Unravelling lactate-acetate and sugar conversion into butyrate by intestinal Anaerobutyricum and Anaerostipes species by comparative proteogenomics

Thed- andl-forms of lactate are important fermentation metabolites produced by intestinal bacteria but are found to negatively affect mucosal barrier function and human health. Both enantiomers of lactate can be converted with acetate into the presumed beneficial butyrate by a phylogenetically related group of anaerobes, includingAnaerobutyricumandAnaerostipesspp. This is a low energy yielding process with a partially unknown pathway inAnaerobutyricumandAnaerostipesspp. and hence, we sought to address this via a comparative genomics, proteomics and physiology approach. We compared growth ofAnaerobutyricum soehngeniion lactate with that on sucrose and sorbitol. Comparative proteomics revealed complete pathway of butyrate formation from sucrose, sorbitol and lactate. Notably, a gene cluster,lctABCDEFwas abundantly expressed when grown on lactate. This gene cluster encodes a lactate dehydrogenase (lctD), electron transport proteins A and B (lctCB), nickel-dependent racemase (lctE), lactate permease (lctF) and short-chain acyl-CoA dehydrogenase (lctG). Investigation of available genomes of intestinal bacteria revealed this new gene cluster to be highly conserved in onlyAnaerobutyricumandAnaerostipesspp. Present study demonstrates thatA. soehngeniiand several relatedAnaerobutyricumandAnaerostipesspp. are highly adapted for a lifestyle involving lactate plus acetate utilization in the human intestinal tract.Peer reviewe

Stakeholder Expectations of Future Policy Implementation Compared to Formal Policy Trajectories: Scenarios for Agricultural Food Systems in the Mekong Delta

The development of a coherent and coordinated policy for the management of large socio-agricultural systems, such as the Mekong delta in southern Vietnam, is reliant on aligning the development, delivery, and implementation of policy on national to local scales. Effective decision making is linked to a coherent, broadly-shared vision of the strategic management of socio-agricultural systems. However, when policies are ambiguous, and at worst contradictory, long-term management and planning can consequently suffer. These potential adverse impacts may be compounded if stakeholders have divergent visions of the current and future states of socio-agricultural systems. Herein we used a transferable, scenario-based methodology which uses a standard quadrant matrix in order to explore both anticipated and idealized future states. Our case study was the Mekong delta. The scenario matrix was based upon two key strategic choices (axis) for the delta, derived from analysis of policy documents, literature, stakeholder engagement, and land use models. These are: (i) who will run agriculture in the future, agri-business or the established commune system; and (ii) to what degree sustainability will be incorporated into production. During a workshop meeting, stakeholders identified that agri-business will dominate future agricultural production in the delta but showed a clear concern that sustainability might consequently be undermined despite policy claims of the contrary. As such, our study highlights an important gap between national expectations and regional perspectives. Our results suggest that the new development plans for the Mekong delta (which comprise a new Master Plan and a new 5-year socio-economic development plan), which emphasize agro-business development, should adopt approaches that address concerns of sustainability as well as a more streamlined policy formulation and implementation that accounts for stakeholder concerns at both provincial and national levels

A breakthrough dynamic-osmotic membrane bioreactor/nanofiltration hybrid system for real municipal wastewater treatment and reuse.

This study designed a Dynamic-Osmotic membrane bioreactor/nanofiltration (OsMBR/NF) system for municipal wastewater treatment and reuse. Results indicated that a continuously rotating FO module with 60 RPM in Dynamic-OsMBR system could enhance shear stress and reduce cake layer of foulants, leading to higher flux (50%) compared to Traditional-OsMBR during a 40-operation day. A negligible specific reverse salt flux (0.059 G/L) and a water flux of 2.86 LMH were recorded when a mixture of 0.1 M EDTA-2Na/0.1 M Na2CO3/0.9 mM Triton114 functioned as draw solution (DS). It was found that the Dynamic-OsMBR/NF hybrid system could effectively remove pollutants (∼98% COD, ∼99% PO43-P, ∼93% NH4+-N, > 99% suspended solids) from wastewater. In short, this developed system can be considered a breakthrough technology as it successfully minimizes membrane fouling by shear force, and achieves high water quality for reuse by two membrane- barriers

A Multi-Center Randomized Trial to Assess the Efficacy of Gatifloxacin versus Ciprofloxacin for the Treatment of Shigellosis in Vietnamese Children

The bacterial genus Shigella is the most common cause of dysentery (diarrhea containing blood and/or mucus) and the disease is common in developing countries with limitations in sanitation. Children are most at risk of infection and frequently require hospitalization and antimicrobial therapy. The WHO currently recommends the fluoroquinolone, ciprofloxacin, for the treatment of childhood Shigella infections. In recent years there has been a sharp increase in the number of organisms that exhibit resistance to nalidixic acid (an antimicrobial related to ciprofloxacin), corresponding with reduced susceptibility to ciprofloxacin. We hypothesized that infections with Shigella strains that demonstrate resistance to nalidixic acid may prevent effective treatment with ciprofloxacin. We performed a randomized controlled trial to compare 3 day ciprofloxacin therapy with 3 days of gatifloxacin, a newer generation fluoroquinolone with greater activity than ciprofloxacin. We measured treatment failure and time to the cessation of individual disease symptoms in 249 children with dysentery treated with gatifloxacin and 245 treated with ciprofloxacin. We could identify no significant differences in treatment failure between the two groups or in time to the cessation of individual symptoms. We conclude that, in Vietnam, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute dysentery

Oseltamivir Is Adequately Absorbed Following Nasogastric Administration to Adult Patients with Severe H5N1 Influenza

In the absence of a parenteral drug, oral oseltamivir is currently recommended by the WHO for treating H5N1 influenza. Whether oseltamivir absorption is adequate in severe influenza is unknown. We measured the steady state, plasma concentrations of nasogastrically administered oseltamivir 150 mg bid and its active metabolite, oseltamivir carboxylate (OC), in three, mechanically ventilated patients with severe H5N1 (male, 30 yrs; pregnant female, 22 yrs) and severe H3N2 (female, 76 yrs). Treatments were started 6, 7 and 8 days after illness onset, respectively. Both females were sampled while on continuous venovenous haemofiltration. Admission and follow up specimens (trachea, nose, throat, rectum, blood) were tested for RNA viral load by reverse transcriptase PCR. In vitro virus susceptibility to OC was measured by a neuraminidase inhibition assay. Admission creatinine clearances were 66 (male, H5N1), 82 (female, H5N1) and 6 (H3N2) ml/min. Corresponding AUC0–12 values (5932, 10,951 and 34,670 ng.h/ml) and trough OC concentrations (376, 575 and 2730 ng/ml) were higher than previously reported in healthy volunteers; the latter exceeded 545 to 3956 fold the H5N1 IC50 (0.69 ng/ml) isolated from the H5N1 infected female. Two patients with follow-up respiratory specimens cleared their viruses after 5 (H5N1 male) and 5 (H3N2 female) days of oseltamivir. Both female patients died of respiratory failure; the male survived. 150 mg bid of oseltamivir was well absorbed and converted extensively to OC. Virus was cleared in two patients but two patients died, suggesting viral efficacy but poor clinical efficacy

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment