Repeat-based holocentromeres influence genome architecture and karyotype evolution.

The centromere represents a single region in most eukaryotic chromosomes. However, several plant and animal lineages assemble holocentromeres along the entire chromosome length. Here, we compare genome organization and evolution as a function of centromere type by assembling chromosome-scale holocentric genomes with repeat-based holocentromeres from three beak-sedge (Rhynchospora pubera, R. breviuscula, and R. tenuis) and their closest monocentric relative, Juncus effusus. We demonstrate that transition to holocentricity affected 3D genome architecture by redefining genomic compartments, while distributing centromere function to thousands of repeat-based centromere units genome-wide. We uncover a complex genome organization in R. pubera that hides its unexpected octoploidy and describe a marked reduction in chromosome number for R. tenuis, which has only two chromosomes. We show that chromosome fusions, facilitated by repeat-based holocentromeres, promoted karyotype evolution and diploidization. Our study thus sheds light on several important aspects of genome architecture and evolution influenced by centromere organization.

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation.

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.

The landscape of genomic structural variation in Indigenous Australians.

Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets1-3. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here we apply population-scale whole-genome long-read sequencing4 to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large insertion-deletion variants (20-49 bp; n = 136,797), structural variants (50 b-50 kb; n = 159,912) and regions of variable copy number (>50 kb; n = 156). The majority of variants are composed of tandem repeat or interspersed mobile element sequences (up to 90%) and have not been previously annotated (up to 62%). A large fraction of structural variants appear to be exclusive to Indigenous Australians (12% lower-bound estimate) and most of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short tandem repeats throughout the genome to characterize allelic diversity at 50 known disease loci5, uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among short tandem repeat sequences. Our study sheds new light on the dimensions and dynamics of genomic structural variation within and beyond Australia.

The retroelement Lx9 puts a brake on the immune response to virus infection.

The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago1,2. However, it was not until the advancement of genomic sequencing technologies that the abundance and repertoire of transposable elements were revealed, and they are now known to constitute up to two-thirds of mammalian genomes3,4. The presence of DNA regulatory regions including promoters, enhancers and transcription-factor-binding sites within transposable elements5-8 has led to the hypothesis that transposable elements have been co-opted to regulate mammalian gene expression and cell phenotype8-14. Mammalian transposable elements include recent acquisitions and ancient transposable elements that have been maintained in the genome over evolutionary time. The presence of ancient conserved transposable elements correlates positively with the likelihood of a regulatory function, but functional validation remains an essential step to identify transposable element insertions that have a positive effect on fitness. Here we show that CRISPR-Cas9-mediated deletion of a transposable element-namely the LINE-1 retrotransposon Lx9c11-in mice results in an exaggerated and lethal immune response to virus infection. Lx9c11 is critical for the neogenesis of a non-coding RNA (Lx9c11-RegoS) that regulates genes of the Schlafen family, reduces the hyperinflammatory phenotype and rescues lethality in virus-infected Lx9c11-/- mice. These findings provide evidence that a transposable element can control the immune system to favour host survival during virus infection.

Opinion dynamics in financial markets via random networks.

We investigate financial market dynamics by introducing a heterogeneous agent-based opinion formation model. In this work, we organize individuals in a financial market according to their trading strategy, namely, whether they are noise traders or fundamentalists. The opinion of a local majority compels the market exchanging behavior of noise traders, whereas the global behavior of the market influences the decisions of fundamentalist agents. We introduce a noise parameter, q, to represent the level of anxiety and perceived uncertainty regarding market behavior, enabling the possibility of adrift financial action. We place individuals as nodes in an Erdös-Rényi random graph, where the links represent their social interactions. At any given time, individuals assume one of two possible opinion states ±1 regarding buying or selling an asset. The model exhibits fundamental qualitative and quantitative real-world market features such as the distribution of logarithmic returns with fat tails, clustered volatility, and the long-term correlation of returns. We use Student's t distributions to fit the histograms of logarithmic returns, showing a gradual shift from a leptokurtic to a mesokurtic regime depending on the fraction of fundamentalist agents. Furthermore, we compare our results with those concerning the distribution of the logarithmic returns of several real-world financial indices.

Assessment of barriers to cancer screening and interventions implemented to overcome these barriers in 27 Latin American and Caribbean countries.

There is a gap in the understanding of the barriers to cancer screening participation and complying with downstream management in the Community of Latin American and Caribbean states (CELAC). Our study aimed to assess barriers across the cancer screening pathway from the health system perspective, and interventions in place to improve screening in CELAC. A standardized tool was used to collect information on the barriers across the screening pathway through engagement with the health authorities of 27 member states of CELAC. Barriers were organized in a framework adapted from the Tanahashi conceptual model and consisted of the following dimensions: availability of services, access (covering accessibility and affordability), acceptability, user-provider interaction, and effectiveness of services (which includes governance, protocols and guidelines, information system, and quality assurance). The tool also collected information of interventions in place, categorized in user-directed interventions to increase demand, user-directed interventions to increase access, provider-directed interventions, and policy and system-level interventions. All countries prioritized barriers related to the information systems, such as the population register not being accurate or complete (N = 19; 70.4%). All countries implemented some kind of intervention to improve cancer screening, group education being the most reported (N = 23; 85.2%). Training on screening delivery was the most referred provider-directed intervention (N = 19; 70.4%). The study has identified several barriers to the implementation of cancer screening in the region and interventions in place to overcome some of the barriers. Further analysis is required to evaluate the effectiveness of these interventions in achieving their objectives.

Postoperative Complications and Mobilization Following Major Abdominal Surgery With Versus Without Fitness Tracker-based Feedback (EXPELLIARMUS): A Student-led Multicenter Randomized Controlled Clinical Trial of the CHIR-Net SIGMA Study Group.

OBJECTIVE: To determine whether daily postoperative step goals and feedback through a fitness tracker (FT) reduce the rate of postoperative complications after surgery. BACKGROUND: Early and enhanced postoperative mobilization has been advocated to reduce postoperative complications, but it is unknown whether FT alone can reduce morbidity. METHODS: EXPELLIARMUS was performed at 11 University Hospitals across Germany by the student-led clinical trial network SIGMA. Patients undergoing major abdominal surgery were enrolled, equipped with an FT, and randomly assigned to the experimental (visible screen) or control intervention (blackened screen). The experimental group received daily step goals and feedback through the FT. The primary end point was postoperative morbidity within 30 days using the Comprehensive Complication Index (CCI). All trial visits were performed by medical students in the hospital with the opportunity to consult a surgeon-facilitator who also obtained informed consent. After discharge, medical students performed the 30-day postoperative visit through telephone and electronic questionnaires. RESULTS: A total of 347 patients were enrolled. Baseline characteristics were comparable between the 2 groups. The mean age of patients was 58 years, and 71% underwent surgery for malignant disease, with the most frequent indications being pancreatic, colorectal, and hepatobiliary malignancies. Roughly one-third of patients underwent laparoscopic surgery. No imputation for the primary end point was necessary as data completeness was 100%. There was no significant difference in the CCI between the 2 groups in the intention-to-treat analysis (mean±SD CCI experimental group: 23±24 vs. control: 22±22; 95% CI: -6.1, 3.7; P=0.628). All secondary outcomes, including quality of recovery, 6-minute walking test, length of hospital stay, and step count until postoperative day 7 were comparable between the 2 groups. CONCLUSIONS: Daily step goals combined with FT-based feedback had no effect on postoperative morbidity. The EXPELLIARMUS shows that medical students can successfully conduct randomized controlled trials in surgery.

Sobp modulates the transcriptional activation of Six1 target genes and is required during craniofacial development.

Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, and craniofacial and/or renal defects. Variants in the transcription factor Six1 and its co-factor Eya1, both of which are required for otic development, are linked to BOR. We previously identified Sobp as a potential Six1 co-factor, and SOBP variants in mouse and humans cause otic phenotypes; therefore, we asked whether Sobp interacts with Six1 and thereby may contribute to BOR. Co-immunoprecipitation and immunofluorescence experiments demonstrate that Sobp binds to and colocalizes with Six1 in the cell nucleus. Luciferase assays show that Sobp interferes with the transcriptional activation of Six1+Eya1 target genes. Experiments in Xenopus embryos that either knock down or increase expression of Sobp show that it is required for formation of ectodermal domains at neural plate stages. In addition, altering Sobp levels disrupts otic vesicle development and causes craniofacial cartilage defects. Expression of Xenopus Sobp containing the human variant disrupts the pre-placodal ectoderm similar to full-length Sobp, but other changes are distinct. These results indicate that Sobp modifies Six1 function and is required for vertebrate craniofacial development, and identify Sobp as a potential candidate gene for BOR.

Unlocking the Potential of Nanobubbles: Achieving Exceptional Gas Efficiency in Electrogeneration of Hydrogen Peroxide.

The electrogeneration of hydrogen peroxide (H2 O2 ) via the oxygen reduction reaction is a crucial process for advanced water treatment technologies. While significant effort is being devoted to developing highly reactive materials, gas provision systems used in these processes are receiving less attention. Here, using oxygen nanobubbles to improve the gas efficiency of the electrogeneration of H2 O2 is proposed. Aeration with nanobubbles is compared to aeration with macrobubbles under an identical experimental set-up, with nanobubbles showing a much higher gas-liquid volumetric mass transfer coefficient (KL a) of 2.6 × 10-2 min-1 compared to 2.7 × 10-4 min-1 for macrobubbles. Consequently, nanobubbles exhibit a much higher gas efficiency using 60% of O2 delivered to the system compared to 0.19% for macrobubbles. Further, it is observed that the electrogeneration of H2 O2 using carbon felt electrodes is enhanced using nanobubbles. Under the same dissolved oxygen levels, nanobubbles boost the reaction yield to 84%, while macrobubbles yield only 53.8%. To the authors' knowledge, this is the first study to investigate the use of nanobubbles in electrochemical reactions and demonstrate their ability to enhance gas efficiency and electrocatalytic response. These findings have important implications for developing more efficient chemical and electrochemical processes operating under gas-starving systems.

Effective and efficient active learning for deep learning-based tissue image analysis.

MOTIVATION: Deep learning attained excellent results in digital pathology recently. A challenge with its use is that high quality, representative training datasets are required to build robust models. Data annotation in the domain is labor intensive and demands substantial time commitment from expert pathologists. Active learning (AL) is a strategy to minimize annotation. The goal is to select samples from the pool of unlabeled data for annotation that improves model accuracy. However, AL is a very compute demanding approach. The benefits for model learning may vary according to the strategy used, and it may be hard for a domain specialist to fine tune the solution without an integrated interface. RESULTS: We developed a framework that includes a friendly user interface along with run-time optimizations to reduce annotation and execution time in AL in digital pathology. Our solution implements several AL strategies along with our diversity-aware data acquisition (DADA) acquisition function, which enforces data diversity to improve the prediction performance of a model. In this work, we employed a model simplification strategy [Network Auto-Reduction (NAR)] that significantly improves AL execution time when coupled with DADA. NAR produces less compute demanding models, which replace the target models during the AL process to reduce processing demands. An evaluation with a tumor-infiltrating lymphocytes classification application shows that: (i) DADA attains superior performance compared to state-of-the-art AL strategies for different convolutional neural networks (CNNs), (ii) NAR improves the AL execution time by up to 4.3×, and (iii) target models trained with patches/data selected by the NAR reduced versions achieve similar or superior classification quality to using target CNNs for data selection. AVAILABILITY AND IMPLEMENTATION: Source code: https://github.com/alsmeirelles/DADA.

The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

OBJECTIVES: To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). METHODS: BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. RESULTS: The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. CONCLUSION: Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

Surgery for Locally Advanced Pancreatic Cancer Following Induction Chemotherapy: A Single-Center Experience.

BACKGROUND: The use of surgery in patients with locally advanced pancreatic cancer (LAPC) following induction chemotherapy is increasing. However, most series do not report on the total cohort of patients undergoing surgical exploration; therefore, this single-center study investigates outcomes among all consecutive patients with LAPC who underwent surgical exploration. METHODS: We conducted a retrospective, single-center analysis including all consecutive patients with LAPC (Dutch Pancreatic Cancer Group criteria) who underwent surgical exploration with curative intent (January 2014-June 2023) after induction therapy. Primary outcomes were resection rate and overall survival (OS) from the time of diagnosis. RESULTS: Overall, 127 patients underwent surgical exploration for LAPC, whereby 100 patients (78.7%) underwent resection and 27 patients (21.3%) underwent a non-therapeutic laparotomy due to the extent of vascular involvement (n = 11, 8.7%) or occult metastases (n = 16, 12.6%). The overall in-hospital/30-day mortality rate was 0.8% and major morbidity was 31.3% (in patients after resection: 1.0% and 33.3%, respectively). The overall 90-day mortality rate was 5.5%, which included 3.1% mortality due to disease progression. Resection was associated with longer median OS {29 months (95% confidence interval [CI] 26-43) vs. 17 months (95% CI 11-26); p < 0.001} compared with patients undergoing non-therapeutic laparotomy, with corresponding 5-year OS rates of 28.4% and 7.7%. In Cox proportional hazard regression analysis, only pancreatic body/tail tumors independently predicted OS (hazard ratio 1.788 [95% CI 1.042-3.068]). CONCLUSION: This single-center series found a resection rate of 78.7% in patients with LAPC selected for surgical exploration, with a low risk of mortality and morbidity in all explored patients and a 5-year OS rate after resection of 28.4%.

Beneath the blooms: Unearthing the effect of rhizospheric bacteria on floral signals and pollinator preferences.

The relationship between plants and pollinators is known to be influenced by ecological interactions with other community members. While most research has focused on aboveground communities affecting plant-pollinator interactions, it is increasingly recognized that soil-dwelling organisms can directly or indirectly impact these interactions. Although studies have examined the effects of arbuscular mycorrhizal fungi on floral traits, there is a gap in research regarding similar effects associated with plant growth-promoting rhizobacteria (PGPR), particularly concerning floral scent. Our study aimed to investigate the influence of the PGPR Bacillus amyloliquefaciens on the floral traits of wild (Solanum habrochaites, Solanum pimpinellifolium and Solanum peruvianum) and cultivated tomato (Solanum lycopersicum), as well as the impact of microbially-driven changes in floral scent on the foraging behaviour of the stingless bee Melipona quadrifasciata. Our findings revealed that inoculating tomatoes with PGPR led to an increased number of flowers and enhanced overall floral volatile emission. Additionally, we observed higher flower biomass and pollen levels in all species, except S. peruvianum. Importantly, these changes in volatile emissions influenced the foraging behaviour of M. quadrifasciata significantly. Our results highlight the impact of beneficial soil microbes on plant-pollinator interactions, shedding light on the multiple effects that plant-microbial interactions can have on aboveground organisms.

Updates on lung adenocarcinoma: invasive size, grading and STAS.

Advancements in the classification of lung adenocarcinoma have resulted in significant changes in pathological reporting. The eighth edition of the tumour-node-metastasis (TNM) staging guidelines calls for the use of invasive size in staging in place of total tumour size. This shift improves prognostic stratification and requires a more nuanced approach to tumour measurements in challenging situations. Similarly, the adoption of new grading criteria based on the predominant and highest-grade pattern proposed by the International Association for the Study of Lung Cancer (IASLC) shows improved prognostication, and therefore clinical utility, relative to previous grading systems. Spread through airspaces (STAS) is a form of tumour invasion involving tumour cells spreading through the airspaces, which has been highly researched in recent years. This review discusses updates in pathological T staging, adenocarcinoma grading and STAS and illustrates the utility and limitations of current concepts in lung adenocarcinoma.

Ocean deoxygenation caused non-linear responses in the structure and functioning of benthic ecosystems.

The O2 content of the global ocean has been declining progressively over the past decades, mainly because of human activities and global warming. Nevertheless, how long-term deoxygenation affects macrobenthic communities, sediment biogeochemistry and their mutual feedback remains poorly understood. Here, we evaluate the response of the benthic assemblages and biogeochemical functioning to decreasing O2 concentrations along the persistent bottom-water dissolved O2 gradient of the Estuary and Gulf of St. Lawrence (QC, Canada). We report several of non-linear biodiversity and functional responses to decreasing O2 concentrations, and identify an O2 threshold that occurs at approximately at 63 µM. Below this threshold, macrobenthic community assemblages change, and bioturbation rates drastically decrease to near zero. Consequently, the sequence of electron acceptors used to metabolize the sedimentary organic matter is squeezed towards the sediment surface while reduced compounds accumulate closer (as much as 0.5-2.5 cm depending on the compound) to the sediment-water interface. Our results illustrate the capacity of bioturbating species to compensate for the biogeochemical consequences of hypoxia and can help to predict future changes in benthic ecosystems.

Les teneurs en O2 de l'océan mondial ont diminué progressivement au cours des dernières décennies, principalement en raison des activités humaines et du réchauffement climatique. Néanmoins, les effets à long terme de la désoxygénation sur les communautés macrobenthiques, la biogéochimie des sédiments et leurs interactions mutuelles demeurent mal compris. Dans cette étude, nous évaluons la réponse des assemblages de macrofaune benthiques et de la dynamique biogéochimique sédimentaire aux concentrations décroissantes d'O2 le long du gradient persistant d'O2 dissous dans l'eau de fond de l'estuaire et du golfe du Saint-Laurent (QC, Canada). Nous avons observé plusieurs réponses non linéaires de la biodiversité et de la dynamique biogéochimique sédimentaire face à la diminution de la concentration en O2 avec un seuil situé à environ 63 µM. En dessous de ce seuil, les assemblages de communautés macrobenthiques changent, et les taux de bioturbation diminuent drastiquement pour atteindre des niveaux presque nuls. En conséquence, la séquence des accepteurs d'électrons utilisés pour minéraliser la matière organique sédimentaire se contracte vers la surface du sédiment, tandis que les composés réduits s'accumulent plus près (jusqu'à 0.5 à 2.5 cm selon le composé) de l'interface sédiment-eau. Nos résultats illustrent la capacité des espèces bioturbatrices à compenser les conséquences biogéochimiques de la désoxygénation et peuvent contribuer à prédire les futurs changements dans les écosystèmes benthiques.

Quantifying terpenes in tomato leaf extracts from different species using gas chromatography-mass spectrometry (GC-MS).

Terpenes play a vital role in plant defense; tomato plants produce a diverse range of terpenes within specialized glandular trichomes, influencing interactions with herbivores, predators, and pollinators. This study employed two distinct methods, namely leaf dip and maceration, to extract trichomes from tomato leaves. Terpene quantification was carried out using Gas Chromatography-Mass Spectrometry (GC-MS). The leaf dip method proved effective in selectively targeting trichome content, revealing unique extraction patterns compared to maceration. The GC-MS method demonstrated high linearity, accuracy, sensitivity, and low limits of detection and quantification. Application of the method to different tomato species (Solanum pennellii, Solanum pimpinellifolium, Solanum galapagense, Solanum habrochaites, and Solanum lycopersicum) identified significant variation in terpene content among these species, highlighting the potential of specific accessions for breeding programs. Notably, the terpene α-zingiberene, known for its repellency against whiteflies, was found in high quantities (211.90-9155.13 µg g-1) in Solanum habrochaites accession PI209978. These findings provide valuable insights into terpenoid diversity for plant defense mechanisms, guiding future research on developing pest-resistant tomato cultivars. Additionally, the study underscores the broader applications of terpenes in agriculture.

The Grading System for Lung Adenocarcinoma: Brief Review of its Prognostic Performance and Future Directions.

Histologic grading of tumors is associated with prognosis in many organs. In the lung, the most recent grading system proposed by International association for the Study of Lung Cancer (IASLC) and adopted by the World Health Organization (WHO) incorporates the predominant histologic pattern, as well as the presence of high-grade architectural patterns (solid, micropapillary, and complex glandular pattern) in proportions >20% of the tumor surface. This system has shown improved prognostic ability when compared with the prior grading system based on the predominant pattern alone, across different patient populations. Interobserver agreement is moderate to excellent, depending on the study. IASLC/WHO grading system has been shown to correlate with molecular alterations and PD-L1 expression in tumor cells. Recent studies interrogating gene expression has shown correlation with tumor grade and molecular alterations in the tumor microenvironment that can further stratify risk of recurrence. The use of machine learning algorithms to grade nonmucinous adenocarcinoma under this system has shown accuracy comparable to that of expert pulmonary pathologists. Future directions include evaluation of tumor grade in the context of adjuvant and neoadjuvant therapies, as well as the development of better prognostic indicators for mucinous adenocarcinoma.

Candida parapsilosis: Heterogeneous and strain-specific expression of secreted aspartic proteases (Sapp1 and Sapp2).

The increasing prevalence of Candida parapsilosis as a causative agent of fungal infections underscores the need to comprehensively understand its virulence factors. Secreted aspartic proteases (Saps) play a significant role in adhesion events, promoting biofilm formation, causing tissue damage and evading the host's immune response. In C. parapsilosis, three Saps have been identified: Sapp1, Sapp2 and Sapp3. The present study investigates the production dynamics of Sapp1 and Sapp2 across 10 clinical isolates of C. parapsilosis using various approaches. Each fungal isolate demonstrated the capability to utilize bovine serum albumin (BSA) as the sole nitrogen source, as evidenced by its degradation in a cell-free culture medium, forming low molecular mass polypeptides. Interestingly, the degradation of different proteinaceous substrates, such as BSA, human serum albumin (HSA), gelatin and hemoglobin, was typically isolate-dependent. Notably, higher proteolysis of HSA compared to BSA, gelatin and hemoglobin was observed. A quantitative assay revealed that the cleavage of a peptide fluorogenic substrate (cathepsin D) was isolate-specific, ranging from 44.15 to 270.61 fluorescence arbitrary units (FAU), with a mean proteolysis of 150.7 FAU. The presence of both Sapp1 and Sapp2 antigens on the cell surface of these fungal isolates was confirmed through immunological detection employing specific anti-Sapp1 and anti-Sapp2 antibodies. The surface levels of Sapp1 were consistently higher, up to fourfold, compared to Sapp2. Similarly, higher levels of Sapp1 than Sapp2 were detected in fungal secretions. This study provides insights into the dynamic expression and regulation of Sapps in C. parapsilosis, highlighting a known virulence factor that is considered a potential target for drug development against this increasingly prominent pathogen.

The fungal pathogen Candida parapsilosis can secrete aspartic proteases (Sapps) as part of its arsenal of virulence factors. We demonstrated that Sapps were able to cleave key host proteins, and the production of Sapp1 and Sapp2 antigens was typically dependent on the fungal isolate when grown in both planktonic- and biofilm-forming cells.

Periodontal pathogen Aggregatibacter actinomycetemcomitans JP2 correlates with colonic leukocytes decrease and gut microbiome imbalance in mice.

AIM: Evidence suggests that translocation of oral pathogens through the oral-gut axis may induce intestinal dysbiosis. This study aimed to evaluate the impact of a highly leukotoxic Aggregatibacter actinomycetemcomitans (Aa) strain on the gut microbiota, intestinal mucosal integrity and immune system in healthy mice. METHODS: Eight-week-old male C57BL6 mice were divided into control (n = 16) and JP2 groups (n = 19), which received intragastric gavage with PBS and with a suspension of Aa JP2 (HK921), respectively, twice a week for 4 weeks. Colonic lamina propria, fecal material, serum, gingival tissues, and mandibles were obtained for analyses of leukocyte populations, inflammatory mediators, mucosal integrity, alveolar bone loss, and gut microbiota. Differences between groups for these parameters were examined by non-parametric tests. RESULTS: The gut microbial richness and the number of colonic macrophages, neutrophils, and monocytes were significantly lower in Aa JP2-infected mice than in controls (p < .05). In contrast, infected animals showed higher abundance of Clostridiaceae, Lactobacillus taiwanensis, Helicobacter rodentium, higher levels of IL-6 expression in colonic tissues, and higher splenic MPO activity than controls (p < .05). No differences in tight junction expression, serum endotoxin levels, and colonic inflammatory cytokines were observed between groups. Infected animals presented also slightly more alveolar bone loss and gingival IL-6 levels than controls (p < .05). CONCLUSION: Based on this model, intragastric administration of Aa JP2 is associated with changes in the gut ecosystem of healthy hosts, characterized by less live/recruited myeloid cells, enrichment of the gut microbiota with pathobionts and decrease in commensals. Negligible levels of colonic pro-inflammatory cytokines, and no signs of mucosal barrier disruption were related to these changes.