Systematic elucidation of independently modulated genes in Lactiplantibacillus plantarum reveals a trade-off between secondary and primary metabolism.

Lactiplantibacillus plantarum is a probiotic bacterium widely used in food and health industries, but its gene regulatory information is limited in existing databases, which impedes the research of its physiology and its applications. To obtain a better understanding of the transcriptional regulatory network of L. plantarum, independent component analysis of its transcriptomes was used to derive 45 sets of independently modulated genes (iModulons). Those iModulons were annotated for associated transcription factors and functional pathways, and active iModulons in response to different growth conditions were identified and characterized in detail. Eventually, the analysis of iModulon activities reveals a trade-off between regulatory activities of secondary and primary metabolism in L. plantarum.

Developing better digital health measures of Parkinson's disease using free living data and a crowdsourced data analysis challenge.

One of the promising opportunities of digital health is its potential to lead to more holistic understandings of diseases by interacting with the daily life of patients and through the collection of large amounts of real-world data. Validating and benchmarking indicators of disease severity in the home setting is difficult, however, given the large number of confounders present in the real world and the challenges in collecting ground truth data in the home. Here we leverage two datasets collected from patients with Parkinson's disease, which couples continuous wrist-worn accelerometer data with frequent symptom reports in the home setting, to develop digital biomarkers of symptom severity. Using these data, we performed a public benchmarking challenge in which participants were asked to build measures of severity across 3 symptoms (on/off medication, dyskinesia, and tremor). 42 teams participated and performance was improved over baseline models for each subchallenge. Additional ensemble modeling across submissions further improved performance, and the top models validated in a subset of patients whose symptoms were observed and rated by trained clinicians.

Circulating microbial content in myeloid malignancy patients is associated with disease subtypes and patient outcomes.

Although recent work has described the microbiome in solid tumors, microbial content in hematological malignancies is not well-characterized. Here we analyze existing deep DNA sequence data from the blood and bone marrow of 1870 patients with myeloid malignancies, along with healthy controls, for bacterial, fungal, and viral content. After strict quality filtering, we find evidence for dysbiosis in disease cases, and distinct microbial signatures among disease subtypes. We also find that microbial content is associated with host gene mutations and with myeloblast cell percentages. In patients with low-risk myelodysplastic syndrome, we provide evidence that Epstein-Barr virus status refines risk stratification into more precise categories than the current standard. Motivated by these observations, we construct machine-learning classifiers that can discriminate among disease subtypes based solely on bacterial content. Our study highlights the association between the circulating microbiome and patient outcome, and its relationship with disease subtype.

Illustrating potential effects of alternate control populations on real-world evidence-based statistical analyses.

OBJECTIVE: Case-control study designs are commonly used in retrospective analyses of real-world evidence (RWE). Due to the increasingly wide availability of RWE, it can be difficult to determine whether findings are robust or the result of testing multiple hypotheses. MATERIALS AND METHODS: We investigate the potential effects of modifying cohort definitions in a case-control association study between depression and type 2 diabetes mellitus. We used a large (>75 million individuals) de-identified administrative claims database to observe the effects of minor changes to the requirements of glucose and hemoglobin A1c tests in the control group. RESULTS: We found that small permutations to the criteria used to define the control population result in significant shifts in both the demographic structure of the identified cohort as well as the odds ratio of association. These differences remain present when testing against age- and sex-matched controls. DISCUSSION: Analyses of RWE need to be carefully designed to avoid issues of multiple testing. Minor changes to control cohorts can lead to significantly different results and have the potential to alter even prospective studies through selection bias. CONCLUSION: We believe this work offers strong support for the need for robust guidelines, best practices, and regulations around the use of observational RWE for clinical or regulatory decision-making.

The protective effect and underlying mechanism of Hainan papaya water extract against neuronal apoptosis induced by Aß40.

OBJECTIVE: To investigate whether Hainan papayas has protective effects in an Aß40-induced primary neuron injury model and elucidate the underlying molecular mechanism. METHODS: Cultured primary neurons from the dorsal root ganglia (DRG) of Sprague-Dawley (SD) rats were treated with 20 µM Aß40 peptide, 100 µg/L Hainan papaya water extract, peptide plus extract, or culture medium for 24 h. Cell viability was measured by MTT assay, and neuronal apoptosis was evaluated by DAPI staining. ERK signaling pathway-associated molecule activation and changes in Bax expression were analyzed by Western blotting and immunofluorescence. RESULTS: A cell viability rate of (44.11 ± 6.59)% in the Aß40 group was rescued to (79.13 ± 6.64)% by adding different concentrations of the extract. DAPI showed pyknotic nuclei in 39.5% of Aß40-treated cells; the fraction dropped to 17.4% in the 100 µg/L extract group. ERK phosphorylation was observed in the Aß40 group but was ameliorated by pretreatment with 100 µg/L extract. Hainan papaya water extract also prevented Aß40-induced phosphorylation of MEK, RSK1 and CREB associated with ERK signaling and downregulated Bax expression in the neurons. CONCLUSION: The results suggest that Hainan papaya water extract has protective effects on neurons; the mechanism may be related to suppression of ERK signaling activation.