Prebiotic effect of poly-D-3-hydroxybutyrate prevents dyslipidemia in obese mice.

Obesity is a global health problem caused by genetic, environmental, and psychological factors and is associated with various health disorders. As such, there is a growing focus on the prevention of obesity and related diseases. The gut microbiota plays a crucial role in these diseases and has become a therapeutic target. Prebiotics, such as poly-d-3-hydroxybutyric acid (PHB), have gained attention for their potential to alter the gut microbiota, promote beneficial bacterial growth, and alleviate obesity. In this study, we examined the prebiotic effects of PHB in obese mice. We found that, in C57BL/6N mice, PHB reduced blood lipid levels. Analysis of the intestinal microflora also revealed an increase in short-chain fatty acid-producing bacteria. When PHB was administered to obese mice, subcutaneous fat and dyslipidemia were reduced, and the number of beneficial bacteria in the intestinal microflora increased. Furthermore, fatty degradation and oxidative stress were suppressed in the liver. PHB regulates gut bacterial changes related to obesity and effectively inhibits dyslipidemia, suggesting that it could be a prebiotic agent for curing various obesity-related diseases. In summary, PHB increases the beneficial gut microbiota, leading to an alleviation of obesity-associated dyslipidemia.

Pilot evaluation of a single oral fecal microbiota transplantation for canine atopic dermatitis.

The gut microbiota has been suggested to be involved in the pathogenesis of canine atopic dermatitis (cAD). However, the gut microbiota has not been well characterized in dogs with atopic dermatitis (AD). In addition, the efficacy of fecal microbiota transplantation (FMT) in dogs with AD remains unclear. This research, therefore, aimed to characterize the gut microbiota of dogs with AD and conduct pilot evaluation of the efficacy of a single oral FMT on clinical signs and the gut microbiota of dogs with AD. For these purposes, we used 12 dogs with AD and 20 healthy dogs. The 16S rRNA analysis of the fecal microbiota revealed significant differences between 12 dogs with AD and 20 healthy dogs. Next, a single oral FMT was performed in 12 dogs with AD as a single-arm, open-label clinical trial for 56 days. A single oral FMT significantly decreased Canine Atopic Dermatitis Extent and Severity Index (CADESI)-04 scores from day 0 (median score, 16.5) to day 56 (8) and Pruritus Visual Analog Scale (PVAS) scores from days 0 (median score, 3) to day 56 (1). Furthermore, a single oral FMT changed the composition of the fecal microbiota of dogs with AD at the phylum and genus levels. The number of common amplicon sequence variants in the fecal microbiota between donor dogs and dogs with AD was positively correlated with CADESI-04 and PVAS reduction ratios 56 days after FMT. Our findings suggest that the gut microbiota plays a pivotal role in the pathogenesis of cAD, and that oral FMT could be a new therapeutic approach targeting the gut microbiota in cAD.

Superlattice-Induced Variations in Morphological and Emission Properties of GaInN/GaN Multiquantum Nanowire-Based Micro-LEDs.

Core-shell GaInN/GaN multiquantum shell (MQS) nanowires (NWs) are gaining great attention for high-efficiency micro-light-emitting diodes (micro-LEDs) owing to the minimized etching region on their sidewall, nonpolar or semipolar emission planes, and ultralow density of dislocations. In this study, we evaluated the changes in NW morphologies and the corresponding device properties induced by GaInN/GaN superlattice (SL) structures. The cathodoluminescence intensities of the samples with 20 and 40 pairs of SLs were about 2.2 and 3.4 times higher, respectively, than that of the sample without SLs. The high-resolution scanning transmission electron microscopy (STEM) inspection confirmed that the high growth temperature of SLs prevented growth in the semipolar plane region close to the n-GaN core. A similar phenomenon was also observed for the GaN quantum barriers of the semipolar MQS region under a high growth temperature of 810 °C. This phenomenon was ascribed to the passivation of the semipolar plane surface by hydrogen atoms and the high probability of decomposition through NH3 or N-H-related bonds. Although no clear SL grew on the semipolar plane near the n-core region, the top area of the nonpolar plane SL was expected to adequately suppress the point defects propagating from the n-GaN core to the semipolar plane MQS. The electroluminescence (EL) spectra and light output curves demonstrated a clear enhancement of more than 3-folds compared to the fabricated micro-LEDs without SL structures, which was associated with the improved crystalline quality of the MQS and enlarged area of the semipolar planes. Moreover, by increasing the growth time of GaN quantum barriers, the EL emission intensity of the micro-LED devices exhibited a 4-fold improvement owing to the reduced carrier overflow in the thickened GaN barriers on the semipolar (11̅01) planes. Thus, the results verified the possibility of realizing highly efficient NW-based micro-LEDs by optimizing the NW morphology using SL structures.

A new detection method for canine and feline cancer using the olfactory system of nematodes.

Cancer is the leading cause of death in dogs and cats. Early diagnosis of cancer is critical for effective treatment and improving survival rates. Nematode-NOSE (N-NOSE) is a commercially available non-invasive human cancer screening test that uses the sense of smell of the nematode Caenorhabditis elegans showing a distinct chemotactic response toward the urine of an individual with cancer compared to healthy ones. 15 types of human cancer (stomach, colon-rectum, lung, breast, pancreas, liver, prostate, uterus, esophagus, gallbladder, bile duct, kidney, urinary bladder, ovary, and oropharynx cancers) can be detected by N-NOSE. A non-invasive method for accurate cancer screening is needed for pets. In this study, we evaluated the effectiveness of N-NOSE in detecting cancer using canine and feline urine samples. We found a significant difference in chemotaxis index values between healthy subjects and cancer patients in both canine (p < 0.01*) and feline (p < 0.04*) urine samples. Receiver operating characteristic (ROC) analysis highlights the good performance of the test with areas under the curve (AUC) of 0.8114 and 0.7851 for dogs and 0.7667 and 0.9000 for cats when using 2 different dilutions of urine samples. Our study suggests that N-NOSE has the potential as a simple, accurate, and low-cost cancer screening test in both dogs and cats.

Screening of bacterial DNA in bile sampled from healthy dogs and dogs suffering from liver- or gallbladder-associated disease.

Although the biliary system is generally aseptic, gallbladder microbiota has been reported in humans and some animals apart from dogs. We screened and analyzed the bacterial deoxyribonucleic acid in canine gallbladders using bile sampled from 7 healthy dogs and 52 dogs with liver- or gallbladder-associated disease. PCR screening detected bacteria in 17.3% of diseased dogs (9/52) and none in healthy dogs. Microbiota analysis of PCR-positive samples showed that the microbial diversity differed between liver- and gallbladder-associated disease groups. Thus, a specific bacterial community appears to occur at a certain frequency in the bile of diseased dogs.

Comparison of Intestinal Microbiota Between Healthy and MMVD Chihuahuas Using 16S rRNA Gene Amplicon Sequencing.

Myxomatous mitral valve disease (MMVD) is the most common cause of congestive heart failure in dogs, and although complications of MMVD to the lungs and kidneys have been identified, complications to the gut are less well understood. The intestinal microbiota is an important factor in the gut, and although the association between heart disease and the intestinal microbiota has been shown in human medicine, it is unknown in dogs. The study aimed to evaluate the relationship between MMVD and gut microbiota. A total of 69 healthy Chihuahuas and Chihuahuas with MMVD were evaluated for cardiac health by echocardiography and chest radiography and grouped according to ACVIM guidelines. Fecal samples were collected from all cases and 16S rRNA sequencing was used to reveal the intestinal microbiota. There were significant differences in LA/Ao, LVIDd, E vel, VHS, and VLAS with the severity of ACVIM. On the other hand, there were no significant differences in the diversity and composition of gut microbiota among the groups. The present study did not identify the effects of MMVD on the gut microbiota.

Global population structure of the Serratia marcescens complex and identification of hospital-adapted lineages in the complex.

Serratia marcescens is an important nosocomial pathogen causing various opportunistic infections, such as urinary tract infections, bacteremia and sometimes even hospital outbreaks. The recent emergence and spread of multidrug-resistant (MDR) strains further pose serious threats to global public health. This bacterium is also ubiquitously found in natural environments, but the genomic differences between clinical and environmental isolates are not clear, including those between S. marcescens and its close relatives. In this study, we performed a large-scale genome analysis of S. marcescens and closely related species (referred to as the 'S. marcescens complex'), including more than 200 clinical and environmental strains newly sequenced here. Our analysis revealed their phylogenetic relationships and complex global population structure, comprising 14 clades, which were defined based on whole-genome average nucleotide identity. Clades 10, 11, 12 and 13 corresponded to S. nematodiphila, S. marcescens sensu stricto, S. ureilytica and S. surfactantfaciens, respectively. Several clades exhibited distinct genome sizes and GC contents and a negative correlation of these genomic parameters was observed in each clade, which was associated with the acquisition of mobile genetic elements (MGEs), but different types of MGEs, plasmids or prophages (and other integrative elements), were found to contribute to the generation of these genomic variations. Importantly, clades 1 and 2 mostly comprised clinical or hospital environment isolates and accumulated a wide range of antimicrobial resistance genes, including various extended-spectrum ß-lactamase and carbapenemase genes, and fluoroquinolone target site mutations, leading to a high proportion of MDR strains. This finding suggests that clades 1 and 2 represent hospital-adapted lineages in the S. marcescens complex although their potential virulence is currently unknown. These data provide an important genomic basis for reconsidering the classification of this group of bacteria and reveal novel insights into their evolution, biology and differential importance in clinical settings.

Successful outcome after a single endoscopic fecal microbiota transplantation in a Shiba dog with non-responsive enteropathy during the treatment with chlorambucil.

A 7-year 6-month-old, castrated male Shiba dog presented with a 1-month history of lethargy, anorexia, vomiting, and frequent watery diarrhea. Weight loss, hypoalbuminemia, anemia, and leukocytosis were detected at the first visit. The dog was diagnosed with non-responsive enteropathy (NRE) based on clinical and histopathological examinations. Since the dog did not respond to the immunosuppressive drugs, fecal microbiota transplantation (FMT) was performed during the treatment with chlorambucil. A single endoscopic FMT into the cecum and colon drastically recovered clinical signs and clinicopathological abnormalities and corrected dysbiosis in the dog. No recurrence or adverse events were observed. The present case report suggests that FMT, possibly together with chlorambucil, might be a treatment option for NRE in Shiba dogs that have poorer prognosis compared with other dog breeds.

Tratamiento ayurveda (Virechana y Basti) y cambios de la microbiota intestinal a nivel de Phylum y especie / Ayurveda Treatment (Virechana and Basti) and Changes of Intestinal Microbiota at Phyla and Species Level

Introducción: Se han analizado terapias ayurvédicas y prácticas médicas para un grupo de pacientes en Japón. La característica del tratamiento ayurvédico es una desintoxicación con una gran cantidad de tratamiento con aceite mediante un masaje con aceite en la superficie del cuerpo y una terapia de purificación con ghee o aceite de hierbas especialmente preparado. Los cambios de la microbiota intestinal durante estos tratamientos no han sido bien estudiados. Mé- LA PRENSA MÉDICA ARGENTINA Ayurveda Treatment (Virechana and Basti) and Changes of Intestinal Microbiota at Phyla and Species Level 79 V.107/Nº 2 todo: Los participantes fueron reclutados de la Clínica Hatai Ayurveda en Tokio. La terapia de Virechana, una terapia de purificación o la terapia de Basti (decocción y enema de aceite) se llevó a cabo en 13 pacientes con diversas manifestaciones. Todos los participantes proporcionaron el detalle de su estilo de vida, hábitos dietéticos, enfermedades pasadas y presentes mediante el cuestionario, y se registró la condición precisa durante la admisión al final del campamento. Se tomaron muestras fecales a la entrada, durante el tratamiento, al alta y tres semanas después para analizar la microbiota intestinal por el gen seqyebcubg 16srRNA. Resultados: el peso corporal disminuyó aproximadamente un 5% con la terapia de Virechana, mientras que no ocurrió con Basti, pero la grasa corporal aumentó un 4% (2,2 kg) en promedio en ambos grupos. Varias manifestaciones clínicas de los participantes mejoraron, especialmente en una erupción cutánea y un cambio atópico. El paciente deprimido también remitió mejoras en sus ganas de vivir. En su mayoría son vegetarianos y tenían más Bacteroides (48.09 ± 7.51%), Firmicutes (38.27 ± 10.82%) y Actinobacteria (3.30 ± 3.58%) que los omnívoros que tenían más Proteobacteria (10.73 ± 4.75%), Fusobacteria (2.40 ± 6.25%) y cianobacterias (0,09 ± 0,24%). Cuando los grupos se dividieron por el consumo de aceite, los usuarios de ghee mostraron más Fusobacterium y menos Firmicutes y Actinobacteria. La terapia con Virechana provocó cambios notables en la microbiota después del pretratamiento, como la disminución de Firmicutes y el aumento de Proteobacterias. A nivel género-especie, destacan el aumento de Enterobacteriaceae y la pérdida de Akkermansia municiphila. Niruha Basti y Matra Basti disminuyeron Firmicutes y aumentaron Proteobacteria (p = 0.096). Fusobacterium también aumentó. Después del alta, la Proteobateria se mantuvo alta, pero Firmicutes regresó al 30% en promedio, oscilando entre el 25% y el 50%. Tres semanas después, la variedad aumentó con Fusobacterium, Verrucomicrobia, Tenericutes y Lentisphaerae. La variedad de especies también aumentó tres semanas después. Conclusión: Varias quejas de los participantes mejoraron por el tratamiento ayurvédico con una gran cantidad de tratamiento de aceite por masaje de aceite de superficie corporal y terapia de purga. Causó cambios en la microbiota intestinal y los metabolitos bacterianos pueden afectar las lesiones cutáneas y la salud mental como la sensación depresiva

Uropathogenic E. coli induces DNA damage in the bladder.

Urinary tract infections (UTIs) are among the most common outpatient infections, with a lifetime incidence of around 60% in women. We analysed urine samples from 223 patients with community-acquired UTIs and report the presence of the cleavage product released during the synthesis of colibactin, a bacterial genotoxin, in 55 of the samples examined. Uropathogenic Escherichia coli strains isolated from these patients, as well as the archetypal E. coli strain UTI89, were found to produce colibactin. In a murine model of UTI, the machinery producing colibactin was expressed during the early hours of the infection, when intracellular bacterial communities form. We observed extensive DNA damage both in umbrella and bladder progenitor cells. To the best of our knowledge this is the first report of colibactin production in UTIs in humans and its genotoxicity in bladder cells.

Dissemination of IncF group F1:A2:B20 plasmid-harbouring multidrug-resistant Escherichia coli ST131 before the acquisition of blaCTX-M in Japan.

OBJECTIVES: The Escherichia coli O25-ST131 clone is responsible for global dissemination of the blaCTX-M gene. However, the prevalence of this clone in the digestive tract, devoid of antimicrobial selection, and its molecular epidemiology remain unclear. In this study, we examined the origin of blaCTX-M-positive E. coli O25-ST131 and its distribution. METHODS: We separately sequenced the chromosomal and plasmid genomes of 50 E. coli O25 isolates obtained from faecal samples of patients with diarrhoea in Japan. RESULTS: Although 36 (72%) of 50 E. coli O25 isolates were ST131, only 6 harboured blaCTX-M. According to the fimH and ybbW sequences and fluoroquinolone susceptibility, H30R1 isolates were dominant (27/36; 75%) and possessed IncFII-FIA-FIB with FAB formula subtype F1:A2:B20 plasmids at a high frequency (24/27; 89%). The F1:A2:B20 plasmids possessed more resistance genes such as blaTEM-1, aminoglycoside resistance genes and trimethoprim/sulfamethoxazole resistance genes compared with non-F1:A2:B20 plasmids. In contrast, only one blaCTX-M-14 gene was located on the F1:A2:B20 plasmids, whereas the other three were located on IncFII (F4:A-:B-) (n = 1) and IncZ (n = 2) plasmids. Two H30Rx-ST131 isolates harboured blaCTX-M-15: one was on the chromosome and the other on the IncFIA-R plasmid. The stability and conjugation ability of the F1:A2:B20 plasmids were compared with those of non-F1:A2:B20 plasmids, which revealed higher stability but lower conjugative ability. CONCLUSIONS: These results suggest that E. coli H30R1-ST131 is a multidrug-resistant clone containing several resistance genes in the F1:A2:B20 plasmid, which were widely distributed before the acquisition of blaCTX-M.

Examination of the fecal microbiota in dairy cows infected with bovine leukemia virus.

Infection of cattle by bovine leukemia virus (BLV) causes significant economic losses in terms of milk and meat production in many countries. Because the gut microbiota may be altered by immunomodulation resulting from viral infections, we hypothesized that latent BLV infection would change the gut (i.e., rumen and hindgut) microbiota of infected cattle. In this study, we compared the gut microbiota of 22 uninfected and 29 BLV-infected Holstein-Friesian cows kept on the same farm, by 16S rRNA amplicon sequence analysis of fecal samples. First, we found that the fecal microbial diversity of BLV-infected cows differed slightly from that of uninfected cows. According to differential abundance analysis, some bacterial taxa associated with ruminal fermentation, such as Lachnospiraceae and Veillonellaceae families, were enriched in the fecal microbiota of uninfected cows. Second, the virus propagation ability of BLV strains was examined in vitro, and the correlation of the fecal microbiota with this virus propagation ability was analyzed. Higher virus propagation was shown to lead to less diversity in the microbiota. Differential abundance analysis showed that one bacterial taxon of genus Sanguibacteroides was negatively correlated with the virus propagation ability of BLV strains. Considering these results, BLV infection was speculated to decrease energy production efficiency in the cows via modification of rumen and hindgut microbiota, which partly relies on the virus propagation ability of BLV strains. This may explain the secondary negative effects of BLV infections such as increased susceptibility to other infections and decreased lifetime milk production and reproductive efficiency.

Age-related analysis of the gut microbiome in a purebred dog colony.

Dogs are model animals that can be used to study the gut microbiome. Although the gut microbiome is assumed to be closely related to aging, information pertaining to this relationship in dogs is limited. Here, we examined the association between the canine gut microbiome and age via a bacterial 16S rRNA gene amplicon sequence analysis in a colony of 43 Japanese purebred Shiba Inu dogs. We found that microbial diversity tended to decrease with aging. A differential abundance analysis showed an association of a single specific microbe with aging. The age-related coabundance network analysis showed that two microbial network modules were positively and negatively associated with aging, respectively. These results suggest that the dog gut microbiome is likely to vary with aging.

Providencia in retail meats from Guangzhou, China and Osaka, Japan: prevalence, antimicrobial resistance and characterization of classes 1, 2 and 3 integrons.

Bacteria of the genus Providencia are opportunistic pathogens of clinical significance due to their association with diarrhea and urinary tract infections. The present study was conducted to examine the prevalence and antimicrobial resistance of Providencia spp. in retail meats sold in Guangzhou, China and Osaka, Japan. Out of 158 meat samples including beef, pork and chicken, 67 Providencia (42%) belonging to four species viz., P. alcalifaciens, P. rustigianii, P. stuartii and P. rettgeri were isolated, and most of them were resistant to tetracycline (91%) followed by ampicillin (69%) and streptomycin (49%). Of 67 isolates, 29 (43%) were MDR, which is defined to be resistant to more than three classes of antimicrobials. No statistically significant differences were observed between Chinese and Japanese retail meat samples regarding contamination rate of Providencia spp. as well as frequency of the antimicrobial resistance of the isolates including MDR. Class 1 and/or class 2 integrons were detected in six of the eight isolates that were resistant to more than 4 antimicrobials, however none of the isolates harbored class 3 integron. A P. rustigianii harboring the blaOXA-10 gene was isolated, which is the first report of Providencia with blaOXA-10 gene of food origin. These data suggest that retail meats in China and Japan are substantially contaminated with Providencia spp., which displayed a high frequency of antimicrobial resistance, and establishing the surveillance of Providencia spp., especially antimicrobial resistant one, in retail meats is imperative.

Elucidation of quantitative structural diversity of remarkable rearrangement regions, shufflons, in IncI2 plasmids.

A multiple DNA inversion system, the shufflon, exists in incompatibility (Inc) I1 and I2 plasmids. The shufflon generates variants of the PilV protein, a minor component of the thin pilus. The shufflon is one of the most difficult regions for de novo genome assembly because of its structural diversity even in an isolated bacterial clone. We determined complete genome sequences, including those of IncI2 plasmids carrying mcr-1, of three Escherichia coli strains using single-molecule, real-time (SMRT) sequencing and Illumina sequencing. The sequences assembled using only SMRT sequencing contained misassembled regions in the shufflon. A hybrid analysis using SMRT and Illumina sequencing resolved the misassembled region and revealed that the three IncI2 plasmids, excluding the shufflon region, were highly conserved. Moreover, the abundance ratio of whole-shufflon structures could be determined by quantitative structural variation analysis of the SMRT data, suggesting that a remarkable heterogeneity of whole-shufflon structural variations exists in IncI2 plasmids. These findings indicate that remarkable rearrangement regions should be validated using both long-read and short-read sequencing data and that the structural variation of PilV in the shufflon might be closely related to phenotypic heterogeneity of plasmid-mediated transconjugation involved in horizontal gene transfer even in bacterial clonal populations.

Isolation and Characterization of an Escherichia albertii Strain Producing Three Different Toxins from a Child with Diarrhea.

Here, we report a bacterium-isolated as the sole pathogen from a child with diarrhea-harboring eae and 2 different cytolethal distending toxin genes (cdt) that are homologous to Escherichia coli cdt-I and cdt-II. The bacterium was originally identified as atypical E. coli by conventional biochemical testing, but was finally identified as E. albertii by multilocus sequence analysis, which is the only method that can currently differentiate E. albertii from E. coli. The Shiga toxin 2f (stx2f) genes were also detected in the strain. Production of these 3 toxins was confirmed by western blotting and/or a cytotoxicity assay using eukaryotic cell lines. This is the first report showing the biological activity of CDT-I, CDT-II, and Stx2f in E. albertii.

Inhibitors of retrograde trafficking active against ricin and Shiga toxins also protect cells from several viruses, Leishmania and Chlamydiales.

Medical countermeasures to treat biothreat agent infections require broad-spectrum therapeutics that do not induce agent resistance. A cell-based high-throughput screen (HTS) against ricin toxin combined with hit optimization allowed selection of a family of compounds that meet these requirements. The hit compound Retro-2 and its derivatives have been demonstrated to be safe in vivo in mice even at high doses. Moreover, Retro-2 is an inhibitor of retrograde transport that affects syntaxin-5-dependent toxins and pathogens. As a consequence, it has a broad-spectrum activity that has been demonstrated both in vitro and in vivo against ricin, Shiga toxin-producing O104:H4 entero-hemorrhagic E. coli and Leishmania sp. and in vitro against Ebola, Marburg and poxviruses and Chlamydiales. An effect is anticipated on other toxins or pathogens that use retrograde trafficking and syntaxin-5. Since Retro-2 targets cell components of the host and not directly the pathogen, no selection of resistant pathogens is expected. These lead compounds need now to be developed as drugs for human use.

Prevalence of Colistin Resistance Gene mcr-1 and Absence of mcr-2 in Escherichia coli Isolated from Healthy Food-Producing Animals in Japan.

We screened mcr-1 and mcr-2 genes in 9,306 Escherichia coli strains isolated from healthy animals in the Japanese Veterinary Antimicrobial Resistance Monitoring (JVARM) system. mcr-1 was detected in 39 strains (5, 20, and 14 strains isolated from cattle, swine, and broilers, respectively), whereas mcr-2 was not detected. mcr-2 was also not detected with the investigation sequence homology search against our curated GenEpid-J database.

Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type, with Primary Manifestation as an Upper Eyelid Swelling.

Extranodal natural killer/T-cell lymphoma (ENK/TCL) is most often in the nose or the nasopharynx but can present elsewhere. We report a rare case of ENK/TCL that presented as swelling of an upper eyelid without ocular involvement. A 76-year-old man visited our hospital with a swollen lesion of the left upper eyelid which had appeared 2 months earlier. A biopsy of the upper eyelid revealed slight perivascular and periadnexal infiltration of mononuclear cells with dermal edema. Treatment with oral prednisolone at a dosage of 20 mg/day decreased the eyelid swelling. However, 5 months later, exacerbation of the swelling and nasal congestion were observed. A second biopsy of the upper eyelid revealed a diffuse dermal infiltrate composed of mononuclear cells with an angiocentic growth pattern. Immunohistochemical studies and in situ hybridization showed natural killer-lineage antigens (CD56, granzyme B, and T-cell intracellular antigen 1) with expression of Epstein-Barr virus. These findings lead to the diagnosis of ENK/TCL. We treated the patient with radiation therapy (50 Gy) and 3 courses of a regimen including dexamethasone, carboplatin, etoposide, and ifosphamide. This case suggests that ENK/TCL can present with swelling of an upper eyelid as the primary sign of the skin lesion. Swelling of an upper eyelid should be considered in the differential diagnosis of ENK/TCL.

MATE transport of the E. coli-derived genotoxin colibactin.

Various forms of cancer have been linked to the carcinogenic activities of microorganisms(1-3). The virulent gene island polyketide synthase (pks) produces the secondary metabolite colibactin, a genotoxic molecule(s) causing double-stranded DNA breaks(4) and enhanced colorectal cancer development(5,6). Colibactin biosynthesis involves a prodrug resistance strategy where an N-terminal prodrug scaffold (precolibactin) is assembled, transported into the periplasm and cleaved to release the mature product(7-10). Here, we show that ClbM, a multidrug and toxic compound extrusion (MATE) transporter, is a key component involved in colibactin activity and transport. Disruption of clbM attenuated pks+ E. coli-induced DNA damage in vitro and significantly decreased the DNA damage response in gnotobiotic Il10(-/-) mice. Colonization experiments performed in mice or zebrafish animal models indicate that clbM is not implicated in E. coli niche establishment. The X-ray structure of ClbM shows a structural motif common to the recently described MATE family. The 12-transmembrane ClbM is characterized as a cation-coupled antiporter, and residues important to the cation-binding site are identified. Our data identify ClbM as a precolibactin transporter and provide the first structure of a MATE transporter with a defined and specific biological function.