Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin.

Colibactin is an as-yet-uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.

MicroRNA-21 in glomerular injury.

TGF-ß(1) is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA-21 (miR-21) is regulated by TGF-ß(1), and miR-21 inhibits apoptosis in cancer cells. TGF-ß(1)-transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-ß(1) and is higher in kidneys of TGF-ß(1)-transgenic mice than wild-type mice. miR-21-deficient TGF-ß(1)-transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-ß(1)-transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-ß/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin-to-creatinine ratio was positively associated with miR-21 expression in glomerular fractions (r=0.6; P<0.001) but not tubulointerstitial fractions (P=0.80). These findings suggest that miR-21 ameliorates TGF-ß(1) and hyperglycemia-induced glomerular injury through repression of proapoptotic signals, thereby inhibiting podocyte loss. This finding is in contrast to observations in murine models of tubulointerstitial kidney injury but consistent with findings in cancer models. The aggravation of glomerular disease in miR-21-deficient mice and the positive association with albumin-to-creatinine ratio in patients with diabetic nephropathy support miR-21 as a feedback inhibitor of TGF-ß signaling and functions.

Critical Intermediates Reveal New Biosynthetic Events in the Enigmatic Colibactin Pathway.

Colibactin is a potent genotoxin that induces DNA double-strand breaks; it is produced by Escherichia coli strains harboring a pks+ island. However, the structure of this compound remains elusive. Here, using transformation-associated recombination (TAR) cloning to perform heterologous expression, we took advantage of the significantly increased yield of colibactin pathway-related compounds to determine and isolate a series of vital (pre)colibactin intermediates. The chemical structures of compounds 8, 10 and 11 were identified by NMR and MS(n) analyses. The new 1H-pyrrolo[3,4-c]pyridine-3,6(2H,5H)-dione- and thiazole-containing compound 10 provides new insights regarding the biosynthetic pathway to (pre)colibactin and establishes foundations for future investigation of the intriguing (pre)colibactin structures and its modes of action.

The influence of physicians on colorectal cancer screening behavior.

BACKGROUND: Our aims were to determine clinical factors associated with colorectal cancer (CRC) screening and to evaluate the relative role of patient contact with physicians and the quality of these patient-physician interactions in affecting screening. METHODS: Screening-eligible patients were identified from the Health Information National Trends Survey. Determinants of CRC screening were assessed with logistic regression, and a joint effects model that considered the frequency and quality of contact with physicians was developed to explore their influence on screening. RESULTS: There were 4,615 respondents of whom only 66% reported receiving CRC screening. Older age, personal history of non-CRC, family history of any cancer, high-income earners, individuals who visited their physicians ≥5 times per year, and those who rated the interactions with their physicians highly were more likely to be screened (all p < 0.05). The joint effects model revealed that quality rather than frequency of physician contact was a stronger predictor of CRC screening, but the odds of screening was highest for those who experienced both frequent and high-quality interactions with their physicians. CONCLUSIONS: Contact with physicians and the quality of this interaction are associated with screening behavior. Interventions to improve these provider-related factors may promote CRC screening.

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention.

Changing experiences of work dirtiness, occupational disidentification, and employee withdrawal.

Research and theory concerning "dirty work" has largely focused on how employees cope with stable features of their jobs. From a study of employees' experiences across 6 weekly repeated measurements, we found that within-person increases in experienced dirtiness were positively related to their withdrawal behaviors and job change propensity indirectly through occupational disidentification. Assessed at the between-subjects level, team-oriented leadership moderated the indirect within-person effects of work dirtiness experiences on these outcomes. The relationships between elevations in experienced work dirtiness and occupational disidentification were more strongly positive at lower levels of team-oriented leadership. Analyses also showed that individuals' perceptions of occupational stigma independently moderated the within-person relationship between experienced dirtiness and occupational disidentification. We discuss theoretical implications for the literature on dirty work and practical implications for mitigating the adverse outcomes associated with experienced work dirtiness. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy.

It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication. Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression. Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-ß1 (TGF- ß1) or high glucose. Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Cluster microRNAs and lnc-MGC are decreased in diabetic Chop-/- mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Relevance to human DN is also demonstrated. These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression.

Association between renal function and cognitive ability domains in the Einstein aging study: a cross-sectional analysis.

BACKGROUND: The relationships between renal function and specific domains of cognitive function have rarely been explored in representative, community-based samples of older adults. We assessed the association between renal and cognitive function based on an extensive battery of neurocognitive tests. METHODS: In a sample of Einstein Aging Study participants (n = 649, age = 70+ years) we calculated estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration formula. We predefined three groups based on eGFR units of mL/min/1.73 m(2) as low (<45), medium (45-59), and high (≥60). Thirteen neurocognitive tests were subjected to principle component analysis revealing three components: a global component, an episodic memory component, and a frontal-executive component. We first examined the relationship of eGFR group to cognitive performance in each domain and then examined subtests for the domains which proved to be statistically significant. RESULTS: The sample (mean = 79.2, 61% = female) was distributed among eGFR categories as follows: low (n = 67), medium (n = 151), and high (n = 431). The frontal-executive domain was significantly associated with poor cognitive performance in the low eGFR group (p <.001). When we examined the neuropsychological test components for frontal-executive domain, performance was lower on two of four contributing tests (Trail Making Test Part B and the Digit Symbol Substitution test). Other domains of cognitive function were not associated with eGFR. CONCLUSIONS: Low eGFR is associated with reduced performance on executive function. Individuals with poor renal function should be assessed for cognitive impairment. Potential mechanisms are discussed.

Draft Genome Sequences of Three Escherichia coli Strains Investigated for the Effects of Lysogeny on Niche Diversification.

During the course of investigating the effects of lysogeny on niche diversification of Escherichia coli, we used the temperate phages induced from one E. coli strain to infect another and created an isogenic lysogen of the latter. The draft genome sequences of the three E. coli strains are reported herein.

Draft Genome Sequence of Escherichia coli E1728 Isolated from Marine Sediment in Hong Kong.

Recent findings of Escherichia coli persisting autochthonously in environmental matrices outside animal bodies have revealed largely unknown facets of the lifestyle and ecophysiology of the species that have yet to be explored. Here, we report the draft genome sequence of E. coli E1728 isolated from marine sediment.

Factors influencing the willingness of US women to vaccinate their daughters against the human papillomavirus to prevent cervical cancer.

The human papillomavirus (HPV) vaccine helps to prevent cervical cancer. However, research indicates that public acceptance of the vaccine is suboptimal. Our aims were to evaluate the willingness of US women to use the HPV vaccine in their daughters, examine their current understanding of HPV, and determine the impact of HPV knowledge and other socio-demographic factors on their willingness to get their daughters vaccinated. Women aged ≥ 18 years were identified from the US Health Information National Trends Survey. We developed a 6-point composite scoring system based on individual responses to HPV-related questions to characterize personal understanding about HPV. Logistic regression models were constructed to explore the influence of the women's HPV knowledge level and additional socio-demographic factors on the willingness to use HPV in their daughters. There were 804 female respondents: mean age was 44.9 (SD = 2.53) years and 73 % were White. In total, 75 % of women indicated they would vaccinate their daughters against HPV. Mean knowledge score was 4.6 (SD = 0.80). While White race was associated with higher willingness to use the vaccine in their daughters (OR = 1.86, p = 0.04), HPV knowledge level was not (OR = 0.47, p = 0.22). Among US women, HPV knowledge level was high, but it was not associated with the willingness to vaccinate their daughters against HPV. Interventions focused on alleviating racial disparities might better modify the use of the HPV vaccine.

Transforming growth factor-ß-induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy.

Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However, the mechanisms are unclear. We report that expression levels of transforming growth factor-ß1 (TGF-ß), p53, and microRNA-192 (miR-192) are increased in the renal cortex of diabetic mice, and this is associated with enhanced glomerular expansion and fibrosis relative to nondiabetic mice. Targeting miR-192 with locked nucleic acid-modified inhibitors in vivo decreases expression of p53 in the renal cortex of control and streptozotocin-injected diabetic mice. Furthermore, mice with genetic deletion of miR-192 in vivo display attenuated renal cortical TGF-ß and p53 expression when made diabetic, and have reduced renal fibrosis, hypertrophy, proteinuria, and albuminuria relative to diabetic wild-type mice. In vitro promoter regulation studies show that TGF-ß induces reciprocal activation of miR-192 and p53, via the miR-192 target Zeb2, leading to augmentation of downstream events related to DN. Inverse correlation between miR-192 and Zeb2 was observed in glomeruli of human subjects with early DN, consistent with the mechanism seen in mice. Our results demonstrate for the first time a TGF-ß-induced feedback amplification circuit between p53 and miR-192 related to the pathogenesis of DN, and that miR-192-knockout mice are protected from key features of DN.