tbuckley/cabot-search huggingface dataset:
The live biotherapeutic SYNB1353 decreases plasma methionine via directed degradation in animal models and healthy volunteers
Authors: Mylène Perreault, Jillian Means, Erik Gerson, Michael James, Sean Cotton, Christopher G. Bergeron, Mark Simon, Dylan Alexander Carlin, Nathan Schmidt, Theodore C. Moore, Julie Blasbalg, Neal Sondheimer, Kenneth Ndugga-Kabuye, William S. Denney, Vincent M. Isabella, David Lubkowicz, Aoife Brennan, David L. Hava
Journal: Cell Host & Microbe (2024)

Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss of function in cystathionine β-synthase (CBS) cause classic homocystinuria (HCU), which is managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that can be engineered to replicate the benefits of dietary restriction. In this study, we assess whether SYNB1353, an E. coli Nissle 1917 derivative, impacts circulating methionine and homocysteine levels in animals and healthy volunteers. In both mice and nonhuman primates (NHPs), SYNB1353 blunts the appearance of plasma methionine and plasma homocysteine in response to an oral methionine load. A phase 1 clinical study conducted in healthy volunteers subjected to an oral methionine challenge demonstrates that SYNB1353 is well tolerated and blunts plasma methionine by 26%. Overall, SYNB1353 represents a promising approach for methionine reduction with potential utility for the treatment of HCU.
PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression
Authors: Xin Yang, Zhe Wang, Svetlana N. Samovich, Alexander A. Kapralov, Andrew A. Amoscato, Vladimir A. Tyurin, Haider H. Dar, Zhiming Li, Shoufu Duan, Ning Kon, Delin Chen, Benjamin Tycko, Zhiguo Zhang, Xuejun Jiang, Hülya Bayir, Brent R. Stockwell, Valerian E. Kagan, Wei Gu
Journal: Cell Metabolism (2024)
Fate mapping of Spp1 expression reveals age-dependent plasticity of disease-associated microglia-like cells after brain injury
Authors: Yangning Lan, Xiaoxuan Zhang, Shaorui Liu, Chen Guo, Yuxiao Jin, Hui Li, Linyixiao Wang, Jinghong Zhao, Yilin Hao, Zhicheng Li, Zhaoyuan Liu, Florent Ginhoux, Qi Xie, Heping Xu, Jie-Min Jia, Danyang He
Journal: Immunity (2024)
In-hospital mortality during the wild-type, alpha, delta, and omicron SARS-CoV-2 waves: a multinational cohort study in the EuCARE project
Authors: Pontus Hedberg, Milosz Parczewski, Karol Serwin, Giulia Marchetti, Francesca Bai, Björn-Erik Ole Jensen, Joana P.V. Pereira, Francis Drobniewski, Henrik Reschreiter, Daniel Naumovas, Francesca Ceccherini-Silberstein, Gibran Horemheb Rubio Quintanares, Matilu Mwau, Cristina Toscano, Florian König, Nico Pfeifer, Maurizio Zazzi, Iuri Fanti, Francesca Incardona, Alessandro Cozzi-Lepri, Anders Sönnerborg, Pontus Nauclér
Journal: The Lancet Regional Health - Europe (2024)

Investigating outcomes of hospitalised COVID-19 patients throughout the pandemic is crucial to understand the impact of different SARS-CoV-2 variants. We compared 28-day in-hospital mortality of Wild-type, Alpha, Delta, and Omicron variant infections. Whether the difference in risk by variant varied by age was also evaluated. We conducted a cohort study including patients ≥18 years, hospitalised between 2020 and 02-01 and 2022-10-15 with a SARS-CoV-2 positive test, from nine countries. Variant was classified based on sequenced viruses or from national public metadata. Mortality was compared using the cumulative incidence function and subdistribution hazard ratios (SHR) adjusted for age, sex, calendar time, and comorbidities. Results were shown age-stratified due to effect measure modification (P < 0.0001 for interaction between age and variant). We included 38,585 participants: 19,763 Wild-type, 6387 Alpha, 3640 Delta, and 8795 Omicron. The cumulative incidence of mortality decreased throughout the study period. Among participants ≥70 years, the adjusted SHR (95% confidence interval) for Delta vs. Omicron was 1.66 (1.29–2.13). This estimate was 1.66 (1.17–2.36) for Alpha vs. Omicron, and 1.34 (0.92–1.95) for Wild-type vs. Omicron. These were 1.21 (0.81–1.82), 1.21 (0.68–2.17), and 0.98 (0.53–1.82) among unvaccinated participants. When comparing Omicron sublineages, the aSHR for BA.1 was 1.92 (1.43–2.58) compared to BA.2 and 1.52 (1.11–2.08) compared to BA.5. The herein observed decrease in in-hospital mortality seems to reflect a combined effect of immunity from vaccinations and previous infections, although differences in virulence between SARS-CoV-2 variants may also have contributed. European Union's Horizon Europe Research and Innovation Programme.
Non-professional efferocytosis of <i>Salmonella</i>-infected intestinal epithelial cells in the neonatal host
Authors: Kaiyi Zhang, Urska Repnik, Nour Diab, Daniel Friske, Andreas Pütz, Alina Z. Bachmann, Narasimha Murthy Keshava Prasad Gubbi, Michael Hensel, Konrad U. Förstner, Alexander J. Westermann, Aline Dupont, Mathias W. Hornef
Journal: The Journal of Experimental Medicine (2024)

The intestinal epithelium is the first line of defense against enteric pathogens. Removal of infected cells by exfoliation prevents mucosal translocation and systemic infection in the adult host, but is less commonly observed in the neonatal intestine. Instead, here, we describe non-professional efferocytosis of Salmonella-infected enterocytes by neighboring epithelial cells in the neonatal intestine. Intestinal epithelial stem cell organoid cocultures of neonatal and adult cell monolayers with damaged enterocytes replicated this observation, confirmed the age-dependent ability of intestinal epithelial cells for efferocytosis, and identified the involvement of the “eat-me” signals and adaptors phosphatidylserine and C1q as well as the “eat-me” receptors integrin-αv (CD51) and CD36 in cellular uptake. Consistent with this, massive epithelial cell membrane protrusions and CD36 accumulation at the contact site with apoptotic cells were observed in the infected neonatal host in vivo. Efferocytosis of infected small intestinal enterocytes by neighboring epithelial cells may represent a previously unrecognized mechanism of neonatal antimicrobial host defense to maintain barrier integrity.
Mapping the functional impact of non-coding regulatory elements in primary T cells through single-cell CRISPR screens
Authors: Celia Alda-Catalinas, Ximena Ibarra-Soria, Christina Flouri, Jorge Esparza Gordillo, Diana Cousminer, Anna Hutchinson, Bin Sun, William Pembroke, Sebastian Ullrich, Adam Krejci, Adrian Cortes, Alison Acevedo, Sunir Malla, Carl Fishwick, Gerard Drewes, Radu Rapiteanu
Journal: Genome biology (2024)

Abstract Background Drug targets with genetic evidence are expected to increase clinical success by at least twofold. Yet, translating disease-associated genetic variants into functional knowledge remains a fundamental challenge of drug discovery. A key issue is that the vast majority of complex disease associations cannot be cleanly mapped to a gene. Immune disease-associated variants are enriched within regulatory elements found in T-cell-specific open chromatin regions. Results To identify genes and molecular programs modulated by these regulatory elements, we develop a CRISPRi-based single-cell functional screening approach in primary human T cells. Our pipeline enables the interrogation of transcriptomic changes induced by the perturbation of regulatory elements at scale. We first optimize an efficient CRISPRi protocol in primary CD4 + T cells via CROPseq vectors. Subsequently, we perform a screen targeting 45 non-coding regulatory elements and 35 transcription start sites and profile approximately 250,000 T -cell single-cell transcriptomes. We develop a bespoke analytical pipeline for element-to-gene (E2G) mapping and demonstrate that our method can identify both previously annotated and novel E2G links. Lastly, we integrate genetic association data for immune-related traits and demonstrate how our platform can aid in the identification of effector genes for GWAS loci. Conclusions We describe “primary T cell crisprQTL” — a scalable, single-cell functional genomics approach for mapping regulatory elements to genes in primary human T cells. We show how this framework can facilitate the interrogation of immune disease GWAS hits and propose that the combination of experimental and QTL-based techniques is likely to address the variant-to-function problem.
Increase in dengue fever in travellers returning from Egypt, Germany 2023
Authors: Christina Frank, Raskit Lachmann, Hendrik Wilking, Klaus Stark
Journal: Eurosurveillance (2024)

Dengue virus (DENV) infections after exposure in Egypt increased in Germany in 2023, with 36 cases vs zero to eight in 2017 to 2022. Over 90% of the patients had stayed on the Red Sea Coast (mostly Hurghada), almost 50% in private residences. Case numbers increased more strongly than traveller numbers. Mosquito control is more difficult in towns than hotel grounds, increasing the risk of infection at private residences. Physicians should consider dengue for unexplained fever after return from Egypt.
Investigation of an airport-associated cluster of falciparum malaria in Frankfurt, Germany, 2022
Authors: Johanna Kessel, Anna Rosanas-Urgell, Tobias Dingwerth, Udo Goetsch, Jonas Haller, Ralph Huits, Johanna H Kattenberg, Anna Meinecke, Pieter Monsieurs, Michael Sroka, Torsten Witte, Timo Wolf
Journal: Eurosurveillance (2024)

Airport malaria is uncommon but increasing in Europe and often difficult to diagnose. We describe the clinical, epidemiological and environmental investigations of a cluster of airport malaria cases and measures taken in response. Three Frankfurt International Airport employees without travel histories to malaria-endemic areas were diagnosed with Plasmodium falciparum malaria in Germany in 2022. Two cases were diagnosed within 1 week, and the third one after 10 weeks. Two cases had severe disease, all three recovered fully. The cases worked in separate areas and no specific location for the transmissions could be identified. No additional cases were detected among airport employees. In June and July, direct flights from Equatorial Guinea, Nigeria and Angola and one parcel originating in Ghana arrived at Frankfurt airport. No vector-competent mosquitoes could be trapped to identify the source of the outbreak. Whole genome sequencing of P. falciparum genomes showed a high genetic relatedness between samples of the three cases and suggested the geographical origin closest to Ghana. A diagnosis of airport malaria should prompt appropriate and comprehensive outbreak investigations to identify the source and to prevent severe forms of falciparum malaria.
Identification of a measles variant displaying mutations impacting molecular diagnostics, Geneva, Switzerland, 2023
Authors: Francisco-Javier Pérez-Rodríguez, Pascal Cherpillod, Valentine Thomasson, Pauline Vetter, Manuel Schibler
Journal: Eurosurveillance (2024)

Real-time PCR is one of the most widely used techniques to diagnose measles cases. Here we report measles virus variants with three genetic mutations in the reverse primer annealing site of a widely used PCR. The mutations result in a slight loss of the PCR sensitivity. Variants bearing the three mutations presently circulate in different countries since at least the end of 2021. Our findings highlight the usefulness of molecular surveillance in monitoring if oligonucleotides in diagnostic tests remain adequate.
Determining the timing of respiratory syncytial virus (RSV) epidemics: a systematic review, 2016 to 2021; method categorisation and identification of influencing factors
Authors: Lisa Staadegaard, Michel Dückers, Jojanneke van Summeren, Rob van Gameren, Clarisse Demont, Mathieu Bangert, You Li, Jean-Sebastien Casalegno, Saverio Caini, John Paget
Journal: Eurosurveillance (2024)

Background There is currently no standardised approach to estimate respiratory syncytial virus (RSV) epidemics’ timing (or seasonality), a critical information for their effective prevention and control. Aim We aimed to provide an overview of methods to define RSV seasonality and identify factors supporting method choice or interpretation/comparison of seasonal estimates. Methods We systematically searched PubMed and Embase (2016–2021) for studies using quantitative approaches to determine the start and end of RSV epidemics. Studies’ features (data-collection purpose, location, regional/(sub)national scope), methods, and assessment characteristics (case definitions, sampled population’s age, in/outpatient status, setting, diagnostics) were extracted. Methods were categorised by their need of a denominator (i.e. numbers of specimens tested) and their retrospective vs real-time application. Factors worth considering when choosing methods and assessing seasonal estimates were sought by analysing studies. Results We included 32 articles presenting 49 seasonality estimates (18 thereof through the 10% positivity threshold method). Methods were classified into eight categories, two requiring a denominator (1 retrospective; 1 real-time) and six not (3 retrospective; 3 real-time). A wide range of assessment characteristics was observed. Several studies showed that seasonality estimates varied when methods differed, or data with dissimilar assessment characteristics were employed. Five factors (comprising study purpose, application time, assessment characteristics, healthcare system and policies, and context) were identified that could support method choice and result interpretation. Conclusion Methods and assessment characteristics used to define RSV seasonality are heterogeneous. Our categorisation of methods and proposed framework of factors may assist in choosing RSV seasonality methods and interpretating results.
Large outbreak of typhoid fever on a river cruise ship used as accommodation for asylum seekers, the Netherlands, 2022
Authors: Daisy Ooms, Anne de Vries, Femke DH Koedijk, Ellen Generaal, Ingrid HM Friesema, Maxine Rouvroye, Steven FL van Lelyveld, Maaike JC van den Beld, Daan W Notermans, Patrick van Schelven, Janine FH van den Brink, Tanja Hartog, Thijs Veenstra, Serena Slavenburg, Jan C Sinnige, Wilhelmina LM Ruijs
Journal: Eurosurveillance (2024)

On 6 April 2022, the Public Health Service of Kennemerland, the Netherlands, was notified about an outbreak of fever and abdominal complaints on a retired river cruise ship, used as shelter for asylum seekers. The diagnosis typhoid fever was confirmed on 7 April. An extensive outbreak investigation was performed. Within 47 days, 72 typhoid fever cases were identified among asylum seekers (n = 52) and staff (n = 20), of which 25 were hospitalised. All recovered after treatment. Consumption of food and tap water on the ship was associated with developing typhoid fever. The freshwater and wastewater tanks shared a common wall with severe corrosion and perforations, enabling wastewater to leak into the freshwater tank at high filling levels. Salmonella Typhi was cultured from the wastewater tank, matching the patient isolates. In the freshwater tank, Salmonella species DNA was detected by PCR, suggesting the presence of the bacterium and supporting the conclusion of contaminated freshwater as the probable source of the outbreak. Outbreaks of uncommon infections may occur if persons from endemic countries are accommodated in crowded conditions. Especially when accommodating migrants on ships, strict supervision on water quality and technical installations are indispensable to guarantee the health and safety of the residents.
Discrimination of pancreato-biliary cancer and pancreatitis patients by non-invasive liquid biopsy
Authors: Christina Hartwig, Jan Müller, Hagen Klett, Dina Kouhestani, Anke Mittelstädt, Anna Anthuber, Paul David, Maximilian Brunner, Anne Jacobsen, Karolina Glanz, Izabela Swierzy, Lotta Roßdeutsch, Bettina Klösch, Robert Grützmann, Timo Wittenberger, Kai Sohn, Georg F. Weber
Journal: Molecular Cancer (2024)

Abstract Background Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. Methods Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. Results The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training ( n = 45) and a validation ( n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. Conclusions We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.
Aggressive T‐cell lymphomas: 2024: Updates on diagnosis, risk stratification, and management
Authors: Shin Yeu Ong, Jasmine M. Zain
Journal: American Journal of Hematology (2024)

Abstract Introduction Aggressive T‐cell lymphomas continue to have a poor prognosis. There are over 30 different subtypes of peripheral T‐cell lymphoma (PTCL), and we are now beginning to understand the differences between the various subtypes beyond histologic variations. Molecular Pathogenesis of Various Subtypes of PTCL Gene expression profiling and other molecular techniques have enabled deeper understanding of differences in various subtypes as reflected in the latest 5th WHO classification of PTCL. It is becoming increasingly clear that therapeutic approaches that target specific cellular pathways are needed to improve the clinical outcomes of PTCL. Targeted Therapie s There are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. This includes the CD30 directed antibody drug conjugate brentuximab vedotin. Other notable targets are phosphatidylinositol 3‐kinase inhibitors, histone deacetylase inhibitors, CD25, and chemokine receptor 4. Anaplastic lymphoma kinase (ALK) inhibitors are promising for ALK expressing tumors. Immunotherapies Allogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL. The use of checkpoint inhibitors in the treatment of PTCL is still controversial, with best results seen in cases of extranodal natural killer cell/T‐cell lymphoma. Bispecific antibody‐based treatments and chimeric antigen receptor cell‐based therapies are in clinical trials.
Stimuli-responsive peptide assemblies: Design, self-assembly, modulation, and biomedical applications
Authors: Rongqiu Mu, Danzhu Zhu, Sama Abdulmalik, Suranji Wijekoon, Gang Wei, Sangamesh G. Kumbar
Journal: Bioactive Materials (2024)

Peptide molecules have design flexibility, self-assembly ability, high biocompatibility, good biodegradability, and easy functionalization, which promote their applications as versatile biomaterials for tissue engineering and biomedicine. In addition, the functionalization of self-assembled peptide nanomaterials with other additive components enhances their stimuli-responsive functions, promoting function-specific applications that induced by both internal and external stimulations. In this review, we demonstrate recent advance in the peptide molecular design, self-assembly, functional tailoring, and biomedical applications of peptide-based nanomaterials. The strategies on the design and synthesis of single, dual, and multiple stimuli-responsive peptide-based nanomaterials with various dimensions are analyzed, and the functional regulation of peptide nanomaterials with active components such as metal/metal oxide, DNA/RNA, polysaccharides, photosensitizers, 2D materials, and others are discussed. In addition, the designed peptide-based nanomaterials with temperature-, pH-, ion-, light-, enzyme-, and ROS-responsive abilities for drug delivery, bioimaging, cancer therapy, gene therapy, antibacterial, as well as wound healing and dressing applications are presented and discussed. This comprehensive review provides detailed methodologies and advanced techniques on the synthesis of peptide nanomaterials from molecular biology, materials science, and nanotechnology, which will guide and inspire the molecular level design of peptides with specific and multiple functions for function-specific applications.
Thiolation‐Based Protein–Protein Hydrogels for Improved Wound Healing
Authors: Xing Liu, Zhao Guo, Jie Wang, Wenting Shen, Zhenzhen Jia, Shuang Jia, Limiao Li, Jieqi Wang, Liping Wang, Jiaqi Li, Yinan Sun, Yufang Chen, Min Zhang, Jia Bai, Liyao Wang, Xinyu Li
Journal: Advanced Healthcare Materials (2024)

Abstract The limitations of protein‐based hydrogels, including their insufficient mechanical properties and restricted biological functions, arise from the highly specific functions of proteins as natural building blocks. A potential solution to overcome these shortcomings is the development of protein–protein hydrogels, which integrate structural and functional proteins. In this study, a protein–protein hydrogel formed by crosslinking bovine serum albumin (BSA) and a genetically engineered intrinsically disordered collagen‐like protein (CLP) through Ag─S bonding is introduced. The approach involves thiolating lysine residues of BSA and crosslinking CLP with Ag + ions, utilizing thiolation of BSA and the free‐cysteines of CLP. The resulting protein–protein hydrogels exhibit exceptional properties, including notable plasticity, inherent self‐healing capabilities, and gel–sol transition in response to redox conditions. In comparison to standalone BSA hydrogels, these protein–protein hydrogels demonstrate enhanced cellular viability, and improved cellular migration. In vivo experiments provide conclusive evidence of accelerated wound healing, observed not only in murine models with streptozotocin (Step)‐induced diabetes but also in zebrafish models subjected to UV‐burn injuries. Detailed mechanistic insights, combined with assessments of proinflammatory cytokines and the expression of epidermal differentiation‐related proteins, robustly validate the protein–protein hydrogel's effectiveness in promoting wound repair.