Ancient chicken remains reveal the origins of virulence in Marek's disease virus.

The pronounced growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek's disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the past century. Today, MDV infections kill >90% of unvaccinated birds, and controlling it costs more than US$1 billion annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens.

Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.

The Effect of Noise on Initiation and Maintenance of Clear Speech and Associated Mental Demand.

BACKGROUND/OBJECTIVES: The objectives of this study were to explore (a) the influence of different types of background noise and their informational content on the ability of speakers to initiate and maintain clear speech (CS), a widely utilized technique for enhancing speech intelligibility, and (b) the impact of background noise and CS usage on speakers' mental demand. METHOD: Five adult females were asked to read sentences using both habitual and CS under four distinct noise conditions: quiet, multitalker (MT) noise, reversed multitalker (RevMT) noise, and speech-shaped (SS) noise. Following this, speakers rated their perceived level of mental demand for each speaking condition using the modified NASA Task Load Index scale. A two-part listening experiment with 48 listeners was conducted to evaluate the speakers' effectiveness in initiating and maintaining CS. RESULTS: Speakers initiated CS more successfully in noise than in quiet, with better performance observed in the presence of RevMT noise as compared to SS noise. Regarding the maintenance of CS, none of the speakers were successful in a quiet environment. Furthermore, the ability to maintain CS was most adversely affected in MT noise, followed by RevMT noise and SS noise. CONCLUSIONS: Our findings suggest that the effect of background noise on speech production is complex and multifaceted. The noise type affected speakers' ability to initiate and maintain CS as well as the mental demand associated with the speech task. The results underscore the importance of considering the characteristics of background noise and cognitive aspects of speech production when training and evaluating speakers' performance.

IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation.

Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.

Effectiveness of one-on-one coaching in improving pressurized metered dose inhaler (pMDI) technique among COPD patients: a prospective clinical study.

BACKGROUND: Incorrect use of inhalers among asthma and COPD patients is very prevalent. Yet, no single intervention is considered standard of care. We aimed to conduct a COPD-specific investigation of active one-on-one coaching as the educational intervention to improve pressurized metered dose inhaler (pMDI) technique and COPD symptoms management. METHODS: COPD patients who have pMDI in their treatment regimen were enrolled in this prospective study using the Global Initiative for Chronic Obstructive Lung Disease criteria. After rapid cognitive screen, inhaler technique was assessed and an active one-on-one coaching was provided utilizing the 12-step American Thoracic Society instructions. Patients' inhaler technique was assessed and scored again at their regular follow-up visits. RESULTS: One hundred and one patients participated in the study. The percentage of pMDI misuse decreased from 43.5% pre-teaching to 12.9% post-teaching (binomial test p value < 0.001). The mean number of errors decreased from 3.1 errors pre-teaching to 1.7 errors post-teaching (paired t-test p value < 0.001). The number needed to treat was 3.3 patients to prevent one misuse. Patients with an impaired cognitive function were more likely to have inhaler misuse in general and less likely to improve their technique when provided training. CONCLUSIONS: This study reveals that many COPD patients have incorrect pMDI techniques that can be improved with a short training in the clinic. TRIAL REGISTRATION: Not applicable.

Microbiome networks and change-point analysis reveal key community changes associated with cystic fibrosis pulmonary exacerbations.

Over 90% of cystic fibrosis (CF) patients die due to chronic lung infections leading to respiratory failure. The decline in CF lung function is greatly accelerated by intermittent and progressively severe acute pulmonary exacerbations (PEs). Despite their clinical impact, surprisingly few microbiological signals associated with PEs have been identified. Here we introduce an unsupervised, systems-oriented approach to identify key members of the microbiota. We used two CF sputum microbiome data sets that were longitudinally collected through periods spanning baseline health and PEs. Key taxa were defined based on three strategies: overall relative abundance, prevalence, and co-occurrence network interconnectedness. We measured the association between changes in the abundance of the key taxa and changes in patient clinical status over time via change-point detection, and found that taxa with the highest level of network interconnectedness tracked changes in patient health significantly better than taxa with the highest abundance or prevalence. We also cross-sectionally stratified all samples into the clinical states and identified key taxa associated with each state. We found that network interconnectedness most strongly delineated the taxa among clinical states, and that anaerobic bacteria were over-represented during PEs. Many of these anaerobes are oropharyngeal bacteria that have been previously isolated from the respiratory tract, and/or have been studied for their role in CF. The observed shift in community structure, and the association of anaerobic taxa and PEs lends further support to the growing consensus that anoxic conditions and the subsequent growth of anaerobic microbes are important predictors of PEs.

Novel characterization and live imaging of Schlemm's canal expressing Prox-1.

Schlemm's canal is an important structure of the conventional aqueous humor outflow pathway and is critically involved in regulating the intraocular pressure. In this study, we report a novel finding that prospero homeobox protein 1 (Prox-1), the master control gene for lymphatic development, is expressed in Schlemm's canal. Moreover, we provide a novel in vivo method of visualizing Schlemm's canal using a transgenic mouse model of Prox-1-green fluorescent protein (GFP). The anatomical location of Prox-1⁺ Schlemm's canal was further confirmed by in vivo gonioscopic examination and ex vivo immunohistochemical analysis. Additionally, we show that the Schlemm's canal is distinguishable from typical lymphatic vessels by lack of lymphatic vessel endothelial hyaluronan receptor (LYVE-1) expression and absence of apparent sprouting reaction when inflammatory lymphangiogenesis occurred in the cornea. Taken together, our findings offer new insights into Schlemm's canal and provide a new experimental model for live imaging of this critical structure to help further our understanding of the aqueous humor outflow. This may lead to new avenues toward the development of novel therapeutic intervention for relevant diseases, most notably glaucoma.