School of Medicine

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia/hypercapnia (IHC), affects predominantly obese individuals, and increases atherosclerosis risk. Since we and others have implicated gut microbiota and metabolites in atherogenesis, we dissected their contributions to OSA-induced atherosclerosis. Atherosclerotic lesions were compared between conventionally-reared specific pathogen free (SPF) and germ-free (GF) Apoe-/- mice following a high fat high cholesterol diet (HFHC), with and without IHC conditions. The fecal microbiota and metabolome were profiled using 16S rRNA gene amplicon sequencing and untargeted tandem mass spectrometry (LC-MS/MS) respectively. Phenotypic data showed that HFHC significantly increased atherosclerosis as compared to regular chow (RC) in both aorta and pulmonary artery (PA) of SPF mice. IHC exacerbated lesions in addition to HFHC. Differential abundance analysis of gut microbiota identified an enrichment of Akkermansiaceae and a depletion of Muribaculaceae (formerly S24-7) family members in the HFHC-IHC group. LC-MS/MS showed a dysregulation of bile acid profiles with taurocholic acid, taurodeoxycholic acid, and 12-ketodeoxycholic acid enriched in the HFHC-IHC group, long-chain N-acyl amides, and phosphatidylcholines. Interestingly, GF Apoe-/- mice markedly reduced atherosclerotic formation relative to SPF Apoe-/- mice in the aorta under HFHC/IHC conditions. In contrast, microbial colonization did not show a significant impact on the atherosclerotic progression in PA. In summary, this research demonstrated that (1) IHC acts cooperatively with HFHC to induce atherosclerosis; (2) gut microbiota modulate atherogenesis, induced by HFHC/IHC, in the aorta not in PA; (3) different analytical methods suggest that a specific imbalance between Akkermansiaceae and Muribaculaceae bacterial families mediate OSA-induced atherosclerosis; and (4) derived bile acids, such as deoxycholic acid and lithocholic acid, regulate atherosclerosis in OSA. The knowledge obtained provides novel insights into the potential therapeutic approaches to prevent and treat OSA-induced atherosclerosis.

Colistin (COL) is a cationic cyclic peptide that disrupts the membranes of Gram-negative bacteria and is often used as a last resort antibiotic against multidrug-resistant strains. The emergence of plasmid-borne mcr genes, which confer transferable COL resistance, has raised serious concerns, particularly in strains also carrying extended-spectrum β-lactamase and carbapenemase genes. Standard antimicrobial susceptibility testing (AST), performed in enriched bacteriological media, indicates no activity of COL against mcr+ strains, leading to its exclusion from treatment regimens. However, these media poorly reflect in vivo physiology and lack host immune components. Here we show that COL retained bactericidal activity against mcr-1+ Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica when tested in tissue culture medium containing physiological bicarbonate. COL enhanced serum complement deposition on bacterial surfaces and synergized with human serum to kill pathogens. At clinically achievable concentrations, COL killed mcr-1+ strains in freshly isolated human blood and was effective as monotherapy in a murine E. coli bacteremia model. These findings suggest that COL, currently dismissed based on conventional AST, may offer clinical benefit against mcr-1+ infections when evaluated under more physiological conditions - warranting reconsideration in clinical microbiology practices and future trials for high-risk patients.

Background

Methods

Findings

Interpretation

Funding

The Tijuana River, at the US-Mexico border, discharges millions of gallons of wastewater daily-sewage, industrial waste, and runoff-into the Pacific Ocean, making it the dominant source of coastal pollution in this region. This study examines how such wastewater influences coastal aerosols by tracking spatial gradients from near the border northward. Using benzoylecgonine (a nonvolatile cocaine metabolite) as a sewage tracer, we find that wastewater compounds-including a mixture of illicit drugs, drug metabolites, and chemicals from tires and personal care products-become aerosolized and are detectable in both water and air. Spatial analyses confirm that most measured chemicals concentrate in aerosols near the Tijuana River, potentially exposing local populations to tens of nanograms per hour (e.g., octinoxate and methamphetamine) via inhalation. This airborne pathway highlights a largely overlooked source of atmospheric pollution, emphasizing the need to reassess health risks in coastal regions as global water contamination continues to escalate.

"South-South" partnerships forged between institutions in resource-constrained settings, usually in low- and middle-income countries, provide innovative frameworks for resource, knowledge, and expertise exchanges to address public health challenges in regions sharing similar contexts. Population-based cancer registries (PBCRs) and surveillance systems in low- and middle-income countries are essential for cancer control, yet they are scarce. In response, the authors formed a South-South Colombian-Mexican partnership to implement the first PBCR in Tijuana, northwestern Mexico, and an integrated pediatric cancer real-time clinical outcomes monitoring system, replicated from Colombia's successful model, VIGICANCER. The newly established team assessed local needs in Mexico, adapted VIGICANCER protocols to the local context, and conducted training. In 2017, BajaREG was inaugurated in Tijuana, and, in 2018, joined the newly launched Mexican National Cancer Registry Network. In 2020, the Pediatric and Adolescent Cancer Registry Surveillance System (PACARSS) was integrated into BajaREG. Between 2018 and 2024, BajaREG registered 8 231 adult and 268 pediatric cases. PACARSS currently collects population-level data on pediatric cancer clinical outcomes in Tijuana. Despite multiple challenges, including the COVID-19 pandemic, stakeholder engagement enabled success. The authors showcase how locally tailored South-South partnerships can capitalize on collaborations and facilitate the implementation of sustainable PBCRs and surveillance systems in regions sharing similar challenges, resources, and health care systems.

Objectives

Methods

Results

Conclusions

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

The genome-scale model of metabolism and gene expression (ME-model) for Pseudomonas putida KT2440, iPpu1676-ME, provides a comprehensive representation of biosynthetic costs and proteome allocation. Compared to a metabolic-only model, iPpu1676-ME significantly expands on gene expression, macromolecular assembly, and cofactor utilization, enabling accurate growth predictions without additional constraints. Multi-omics analysis using RNA sequencing and ribosomal profiling data revealed translational prioritization in P. putida, with core pathways, such as nicotinamide biosynthesis and queuosine metabolism, exhibiting higher translational efficiency, while secondary pathways displayed lower priority. Notably, the ME-model significantly outperformed the M-model in alignment with multi-omics data, thereby validating its predictive capacity. Thus, iPpu1676-ME offers valuable insights into P. putida's proteome allocation and presents a powerful tool for understanding resource allocation in this industrially relevant microorganism.

Surveys of microbial communities (metagenomics) or isolate genomes have revealed sequence-discrete species. That is, members of the same species show >95% Average Nucleotide Identity (ANI) of shared genes among themselves vs. <83% ANI to members of other species while genome pairs showing between 83-95% ANI are comparatively rare. In these surveys, aquatic bacteria of the ubiquitous SAR11 clade (Class Alphaproteobacteria) are an outlier and often do not exhibit discrete species boundaries, suggesting the potential for alternate modes of genetic differentiation. To explore evolution in SAR11, we analyzed high-quality, single-cell amplified genomes (SAGs) and companion metagenomes from an oxygen minimum zone (OMZ) in the Eastern Tropical Pacific Ocean, where the SAR11 make up ~20% of the total microbial community. Our results show that SAR11 do form several sequence-discrete species, but their ANI range of discreteness is shifted to lower identities between 86-91%, with intra-species ANI ranging between 91-100%. Measuring recent gene exchange among these genomes based on a recently developed methodology revealed higher frequency of homologous recombination within compared to between species that affects sequence evolution at least twice as much as diversifying point mutation across the genome. Recombination in SAR11 appears to be more promiscuous compared to other prokaryotic species, likely due to the deletion of universal genes involved in the mismatch repair, and has facilitated the spreading of adaptive mutations within the species (gene sweeps), further promoting the high intra-species diversity observed. Collectively, these results implicate rampant, genome-wide homologous recombination as the mechanism of cohesion for distinct SAR11 species.