation mapping provides multi-level stiffness assessments of the ascending aorta using multi-phasic computed tomography angiography. Ascending aortic stiffening is a spatially heterogeneous process with stiffening tending to increase with degree of regional dilation and age, whereas lower stiffness was associated with faster growth of the mid-ascending aorta in those with sporadic aTAA.