Chemically informed analyses of metabolomics mass spectrometry data with Qemistree.

Untargeted mass spectrometry is employed to detect small molecules in complex biospecimens, generating data that are difficult to interpret. We developed Qemistree, a data exploration strategy based on the hierarchical organization of molecular fingerprints predicted from fragmentation spectra. Qemistree allows mass spectrometry data to be represented in the context of sample metadata and chemical ontologies. By expressing molecular relationships as a tree, we can apply ecological tools that are designed to analyze and visualize the relatedness of DNA sequences to metabolomics data. Here we demonstrate the use of tree-guided data exploration tools to compare metabolomics samples across different experimental conditions such as chromatographic shifts. Additionally, we leverage a tree representation to visualize chemical diversity in a heterogeneous collection of samples. The Qemistree software pipeline is freely available to the microbiome and metabolomics communities in the form of a QIIME2 plugin, and a global natural products social molecular networking workflow.

Safety and utility of acute electroconvulsive therapy for agitation and aggression in dementia.

OBJECTIVE: Agitation and aggression are among the most frequent and disruptive behavioral complications of dementia that contribute to increased cost of care, hospitalization, caregiver burden, and risk of premature institutionalization. This current study examined the safety and efficacy of electroconvulsive therapy (ECT) as a treatment for behavioral disturbances in dementia. We hypothesized that ECT would result in reduced agitated and aggressive behaviors between baseline and discharge. METHODS: Twenty-three participants admitted to McLean Hospital (Belmont, MA, USA) and Pine Rest Christian Mental Health Services (Grand Rapids, MI, USA), with a diagnosis of dementia who were referred for ECT to treat agitation and/or aggression, were enrolled in the study. We administered the Cohen-Mansfield Agitation Inventory-Short Form, Neuropsychiatric Inventory-Nursing Home Version, Cornell Scale for Depression in Dementia, and the Clinical Global Impression Scale at baseline, during, and after the ECT course. RESULTS: Regression analyses revealed a significant decrease from baseline to discharge on the Cohen-Mansfield Agitation Inventory (F(4,8) = 13.3; p = 0.006) and Neuropsychiatric Inventory (F(4,31) = 14.6; p < 0.001). There was no statistically significant change in scores on the Cornell Scale for Depression in Dementia. The Clinical Global Impression scores on average changed from a rating of "markedly agitated/aggressive" at baseline to "borderline agitated/aggressive" at discharge. Treatment with ECT was well tolerated by most participants; discontinuation of ECT occurred for two participants because of recurrence of agitation and for three participants because of adverse events. CONCLUSIONS: Electroconvulsive therapy may be a safe treatment option to reduce symptoms of agitation and aggression in patients with dementia whose behaviors are refractory to medication management.

Network Topology Evaluation and Transitive Alignments for Molecular Networking.

Untargeted tandem mass spectrometry (MS/MS) is an essential technique in modern analytical chemistry, providing a comprehensive snapshot of chemical entities in complex samples and identifying unknowns through their fragmentation patterns. This high-throughput approach generates large data sets that can be challenging to interpret. Molecular Networks (MNs) have been developed as a computational tool to aid in the organization and visualization of complex chemical space in untargeted mass spectrometry data, thereby supporting comprehensive data analysis and interpretation. MNs group related compounds with potentially similar structures from MS/MS data by calculating all pairwise MS/MS similarities and filtering these connections to produce a MN. Such networks are instrumental in metabolomics for identifying novel metabolites, elucidating metabolic pathways, and even discovering biomarkers for disease. While MS/MS similarity metrics have been explored in the literature, the influence of network topology approaches on MN construction remains unexplored. This manuscript introduces metrics for evaluating MN construction, benchmarks state-of-the-art approaches, and proposes the Transitive Alignments approach to improve MN construction. The Transitive Alignment technique leverages the MN topology to realign MS/MS spectra of related compounds that differ by multiple structural modifications. Combining this Transitive Alignments approach with pseudoclique finding, a method for identifying highly connected groups of nodes in a network, resulted in more complete and higher-quality molecular families. Finally, we also introduce a targeted network construction technique called induced transitive alignments where we demonstrate effectiveness on a real world natural product discovery application. We release this transitive alignment technique as a high-throughput workflow that can be used by the wider research community.

A secondary metabolite drives intraspecies antagonism in a gut symbiont that is inhibited by cell-wall acetylation.

The mammalian microbiome encodes numerous secondary metabolite biosynthetic gene clusters; yet, their role in microbe-microbe interactions is unclear. Here, we characterized two polyketide synthase gene clusters (fun and pks) in the gut symbiont Limosilactobacillus reuteri. The pks, but not the fun, cluster encodes antimicrobial activity. Forty-one of 51 L. reuteri strains tested are sensitive to Pks products; this finding was independent of strains' host origin. Sensitivity to Pks was also established in intraspecies competition experiments in gnotobiotic mice. Comparative genome analyses between Pks-resistant and -sensitive strains identified an acyltransferase gene (act) unique to Pks-resistant strains. Subsequent cell-wall analysis of wild-type and act mutant strains showed that Act acetylates cell-wall components, providing resistance to Pks-mediated killing. Additionally, pks mutants lost their competitive advantage, while act mutants lost their Pks resistance in in vivo competition assays. These findings provide insight into how closely related gut symbionts can compete and co-exist in the gastrointestinal tract.

Minimum risk of intestinal parasitic infection to the visitors of Ghandruk, Kaski, Nepal: a pilot survey.

Ghandruk is one of the famous destinations of both international and domestic tourists situated in Kaski, Nepal. Travel-related diseases are an important aspect that one should consider before making a travel plan. Among diseases, zoonotically important ones make serious worries among visitors. In order to assess the existence of the zoonotically important parasitic disease in Ghandruk, a pilot survey was carried out by examining representative stool samples (n=51) of local residence, domestic animals, pet animals in Ghandruk. Samples were examined using direct smear as well as concentration methods. A questionnaire survey was conducted to see the associated risk factors among residents and their livestock of Ghandruk. None of the faecal samples from residents (n=14) found positive for any kind of intestinal parasites (IPs), while samples from most of the livestock: chicken (86%, 6/7), pigeons (75%, 3/4), cow (66%, 2/3), mule (60%, 3/5), and dog (60%, 3/5) showed heavy infection, except goat and buffalo indicated no infection. Eimeria spp., Ascardia spp. and cestodes spp. were the most prevalent IPs in livestock. Periodic deworming, walking outdoor with sandals/shoes, frequent use of soap and water for handwashing as reported by most of the residents (>80%) could be the main reason behind zero prevalence of IPs in them. The heavy infection among livestock may be incriminated to the contaminated vicinity and free-range livestock and poultry which were noticed in contact with river, sludge, and toilets during our field observation. Conclusively, it indicates that the residents of Ghandruk are conscious about their health, but have not paid satisfactory attention to the hygiene of their domestic animals including livestock, poultry and even pet. Though the observed parasites in livestock are of minimal zoonotic importance regarding safety of visitors, it is deemed necessary for at least to apply some preventive measures to mitigate the burden of parasites in their animals.

Integrating genomics and metabolomics for scalable non-ribosomal peptide discovery.

Non-Ribosomal Peptides (NRPs) represent a biomedically important class of natural products that include a multitude of antibiotics and other clinically used drugs. NRPs are not directly encoded in the genome but are instead produced by metabolic pathways encoded by biosynthetic gene clusters (BGCs). Since the existing genome mining tools predict many putative NRPs synthesized by a given BGC, it remains unclear which of these putative NRPs are correct and how to identify post-assembly modifications of amino acids in these NRPs in a blind mode, without knowing which modifications exist in the sample. To address this challenge, here we report NRPminer, a modification-tolerant tool for NRP discovery from large (meta)genomic and mass spectrometry datasets. We show that NRPminer is able to identify many NRPs from different environments, including four previously unreported NRP families from soil-associated microbes and NRPs from human microbiota. Furthermore, in this work we demonstrate the anti-parasitic activities and the structure of two of these NRP families using direct bioactivity screening and nuclear magnetic resonance spectrometry, illustrating the power of NRPminer for discovering bioactive NRPs.

Tiny Earth: A Big Idea for STEM Education and Antibiotic Discovery.

The world faces two seemingly unrelated challenges-a shortfall in the STEM workforce and increasing antibiotic resistance among bacterial pathogens. We address these two challenges with Tiny Earth, an undergraduate research course that excites students about science and creates a pipeline for antibiotic discovery.

Omics Technologies to Understand Activation of a Biosynthetic Gene Cluster in Micromonospora sp. WMMB235: Deciphering Keyicin Biosynthesis.

DNA sequencing of a large collection of bacterial genomes reveals a wealth of orphan biosynthetic gene clusters (BGCs) with no identifiable products. BGC silencing, for those orphan clusters that are truly silent, rather than those whose products have simply evaded detection and cluster correlation, is postulated to result from transcriptional inactivation of these clusters under standard laboratory conditions. Here, we employ a multi-omics approach to demonstrate how interspecies interactions modulate the keyicin producing kyc cluster at the transcriptome level in cocultures of kyc-bearing Micromonospora sp. and a Rhodococcus sp. We further correlate coculture dependent changes in keyicin production to changes in transcriptomic and proteomic profiles and show that these changes are attributable to small molecule signaling consistent with a quorum sensing pathway. In piecing together the various elements underlying keyicin production in coculture, this study highlights how omics technologies can expedite future efforts to understand and exploit silent BGCs.

Draft Genome Sequence of Micromonospora sp. Strain WMMA1996, a Marine Sponge-Associated Bacterium.

Micromonospora sp. strain WMMA1996 was isolated in 2013 off the coast of the Florida Keys, United States, from a marine sponge as part of bacterial coculture-based drug discovery initiatives. Analysis of the ∼6.44-Mb genome reveals this microbe's potential role in the discovery of new drugs.

Complete Genome Sequence of Dietzia sp. Strain WMMA184, a Marine Coral-Associated Bacterium.

Dietzia sp. strain WMMA184 was isolated from the marine coral Montastraea faveolata as part of ongoing drug discovery efforts. Analysis of the 4.16-Mb genome provides information regarding interspecies interactions as it pertains to the regulation of secondary metabolism and natural product biosynthesis potential.

Frontal lobe γ-aminobutyric acid levels during adolescence: associations with impulsivity and response inhibition.

BACKGROUND: The brain undergoes major remodeling during adolescence, resulting in improved cognitive control and decision-making and reduced impulsivity, components of behavior mediated in part by the maturing frontal lobe. γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter system, also matures during adolescence, with frontal lobe GABA receptors reaching adult levels late in adolescence. Thus, the objective of this study was to characterize in vivo developmental differences in brain GABA levels. METHODS: Proton magnetic resonance spectroscopy was used at 4 T to acquire metabolite data from the anterior cingulate cortex (ACC) and the parieto-occipital cortex (POC) in adolescents (n=30) and emerging adults (n = 20). RESULTS: ACC GABA/creatine (Cr) levels were significantly lower in adolescents relative to emerging adults, whereas no age differences were observed in the POC. Lower ACC GABA/Cr levels were significantly associated with greater impulsivity and worse response inhibition, with relationships being most pronounced for ACC GABA/Cr and No-Go response inhibition in adolescent males. CONCLUSIONS: These data provide the first human developmental in vivo evidence confirming frontal lobe GABA maturation, which was linked to impulsiveness and cognitive control. These findings suggest that reduced GABA may be an important neurobiological mechanism in the immature adolescent brain, contributing to the reduced yet rapidly developing ability to inhibit risky behaviors and to make suboptimal decisions, which could compromise adolescent health and safety.