tbuckley/cabot-search huggingface dataset:
Navigating a fine balance: point-mutant cheater viruses disrupt the viral replication cycle
Authors: Moran Meir, Arielle Kahn, Carmel Farage, Yael Maoz, Noam Harel, Adi Ben Zvi, Shir Segev, Maria Volkov, Ravit Yahud, Uri Gophna, Adi Stern
Journal: Molecular Biology and Evolution (2024)

Abstract Cheater viruses cannot replicate on their own yet replicate faster than the wild type (WT) when the two viruses coinfect the same cell. Cheaters must possess dual genetic features: a defect, which leads to their inability to infect cells on their own, and a selective advantage over WT during co-infection. Previously, we have discovered two point-mutant cheaters of the MS2 bacteriophage. Here, we set out to discover the possible repertoire of cheater MS2 viruses by performing experimental evolution at a very high multiplicity of infection (MOI). Our results revealed a third point-mutant cheater that arose in eight biological replicas. Each of the three primary cheaters disrupts the fine balance necessary for phage replication, in different ways that create a defect + advantage. We found that over time, the point mutant cheaters accumulate additional secondary mutations, which alter other stages of the viral replication cycle, complementing the disruptions created by the original cheater. Intriguingly, cheater and secondary mutations almost always reside in very close proximity on the genome. This region encodes for multiple functions: overlapping reading frames as well as overlapping RNA structures critical for transitioning from one stage to another in the viral replication cycle. This region of overlap explains the dual functions of cheaters, as one mutation can have pleiotropic effects. Overall, these findings underscore how viruses, whose dense genomes often have overlapping functions, can easily evolve point-mutant cheaters, and how cheaters can evolve to alter the intricate balance of the viral replication cycle.
Effective Hydrogel Vascular Patch Dual‐Loaded with Cycloastragenol Nanostructured Lipid Carriers and Doxycycline for Repairing Extravascular Injury in Abdominal Aortic Aneurysm
Authors: Du Chen, Tiantian Song, Yi Liu, Ying Wang, Boyang Qin, Qingyi Zhang, Weipeng Hu, Xiqiao Zhou, Rong Qi
Journal: Advanced Healthcare Materials (2024)

Endovascular aneurysm repair (EVAR) plays a crucial role in the treatment of abdominal aortic aneurysm (AAA) in the clinic, but the aneurysm remains in the patient's body after surgery, continuing to pose a risk of progression. Cycloastragenol (CAG) is proven to be an effective anti-AAA drug, and its vascular protective effects can be further improved when the hydrophobic CAG is encapsulated into nano-sized formulations to enhance its bioavailability. In this context, this study developed an extravascular patch hydrogel loaded with CAG nanostructured lipid carriers and a hydrophilic drug of doxycycline hydrochloride (DOX). The extravascular patch delivered onto the mouse abdominal aortas can promote local permeation of hydrophilic/hydrophobic drugs at the vessel sites and provide effective vascular protection against AAA injury induced by elastase. This study introduces a novel and promising approach for AAA treatment, which can serve as a supplementary strategy after EVAR surgery.
Ginsenoside Rd‐Loaded Antioxidant Polymersomes to Regulate Mitochondrial Homeostasis for Bone Defect Healing in Periodontitis
Authors: Congjiao Hu, Junqiu Shi, Fan Zhang, Mingchen Lv, Zhenghong Ge, Meiting Feng, Zhen Fan, Danqing Liu, Jianzhong Du, Yao Sun
Journal: Advanced Healthcare Materials (2024)

Abstract Periodontitis is the leading cause of tooth loss in adults. Initially triggered by bacterial infection, it is characterized by subsequent dysregulation of mitochondrial homeostasis, leading to ongoing loss of periodontal tissue. Mitophagic flux, a critical physiological mechanism for maintaining mitochondrial homeostasis, is compromised in periodontitis. Additionally, increased release of reactive oxygen species (ROS) exacerbates mitochondrial damage. In this study, a ginsenoside Rd (Rd)‐loaded antioxidative polymersome (RdAP) is designed, which is self‐assembled from a mitochondrial‐protective and ROS‐scavenging block copolymer, poly(ethylene oxide)‐ block ‐poly(phenylboronic acid pinacol ester‐conjugated polylysine) (PEO 113 ‐ b ‐P(Lys‐PAPE) 60 ). The phenylboronic acid pinacol ester (PAPE) segment exhibits excellent ROS‐responsive properties, enabling effective ROS scavenging through antioxidant production. Rd significantly enhances mitophagic flux by 2.5‐fold in periodontal ligament stem cells (PDLSCs) under oxidative stress. Together with the antioxidative polymersome, RdAPs restore mitochondrial homeostasis and enhance the osteogenic capacity of PDLSCs, bringing it closer to that of healthy controls. In a mouse model of periodontitis, the bone mass in the RdAP‐treated group is 1.37 times greater than that in the untreated periodontitis group. Overall, the findings propose a novel strategy for addressing refractory periodontitis, which may also be applicable to other diseases characterized by mitochondrial homeostasis imbalance.
Effects of azithromycin in severe eosinophilic asthma with concomitant monoclonal antibody treatment
Authors: Gabriel Lavoie, Imran Howell, James Melhorn, Catherine Borg, Laura Bermejo-Sanchez, Jack Seymour, Maisha F Jabeen, Anastasia Fries, Gareth Hynes, Ian D Pavord, Nayia Petousi, Timothy Sc Hinks
Journal: Thorax (2024)

Macrolides reduce exacerbations when added to inhaled therapy in severe asthma. However, there is little published evidence for effectiveness in patients treated with biologics. We conducted a retrospective audit of all patients who started azithromycin while on biologics in our centre. Compared with those that did not start azithromycin, these individuals had more exacerbations and a phenotype of chronic bronchitis and/or frequent purulent exacerbations. The addition of azithromycin to biologics was associated with reduced annual rates of steroid-treated and antibiotic-treated exacerbations and improved symptom scores (Asthma Control Questionnaire-5) but not with any improvement in lung function. Data support testing azithromycin in clinical trials in patients on biologics with residual exacerbations.
Engineered virus-mimicking nanovaccine with lymph node–tumor dual-targeting and STING-activating capacity for robust cancer immunotherapy
Authors: Zhongjie Wang, Shujun Liu, Ruiqi Ming, Weiwei Wang, Chenguang Wang, Chuyu Li, Jiahua Yang, Fan Zhang, Guihong Lu, Lin Mei, Li-Li Huang
Journal: Journal of Controlled Release (2024)
Metabolic glycan labelling with bio-orthogonal targeting and its potential in drug delivery
Authors: Yuen Yi Lam, Angel Tan, Kristian Kempe, Ben J Boyd
Journal: Journal of Controlled Release (2024)

New modes of targeted drug delivery are emerging with promise of enhancing therapeutic efficacy while reducing side effects. This review examines the landscape of metabolic glycan labelling-a technique gaining traction for its potential in specific drug targeting. By exploiting the natural glycan synthetic pathway of monosaccharides, unnatural sugar analogues are incorporated into glycoproteins, allowing for the presentation of unique functional groups on cells. This enables specific targeting using 'clickable' probes with complementary click chemistry functional groups. The selection of sugar analogues and chemical tags are crucial components explored in this review, alongside considerations for cell lines, tissues, and cargo selection. The review discusses non-therapeutic and therapeutic applications of metabolic glycan labelling, as well as its potential beyond labelling of cell surfaces. The review also highlights underexplored areas of metabolic glycan labelling by assessing the limited literature addressing labelling efficiency, turnover rates, the impact of sugar supplements in cell culture, and the critical cell to functionalised sugar ratio. Furthermore, this review delves into the future landscape and goals of metabolic glycan labelling, envisioning its potential in targeted drug delivery.
Tracing carriage, acquisition, and transmission of ESBL-producing Escherichia coli over two years in a tertiary care hospital
Authors: Minh Ngoc Nguyen, Beryl Primrose Gladstone, Giulia De Angelis, Michael Biggel, Basil Britto Xavier, Christine Lammens, Qiang Lin, Sandra Van Puyvelde, Herman Goossens, Samir Kumar-Singh, Youri Glupczynski, Yehuda Carmeli, Evelina Tacconelli, Surbhi Malhotra-Kumar, Stephan Harbarth, Jacques Schrenzel, Giovanni Restuccia, Silvia Venturiello, Roberto Cauda, Shimrit Percia, Liliana Preotescu, Mona Popoiu, Biljana Carevic, Tanja Tošić, Amos Adler
Journal: Genome Medicine (2024)

The impact of community carriage on the influx of extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) into hospitals remains understudied. In this prospective 2-year single-centre study, we investigate the community ESBL-E influx and trace the colonisation, nosocomial acquisition, transmission, and infection dynamics of ESBL-producing Escherichia coli (ESBL-Ec) in non-ICU wards at a tertiary care hospital. This study reports primary and post hoc outcomes of the clinical trial NCT01208519 in which hospitalised patients were screened for rectal carriage of ESBL-E. ESBL-Ec isolates from ≈50% of carriers, including all patients who developed infections, were sequenced and genotyped. Endogenous infection was defined as infection by the same strain (< 10 SNPs distance) as colonizing strain. Of 3703 screened patients, 456 (12.3%) were ESBL-positive-at-admission (PA-ESBL). Of the 2268 ESBL-negative-at-admission (NA-ESBL) patients with follow-up samples, 240 (10.6%) acquired ESBL-E (HA-ESBL), with an incidence density rate of 7.96 cases/1000 patient-day, notably higher in patients receiving antibiotics (P < 0.001). PA- and HA-ESBL patients developed significantly more ESBL-E infections than ESBL-free patients (P < 0.001). Sequenced ESBL-Ec showed high clonal diversity dominated by the multidrug-resistant and highly virulent ST131 clade, C2/H30-Rx. Among ESBL-Ec infections, 60% (18/30) were endogenous. Direct between-patients transmission clusters (n = 21) involved 23.9% (48/201) of patients and 23.0% (84/366) of ESBL-Ec isolates. Our data show a high prevalence of nosocomial acquisition of ESBL-E in a non-ICU setting. The study provides genomic evidence that the endogenous reservoir is the main driver of ESBL-Ec infections underscoring the need for wide implementation of antibiotic stewardship programmes to reduce antibiotic pressure.
Persistence of Oropouche virus in body fluids among imported cases in France, 2024
Authors: Cyrille Gourjault, Laura Pezzi, Barbara Doudier, Philippe Minodier, Raphaëlle Klitting, Philippe Cano, Nazli Ayhan, Franck Touret, Gilda Grard, Guillaume A Durand, Jean-Sélim Driouich, Léa Luciani, Antoine Nougairède, Jean-Christophe Lagier, Xavier de Lamballerie, Nadim Cassir
Journal: The Lancet Infectious Diseases (2024)
Effect of a spatial repellent on malaria incidence in an area of western Kenya characterised by high malaria transmission, insecticide resistance, and universal coverage of insecticide treated nets (part of the AEGIS Consortium): a cluster-randomised, controlled trial
Authors: Eric O Ochomo, John E Gimnig, Quentin Awori, Bernard Abong'o, Prisca Oria, Nickline K Ashitiba, Brian Polo, Vincent Moshi, Hilda Otanga, Ferdinard Adung'o, Eunice A Ouma, Susan Outa, Edith Ramaita, Rebecca Levine, Wycliffe Odongo, Steven A Harvey, April Monroe, Ashley Hudson, Bradley Sandberg, Jared Hendrickson, Xingyuan Zhao, Ruyu Zhou, Fang Liu, Nicole L Achee, John P Grieco
Journal: The Lancet (2024)
Comments on “Band-on-band endoscopic variceal ligation: a technique for the treatment of esophageal varices in case of band misplacement”
Authors: Ye Hu, Yi Zhang, Leiming Xu
Journal: Endoscopy (2024)

Letter to: Band-on-band endoscopic variceal ligation: a technique for the treatment of esophageal varices in case of band misplacementEndoscopy 2024; 56(S 01): E211-E212DOI: 10.1055/a-2268-5513
Band-on-band endoscopic variceal ligation and alternative treatment strategies: Reply to Hu et al.
Authors: Andrea Sorge, Giulia Tosetti, Massimo Primignani, Gian Eugenio Tontini
Journal: Endoscopy (2024)

Letter to: Comments on "Band-on-band endoscopic variceal ligation: a technique for the treatment of esophageal varices in case of band misplacement"Endoscopy 2025; 57(01): 90-90DOI: 10.1055/a-2386-9001
Survival and quality of life after first-time diagnosis of brain metastases: a multicenter, prospective, observational study
Authors: Olav Erich Yri, Guro Lindviksmoen Astrup, Astrid Telhaug Karlsson, Rene van Helvoirt, Marianne Jensen Hjermstad, Kristin Moksnes Husby, Jon Håvard Loge, Jo-Åsmund Lund, Tonje Lundeby, Ørnulf Paulsen, Eva Skovlund, Marius-Ioan Taran, Rebecca Rootwelt Winther, Nina Aass, Stein Kaasa
Journal: The Lancet Regional Health - Europe (2024)
Dexterity assessment of hospital workers: prospective comparative study
Authors: Tobin Joseph, Oliver I Brown, Sara Khalid, Marilena Giannoudi, Rebecca C Sagar, Elena Bunola-Hadfield, Stephen J Chapman, Thomas A Slater, Sam Straw, Michael Drozd
Journal: BMJ (2024)

Abstract Objectives To compare the manual dexterity and composure under pressure of people in different hospital staff roles using a buzz wire game. Design Prospective, observational, comparative study (Tremor study). Setting Leeds Teaching Hospitals NHS Trust, Leeds, UK, during a three week period in 2024. Participants 254 hospital staff members comprising of 60 physicians, 64 surgeons, 69 nurses, and 61 non-clinical staff. Main outcome measures Successful completion of the buzz wire game within five minutes and occurrence of swearing and audible noises of frustration. Results Of the 254 hospital staff that participated, surgeons had significantly higher success rates in completing the buzz wire game within five minutes (84%, n=54) compared with physicians (57%, n=34), nurses (54%, n=37), and non-clinical staff (51%, n=31) (P&lt;0.001). Time-to-event analysis showed that surgeons were quicker to successfully complete the game, independent of age and gender. Surgeons exhibited the highest rate of swearing during the game (50%, n=32), followed by nurses (30%, n=21), physicians (25%, n=60), and non-clinical staff (23%, n=14) (P=0.004). Non-clinical staff showed the highest use of frustration noises (75%), followed by nurses (68%), surgeons (58%), and physicians (52%) (P=0.03). Conclusions Surgeons showed greater dexterity, but higher levels of swearing compared with other hospital staff roles, while nurses and non-clinical staff showed the highest rates of audible noises of frustration. The study highlights the diverse skill sets across hospital staff roles. Implementation of a surgical swear jar initiative should be considered for future fundraising events.
Identification of α-galactosylceramide as an endogenous mammalian antigen for iNKT cells
Authors: Yuki Hosono, Noriyuki Tomiyasu, Hayato Kasai, Eri Ishikawa, Masatomo Takahashi, Akihiro Imamura, Hideharu Ishida, Federica Compostella, Hiroshi Kida, Atsushi Kumanogoh, Takeshi Bamba, Yoshihiro Izumi, Sho Yamasaki
Journal: The Journal of Experimental Medicine (2024)

Invariant natural killer T (iNKT) cells are unconventional T cells recognizing lipid antigens in a CD1d-restricted manner. Among these lipid antigens, α-galactosylceramide (α-GalCer), which was originally identified in marine sponges, is the most potent antigen. Although the presence of α-anomeric hexosylceramide and microbiota-derived branched α-GalCer is reported, antigenic α-GalCer has not been identified in mammals. Here, we developed a high-resolution separation and detection system, supercritical fluid chromatography tandem mass spectrometry (SFC/MS/MS), that can discriminate hexosylceramide diastereomers (α-GalCer, α-GlcCer, β-GalCer, or β-GlcCer). The B16 melanoma tumor cell line does not activate iNKT cells; however, ectopic expression of CD1d was sufficient to activate iNKT cells without adding antigens. B16 melanoma was unlikely to generate iNKT cell antigens; instead, antigen activity was detected in cell culture serum. Activity-based purification and SFC/MS/MS identified dihydrosphingosine-based saturated α-GalCer as an antigenic component in serum, bile, and lymphoid tissues. These results show the first evidence for the presence of potent antigenic α-GalCer in mammals.
GLP-1 Agonists May Reduce Risk of Alcohol Use Disorder Hospitalizations
Authors: Samantha Anderer
Journal: JAMA (2024)

Some glucagon-like peptide-1 receptor (GLP-1) agonists, prescribed for treatment of diabetes or obesity, may outperform traditional medications in reducing alcohol use disorder (AUD)–related hospitalizations, according to a cohort study published in JAMA Psychiatry.
Universal Health Checkups and Risk of Incident Diabetes and Hypertension
Authors: Masato Takeuchi, Tomohiro Shinozaki, Koji Kawakami
Journal: JAMA Network Open (2024)

Type 2 diabetes and hypertension are obesity-related, noncommunicable diseases becoming increasingly common worldwide. In 2008, Japan launched a nationwide universal health checkup program, Specific Health Checkup (SHC), for the primary prevention of obesity-related diseases, but its effectiveness has been understudied.
β-Lactam Inoculum Effect in Methicillin-Susceptible <i>Staphylococcus aureus</i> Infective Endocarditis
Authors: Baptiste Jean, Maelys Crolle, Candice Pollani, Adèle Le Guilloux, Guillaume Martin-Blondel, Pierre Tattevin, Audrey Le Bot, David Luque Paz, François Guérin, Vincent Cattoir, Laurence Armand-Lefevre, Signara Gueye, François-Xavier Lescure, Xavier Duval, Clémence Massip, Pierre Delobel
Journal: JAMA Network Open (2024)

Importance Infective endocarditis (IE) caused by Staphylococcus aureus is associated with high mortality, approximately 20% to 30%, mostly in the first month, with no improvement in recent decades. Current opinion is that antistaphylococcal penicillin and cefazolin are equally effective in treating methicillin-susceptible S aureus (MSSA) IE, and both are recommended as possible first-line treatments. Most MSSA strains carry the β-lactamase blaZ gene, and some blaZ -positive strains exhibit an inoculum effect, meaning increased minimum inhibitory concentrations at high inoculum. This reduced susceptibility to an antibiotic at high bacterial inoculum may be particularly relevant in IE, where vegetations have very high bacterial densities. Objective To evaluate the association between phenotypic characteristics of S aureus isolates, β-lactam used, and outcome in patients with MSSA IE. Design, Settings, and Participants This retrospective case series included MSSA cases treated at 3 French university hospitals between February 2016 and February 2022. The study included patients who had clinical isolates available and had definite or possible S aureus IE that involved native or prosthetic valves. Data were analyzed from July 2023 to June 2024. Main Outcomes and Measures MSSA isolates were tested for the presence of blaZ and for inoculum effects to cefazolin and oxacillin. The association between first-month mortality and the β-lactam used, the presence of blaZ , and the presence of an inoculum effect to the treatment received was evaluated. Results This study included 216 patients with MSSA IE (median [IQR] age, 65 [49-73] years; 152 [70.4%] male) who were treated with antistaphylococcal penicillin (139 [64.4%]) or cefazolin (77 [35.6%]). One-month mortality of left-sided IE was 44 of 180 patients (24.4%), with no overall difference between patients treated with antistaphylococcal penicillin or cefazolin. However, 1-month mortality was higher in patients infected with blaZ -positive strains than with blaZ -negative strains (38 of 129 [29.5%] vs 6 of 51 [11.8%]; P = .01), and with strains with an inoculum effect to the β-lactam received than with strains without an inoculum effect (25 of 62 [40.3%] vs 13 of 67 [19.4%]; P = .005). On multivariable analysis, the presence of an inoculum effect was independently associated with first-month mortality (HR, 2.84; 95% CI, 1.28-6.30; P = .01). Conclusions and Relevance In this case series of MSSA IE, the presence of an inoculum effect to the β-lactam received was a risk factor for death in the first month. Phenotyping MSSA isolates for inoculum effect may guide β-lactam choice and improve outcomes.
FDA Seeks to Remove Oral Phenylephrine From Decongestants
Authors: Samantha Anderer
Journal: JAMA (2024)

The US Food and Drug Administration (FDA) is considering removal of oral phenylephrine, a widely used ingredient to treat nasal congestion, from over-the-counter (OTC) cold medications—including DayQuil, Theraflu, and Sudafed—after an extensive review of available data determined a lack of efficacy.
Nanotherapeutics in Kidney Disease
Authors: Amir Roointan, Rong Xu, Simon Corrie, Christoph E. Hagemeyer, Karen Alt
Journal: Journal of the American Society of Nephrology (2024)

Abstract The treatment and management of kidney disease present a significant global challenge, affecting over 800 million individuals and necessitating innovative therapeutic strategies that transcend symptomatic relief. The application of nanotechnology to renal therapies, while still in its early stages, holds transformative potential for improving treatment outcomes. Recent advancements in nanoparticle-based drug delivery leverage the unique physicochemical properties of nanoparticles for targeted and controlled therapeutic delivery to the kidneys. Current research is focused on understanding the functional and phenotypic changes in kidney cells during both acute and chronic conditions, allowing for the identification of optimal target cells. Additionally, the development of tailored nanomedicines enhances their retention and binding to key renal membranes and cell populations, ultimately improving localization, tolerability, and efficacy. However, significant barriers remain, including inconsistent nanoparticle synthesis and the complexity of kidney-specific targeting. To overcome these challenges, the field requires advanced synthesis techniques, refined targeting strategies, and the establishment of animal models that accurately reflect human kidney disease. These efforts are critical for the clinical application of nanotherapeutics, which promise novel solutions for kidney disease management. This review evaluates a substantial body of in vivo research, highlighting the prospects, challenges, and opportunities presented by nanotechnology-mediated therapies and their potential to transform kidney disease treatment.
Tracing the Evolution of Human Immunity Through Ancient DNA
Authors: Etienne Patin, Lluis Quintana-Murci
Journal: Annual Review of Immunology (2024)

Infections have imposed strong selection pressures throughout human evolution, making the study of natural selection's effects on immunity genes highly complementary to disease-focused research. This review discusses how ancient DNA studies, which have revolutionized evolutionary genetics, increase our understanding of the evolution of human immunity. These studies have shown that interbreeding between modern humans and Neanderthals or Denisovans has influenced present-day immune responses, particularly to viruses. Additionally, ancient genomics enables the tracking of how human immunity has evolved across cultural transitions, highlighting strong selection since the Bronze Age in Europe (&lt;4,500 years) and potential genetic adaptations to epidemics raging during the Middle Ages and the European colonization of the Americas. Furthermore, ancient genomic studies suggest that the genetic risk for noninfectious immune disorders has gradually increased over millennia because alleles associated with increased risk for autoimmunity and inflammation once conferred resistance to infections. The challenge now is to extend these findings to diverse, non-European populations and to provide a more global understanding of the evolution of human immunity.