Bipar

Human milk oligosaccharides (HMOs) are complex sugars in breast milk that protect babies by preventing harmful bacteria from colonizing the gut. Our team extended the study of HMOs beyond the neonatal gut and characterized their antimicrobial activity against group B Streptococcus (GBS), a diplococcus responsible for invasive perinatal infection. To date, the mechanism of action of this antimicrobial activity has remained obscure. To address this key gap, we employed untargeted proteomics, which revealed downregulation of PcsB, an essential murein hydrolase required for cell division. Following successful purification of the active domain of PcsB, we found that this protein domain restores GBS growth in the presence of HMOs, thereby validating PcsB as an HMO protein-interacting partner. In silico docking and molecular dynamics simulations predicted that two fucosylated HMOs, lacto-N-fucopentaose I (LNFPI) and lacto-N-fucopentaose III (LNFPIII), bind to PcsB. In silico predictions were validated using microscale thermophoresis assays, which reported dissociation constants of 5 ± 1 mM for LNFPI and 263 ± 72 μM for LNFPIII. Lastly, to test the hypothesis that HMOs may directly modulate the enzymatic activity of the CHAP domain, we employed a turbidimetric assay with commercial PG as the substrate. This assay provided further evidence that HMOs inhibit CHAP. Together, these data suggest that HMOs inhibit GBS growth by binding PcsB at its catalytic site, disturbing essential cell wall separation and division.

According to the current WHO classification, noninvasive germ cell neoplasia of the testis comprises germ cell neoplasia in situ (GCNIS), specific forms of intratubular germ cell neoplasia, and gonadoblastoma. Because type II germ cell tumors (GCT, type II) arise from GCNIS, accurate detection of precursor lesions is diagnostically important. In preparation for the 2024 International Society of Urological Pathology (ISUP) Consensus Conference on genitourinary precursor lesions, which took place in Florence, Italy, an anonymous survey was distributed to ISUP members to assess current diagnostic practices regarding testicular precursor lesions. The literature and current WHO classification affirm the significance of precursor lesions in testicular tumours. Working Group 4-Precursor Lesions of the Testis-focused on their practical application by individual pathologists rather than establishing consensus from scientific data. There is strong agreement that GCNIS is the preferred and appropriate term for GCT precursor lesions and that its presence should be reported in cases of invasive GCT. Respondents also agree that "seminoma with intratubular nonseminoma" is the appropriate terminology for seminoma with an associated noninvasive nonseminomatous (embryonal carcinoma, yolk sac tumor, trophoblasts, or teratoma) component. Most pathologists prefer to use OCT3/4 as the primary immunohistochemical marker, and a panel was generally not considered necessary. No consensus is reached regarding the requirement for immunohistochemistry to confirm GCT precursor lesions in the testis. Three questions remain open: the value of subtyping intratubular lesions, the immunohistochemical approach to gonadoblastoma, and the criteria distinguishing Sertoli cell nodules from Sertoli cell tumors.

The advent of high-throughput data generation and artificial intelligence has transformed allergy research. Open-access database (OAD) and cohort-based database (CBD) provide essential resources for machine learning (ML)-driven algorithms for risk stratification and decision support. It is crucial for allergologists to understand their construction, strengths, and limitations. We review recently published databases with a focus on how these datasets can be combined to enhance research. OAD, including environmental monitoring resources, omics repositories, and electronic health records, offer scale, diversity, and opportunities for new hypotheses, but are often limited by sparse clinical annotation, heterogeneous data generation, and incomplete linkage to patient-level outcomes. CBD provide well-phenotyped patients, longitudinal follow up, and high-quality clinical and immunological measurements, yet face constraints in sample size, population diversity, and data sharing. Studies integrating OAD breadth with CBD label fidelity report improved predictive performance when paired with disciplined evaluation. Federated learning and portable feature specifications are emerging to enable privacy-preserving collaborations. Allergologists play a central role in building ML-ready resources. By ensuring rigorous clinical annotation, standardization of data, transparent methods, and independent validation, they can maximize the utility of OAD and CBD and their combination to accelerate progress toward precision allergy medicine.

Radiolabelled amino acids offer a broad spectrum of applications in clinical care and pharmaceutical development. Traditional methods of labelling are limited in their availability, requiring specialized equipment and reagents, and in their scope, addressing only select amino acids. We discovered a simple and efficient approach using aldehyde-catalysed carboxylate exchange to 11 C-amino acids. Seeking enrichment of the carbon-11 methodology and the preparation of radiotracers suitable for animal imaging, we explored further optimization and probe development. We detail herein method development, including evaluations of aldehyde catalysts, discovering optimal reaction conditions, and the production of enantiopure radiolabelled amino acids.

Recent zoonotic disease emergences emphasize the importance of studying wildlife parasite communities. As wild hosts frequently harbour diverse parasite species, understanding the drivers of multiple infection patterns in free-ranging hosts is critical for elucidating the ecological and epidemiological dynamics of parasite communities. In this study, we analysed co-infection patterns in European roe deer (Capreolus capreolus) inhabiting a fragmented rural landscape in southwestern France. Using data from 130 samples of GPS-tracked deer, we examined the influence of proximity to livestock, host activity levels, age, sex and between-parasite interactions on the presence of 11 parasitic taxa. Hierarchical modelling of species communities (HMSC) revealed that proximity to livestock significantly increased the likelihood of infection with orofecally transmitted parasites (Toxoplasma gondii, gastrointestinal parasites). Sex and age were other key predictors, with males and juveniles exhibiting a higher frequency of parasite presence, likely influenced by hormonal and immune system differences. Activity levels showed distinct age-related effects, with higher activity levels being positively associated with increased parasite prevalence in yearlings, but not in adults. In contrast, parasite association patterns within individual hosts were weak, suggesting minimal interactions between parasite species. Our findings highlight the interplay between exposure and susceptibility in shaping co-infection patterns and underscore the value of hierarchical modelling approaches in multi-parasite systems.

The cell envelope is an oft-cited factor in the ability of mycobacteria to tolerate antibiotics, host immunity, and environmental stress. In vitro studies have led to a prevailing model in which the mycobacterial envelope exhibits low fluidity that hinders the entry of antibiotics and other stressors. Although fluidity affects essential processes and is dynamically regulated across all domains of life, few studies have measured membrane fluidity in live mycobacteria. To address this gap, we used the environmentally-sensitive probe C-Laurdan to develop an imaging- and flow cytometry-based method for measuring cell envelope fluidity directly in live cells. Our approach enables cell envelope labeling across diverse mycobacterial species, including M. smegmatis and M. tuberculosis . We characterized fluidity as a function of subcellular localization, antibiotic treatment, and genetic perturbation. The unusual growth characteristics of mycobacteria, including polar growth and asymmetric growth and division, contribute to intercellular heterogeneity that is thought to enhance survival under stress. Indeed, we observed that the poles are more fluid than sidewalls, and that the old pole is more fluid than the new pole. Further, daughter cells have unequal membrane fluidity upon division and this asymmetry is reduced in a mutant with decreased asymmetric polar growth. Chemical or genetic disruption of the mycomembrane led to a shared alteration of the fluidity pattern and susceptibility to two antibiotics, suggesting that GP signatures may predict antibiotic susceptibility. This approach expands the toolkit for assessing fluidity in mycobacteria and enables deeper investigation into how biophysical properties influence bacterial physiology and antibiotic susceptibility.

Cancer-associated fibroblasts (CAFs) are part of the tumor microenvironment (TME) that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identified a paracrine mechanism in which CAF-secreted asporin (ASPN) activated ErbB signaling and subsequent migration of adjacent prostate cancer cells. Our data support that ASPN bound directly to the ligand binding domain of human epidermal growth factor 3 (HER3) and induced HER2/HER3 heterodimerization and activation of the PI3K, MAPK, and calcium pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Clinically, ASPN was detected in the stroma of HER2/HER3-expressing human metastatic prostate cancer, supporting the clinical relevance of these findings and highlighting a potential therapeutic vulnerability. Antibody-drug conjugate (ADC) therapies designed to target HER2 (trastuzumab-deruxtecan) or HER3 (patritumab-deruxtecan) significantly diminished prostate cancer cell growth in vitro and tumor size in vivo, despite Aspn in the TME. Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer that expresses HER2 or HER3.

Emotional states like anxiety are adaptive, preparing individuals to respond to (socially-)aversive situations. Adult humans can self-report anxiety, but assessing comparable states in animals requires objective measures. Self-directed behaviors (SDBs)—including self-scratch, autogroom, and yawn—are indicators of anxiety across species, particularly in nonhuman primates. Prevailing hypotheses suggest that social status modulates SDBs, as they offer predictability. Yet, it remains untested how broader social dynamics influence SDBs, given that they influence the quality of life of individuals. We studied 13 macaque groups across six species spanning four social styles (despotic—egalitarian). Our findings revealed partial correlational consistency among the elemental behaviors constituting composite SDB measures, highlighting their differential functions. Age and sex were associated with self-scratch and yawn. Individuals receiving more aggression self-scratched more frequently. While the most despotic species tended to exhibit least amounts of SDBs, within species′ rank effects were non-linear. High-ranking individuals self-scratched less but yawned more, and alpha status was linked to increased yawning. This suggests (un)certainty in social interactions—mediated by individual rank and societal structure—influence anxiety. Thus, SDBs are not byproducts of subordination, instead reflect partially overlapping emotional responses. We provide insights into how social structure and complexity shape the evolution of emotion regulation.