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There is extensive evidence implicating the intestinal microbiota in inflammatory bowel disease [IBD], but no microbial agent has been identified as a sole causative agent. Bacteroidales are numerically dominant intestinal organisms that associate with the mucosal surface and have properties that both positively and negatively affect the host. To determine precise numbers and species of Bacteroidales adherent to the mucosal surface in IBD patients, we performed a comprehensive culture based analysis of intestinal biopsies from pediatric Crohn's disease [CD], ulcerative colitis [UC], and control subjects. We obtained biopsies from 94 patients and used multiplex PCR or 16S rDNA sequencing of Bacteroidales isolates for species identification. Eighteen different Bacteroidales species were identified in the study group, with up to ten different species per biopsy, a number higher than demonstrated using 16S rRNA gene sequencing methods. Species diversity was decreased in IBD compared to controls and with increasingly inflamed tissue. There were significant differences in predominant Bacteroidales species between biopsies from the three groups and from inflamed and uninflamed sites. Parabacteroides distasonis significantly decreased in inflamed tissue. All 373 Bacteroidales isolates collected in this study grew with mucin as the only utilizable carbon source suggesting this is a non-pathogenic feature of this bacterial order. Bacteroides fragilis isolates with the enterotoxin gene [bft], previously associated with flares of colitis, were not found more often at inflamed colonic sites or within IBD subjects. B. fragilis isolates with the ability to synthesize the immunomodulatory polysaccharide A [PSA], previously shown to be protective in murine models of colitis, were not detected more often from healthy versus inflamed tissue.

Adult studies suggest antibodies to infliximab (ATI) correlate with loss of response in inflammatory bowel disease but pediatric data are limited.MethodsWe conducted a cross-sectional study of trough infliximab levels and ATI in 134 pediatric and young adult patients receiving infliximab. At the time serum was obtained demographics, disease phenotype, duration of infliximab therapy, use of combination therapy (methotrexate or 6-mercaptopurine with infliximab), and surgery were recorded.ResultsAssays were performed on 134 subjects currently receiving infliximab (85 male; mean age, 17.3 ± 4.3 years; 114 Crohn's disease and 20 ulcerative colitis). Infliximab use ranged from 12 days to 12 years: median 2.0 (interquartile range [1.1–4.3]) years. Twenty-seven of 134 (20%) patients had ATI ≥5 U/mL. Of patients with ATI ≥5 U/mL, 59% had infliximab levels <5 μg/mL, compared with 14% of patients with ATI <5 U/mL (P < 0.001). Ten (7%) patients (9 Crohn's disease, 1 ulcerative colitis) underwent bowel resections after beginning infliximab infusions. Sixty percent who underwent surgery had ATI ≥12 U/mL; in contrast, only 8% of patients who did not undergo surgery had ATI ≥12 U/mL (P = 0.01). At the time of serum sampling, 50 (37%) patients were receiving combination therapy, compared with 84 (63%) on infliximab alone. Combination therapy at the time of serum sampling did not correlate with either increase infliximab levels or lower ATI compared with infliximab monotherapy. However, prior immunomodulator use was associated with lower antibody levels (P = 0.007).ConclusionsATI correlates with reduction in infliximab level and a higher risk of surgery in patients with inflammatory bowel disease.

There is extensive evidence implicating the intestinal microbiota in inflammatory bowel disease [IBD], but no microbial agent has been identified as a sole causative agent. Bacteroidales are numerically dominant intestinal organisms that associate with the mucosal surface and have properties that both positively and negatively affect the host. To determine precise numbers and species of Bacteroidales adherent to the mucosal surface in IBD patients, we performed a comprehensive culture based analysis of intestinal biopsies from pediatric Crohn's disease [CD], ulcerative colitis [UC], and control subjects. We obtained biopsies from 94 patients and used multiplex PCR or 16S rDNA sequencing of Bacteroidales isolates for species identification. Eighteen different Bacteroidales species were identified in the study group, with up to ten different species per biopsy, a number higher than demonstrated using 16S rRNA gene sequencing methods. Species diversity was decreased in IBD compared to controls and with increasingly inflamed tissue. There were significant differences in predominant Bacteroidales species between biopsies from the three groups and from inflamed and uninflamed sites. Parabacteroides distasonis significantly decreased in inflamed tissue. All 373 Bacteroidales isolates collected in this study grew with mucin as the only utilizable carbon source suggesting this is a non-pathogenic feature of this bacterial order. Bacteroides fragilis isolates with the enterotoxin gene [bft], previously associated with flares of colitis, were not found more often at inflamed colonic sites or within IBD subjects. B. fragilis isolates with the ability to synthesize the immunomodulatory polysaccharide A [PSA], previously shown to be protective in murine models of colitis, were not detected more often from healthy versus inflamed tissue.

Admixed populations are routinely excluded from genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulated and empirical two-way admixed African–European cohorts. Tractor generates accurate ancestry-specific effect-size estimates and P  values, can boost genome-wide association study (GWAS) power and improves the resolution of association signals. Using a local ancestry-aware regression model, we replicate known hits for blood lipids, discover novel hits missed by standard GWAS and localize signals closer to putative causal variants. Tractor is a statistical framework that facilitates the inclusion of admixed individuals in association studies by leveraging local ancestry. Tractor generates accurate ancestry-specific effect-size estimates and improves the resolution of association signals.

Feldspar minerals are shown to dominate ice nucleation by mineral dust in clouds containing both liquid water and ice particles, despite feldspar being a minor component of the dust believed to be the main source of ice nuclei. Feldspar prompts ice formation in clouds Mineral dust aerosols arising in arid regions trigger ice formation in supercooled clouds, which can influence cloud radiative properties and therefore climate. It is thought that clay minerals, the major component of these dusts, are also the most potent ice-nucleating particles. But Ben Murray and colleagues show here that feldspar minerals dominate ice nucleation by mineral dust, despite being a minor dust component. They also suggest that feldspar particles may account for a large proportion of ice nuclei in the Earth's atmosphere at certain temperatures, and as feldspar content can vary, changes in the location of dust sources may alter the concentration of ice nuclei in the atmosphere and the associated climate effects. The amount of ice present in mixed-phase clouds, which contain both supercooled liquid water droplets and ice particles, affects cloud extent, lifetime, particle size and radiative properties 1 , 2 . The freezing of cloud droplets can be catalysed by the presence of aerosol particles known as ice nuclei 2 . One of the most important ice nuclei is thought to be mineral dust aerosol from arid regions 2 , 3 . It is generally assumed that clay minerals, which contribute approximately two-thirds of the dust mass, dominate ice nucleation by mineral dust, and many experimental studies have therefore focused on these materials 1 , 2 , 4 , 5 , 6 . Here we use an established droplet-freezing technique 4 , 7 to show that feldspar minerals dominate ice nucleation by mineral dusts under mixed-phase cloud conditions, despite feldspar being a minor component of dust emitted from arid regions. We also find that clay minerals are relatively unimportant ice nuclei. Our results from a global aerosol model study suggest that feldspar ice nuclei are globally distributed and that feldspar particles may account for a large proportion of the ice nuclei in Earth’s atmosphere that contribute to freezing at temperatures below about −15 °C.

Inhibitors of the PAD4 enzyme that bind the inactive enzyme link this protein deiminase and the resultant arginine-to-citrulline modification to formation of neutrophil extracellular traps, highly decondensed chromatin structures with both host-defense and pathological roles. PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.

Recent global policy developments have highlighted the need for straightforward, robust, and meaningful biodiversity metrics. However, much of conservation science is dominated by the use of a single metric, species richness, despite several known limitations. Here, we review and synthesize why species richness (i.e., the number of species in a local area) is a poor metric for a variety of topical‐ and policy‐relevant conservation problems. We identify the following three key issues: (1) increasing evidence emphasizes that species richness is often not a robust metric for identifying biodiversity change, (2) species richness ignores species identity and so may often not reflect impacts on species of concern, and (3) species richness does not provide information needed on the persistence of biodiversity or the provision of ecosystem services. We highlight the unappreciated practical outcomes of these limitations with examples from three ongoing conservation debates: whether local biodiversity is declining, how habitat fragmentation affects biodiversity, and the extent to which land sharing or sparing is more beneficial for biodiversity conservation. To address these limitations, we offer a set of guidelines for the use of biodiversity metrics in conservation policy and practice.

Single-cell RNA sequencing (scRNASeq) has advanced our understanding of lung biology, but its utility is limited by the need for fresh samples, loss of cell types by death or inadequate dissociation, and transcriptional stress responses induced during tissue digestion. Single-nucleus RNA sequencing (snRNASeq) has addressed these deficiencies in other tissues, but no protocol exists for lung tissue. We present a snRNASeq protocol and compare its results with those of scRNASeq. Two nuclear suspensions were prepared in lysis buffer on ice while one cell suspension was generated using enzymatic and mechanical dissociation. Cells and nuclei were processed using the 10× Genomics platform, and sequencing data were analyzed by Seurat. A total of 16,110 single-nucleus and 11,934 single-cell transcriptomes were generated. Gene detection rates were equivalent in snRNASeq and scRNASeq (∼1,700 genes and 3,000 unique molecular identifiers per cell) when mapping intronic and exonic reads. In the combined data, 89% of epithelial cells were identified by snRNASeq versus 22.2% of immune cells. snRNASeq transcriptomes are enriched for transcription factors and signaling proteins, with reduction in mitochondrial and stress-response genes. Both techniques improved mesenchymal cell detection over previous studies. Homeostatic signaling relationships among alveolar cell types were defined by receptor–ligand mapping using snRNASeq data, revealing interplay among epithelial, mesenchymal, and capillary endothelial cells. snRNASeq can be applied to archival murine lung samples, improves dissociation bias, eliminates artifactual gene expression, and provides similar gene detection compared with scRNASeq.

Antimicrobial peptides (AMPs) are a potential source of new molecules to counter the increase in antimicrobial resistant infections but a better understanding of their properties is required to understand their native function and for effective translation as therapeutics. Details of the mechanism of their interaction with the bacterial plasma membrane are desired since damage or penetration of this structure is considered essential for AMPs activity. Relatively modest modifications to AMPs primary sequence can induce substantial changes in potency and/or spectrum of activity but, hitherto, have not been predicted to substantially alter the mechanism of interaction with the bacterial plasma membrane. Here we use a combination of molecular dynamics simulations, circular dichroism, solid-state NMR and patch clamp to investigate the extent to which temporin B and its analogues can be distinguished both in vitro and in silico on the basis of their interactions with model membranes. Enhancing the hydrophobicity of the N-terminus and cationicity of the C-terminus in temporin B improves its membrane activity and potency against both Gram-negative and Gram-positive bacteria. In contrast, enhancing the cationicity of the N-terminus abrogates its ability to trigger channel conductance and renders it ineffective against Gram-positive bacteria while nevertheless enhancing its potency against Escherichia coli . Our findings suggest even closely related AMPs may target the same bacterium with fundamentally differing mechanisms of action.

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N  = 857) and CART era (2000–2007; N  = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.