816 research outputs found
The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota
The human gut microbiota is engaged in multiple interactions affecting host health during the host's entire life span. Microbes colonize the neonatal gut immediately following birth. The establishment and interactive development of this early gut microbiota are believed to be (at least partially) driven and modulated by specific compounds present in human milk. It has been shown that certain genomes of infant gut commensals, in particular those of bifidobacterial species, are genetically adapted to utilize specific glycans of this human secretory fluid, thus representing a very intriguing example of host-microbe coevolution, where both partners are believed to benefit. In recent years, various metagenomic studies have tried to dissect the composition and functionality of the infant gut microbiome and to explore the distribution across the different ecological niches of the infant gut biogeography of the corresponding microbial consortia, including those corresponding to bacteria and viruses, in healthy and ill subjects. Such analyses have linked certain features of the microbiota/microbiome, such as reduced diversity or aberrant composition, to intestinal illnesses in infants or disease states that are manifested at later stages of life, including asthma, inflammatory bowel disease, and metabolic disorders. Thus, a growing number of studies have reported on how the early human gut microbiota composition/development may affect risk factors related to adult health conditions. This concept has fueled the development of strategies to shape the infant microbiota composition based on various functional food products. In this review, we describe the infant microbiota, the mechanisms that drive its establishment and composition, and how microbial consortia may be molded by natural or artificial interventions. Finally, we discuss the relevance of key microbial players of the infant gut microbiota, in particular bifidobacteria, with respect to their role in health and disease
Visualization of endogenous p27 and Ki67 reveals the importance of a c-Myc-driven metabolic switch in promoting survival of quiescent cancer cells
Rationale: Recurrent and metastatic cancers often undergo a period of dormancy, which is closely associated with cellular quiescence, a state whereby cells exit the cell cycle and are reversibly arrested in G0 phase. Curative cancer treatment thus requires therapies that either sustain the dormant state of quiescent cancer cells, or preferentially, eliminate them. However, the mechanisms responsible for the survival of quiescent cancer cells remain obscure. Methods: Dual genome-editing was carried out using a CRISPR/Cas9-based system to label endogenous p27 and Ki67 with the green and red fluorescent proteins EGFP and mCherry, respectively, in melanoma cells. Analysis of transcriptomes of isolated EGFP-p27highmCherry-Ki67low quiescent cells was conducted at bulk and single cell levels using RNA-sequencing. The extracellular acidification rate and oxygen consumption rate were measured to define metabolic phenotypes. SiRNA and inducible shRNA knockdown, chromatin immunoprecipitation and luciferase reporter assays were employed to elucidate mechanisms of the metabolic switch in quiescent cells. Results: Dual labelling of endogenous p27 and Ki67 with differentiable fluorescent probes allowed for visualization, isolation, and analysis of viable p27highKi67low quiescent cells. Paradoxically, the proto-oncoprotein c-Myc, which commonly drives malignant cell cycle progression, was expressed at relatively high levels in p27highKi67low quiescent cells and supported their survival through promoting mitochondrial oxidative phosphorylation (OXPHOS). In this context, c-Myc selectively transactivated genes encoding OXPHOS enzymes, including subunits of isocitric dehydrogenase 3 (IDH3), whereas its binding to cell cycle progression gene promoters was decreased in quiescent cells. Silencing of c-Myc or the catalytic subunit of IDH3, IDH3α, preferentially killed quiescent cells, recapitulating the effect of treatment with OXPHOS inhibitors. Conclusion: These results establish a rigorous experimental system for investigating cellular quiescence, uncover the high selectivity of c-Myc in activating OXPHOS genes in quiescent cells, and propose OXPHOS targeting as a potential therapeutic avenue to counter cancer cells in quiescence
Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay
The decay channel
is studied using a sample of events collected
by the BESIII experiment at BEPCII. A strong enhancement at threshold is
observed in the invariant mass spectrum. The enhancement can be fit
with an -wave Breit-Wigner resonance function with a resulting peak mass of
and a
narrow width that is at the 90% confidence level.
These results are consistent with published BESII results. These mass and width
values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics
Time Course and Pattern of Metastasis of Cutaneous Melanoma Differ between Men and Women
Background: This study identified sex differences in progression of cutaneous melanoma. Methodology/Principal Findings: Of 7,338 patients who were diagnosed as an invasive primary CM without clinically detectable metastases from 1976 to 2008 at the University of Tuebingen in Germany, 1,078 developed subsequent metastases during follow up. The metastatic pathways were defined in these patients and analyzed using the Kaplan-Meier method. Multivariate survival analysis was performed using Cox modeling. In 18.7 % of men and 29.2 % of women (P,0.001) the first metastasis following diagnosis of primary tumor was locoregional as satellite/in-transit metastasis. The majority of men (54.0%) and women (47.6%, P = 0.035) exhibited direct regional lymph node metastasis. Direct distant metastasis from the stage of the primary tumor was observed in 27.3 % of men and 23.2 % of women (P = 0.13). Site of first metastasis was the most important prognostic factor of survival after recurrence in multivariate analysis (HR:1.3; 95 % CI: 1.0–1.6 for metastasis to the regional lymph nodes vs. satellite/in-transit recurrence, and HR:5.5; 95 % CI: 4.2–7.1 for distant metastasis vs. satellite/ in-transit recurrence, P,0.001). Median time to distant metastasis was 40.5 months (IQR, 58.75) in women and 33 months (IQR, 44.25) in men (P = 0.002). Five-year survival after distant recurrence probability was 5.2 % (95 % CI: 1.4–2.5) for men compared with 15.3 % (95 % CI: 11.1–19.5; P = 0.008) for women. Conclusions/Significance: Both, the pattern of metastatic spread with more locoregional metastasis in women, and th
Strain induced exciton fine-structure splitting and shift in bent ZnO microwires
Lattice strain is a useful and economic way to tune the device performance and is commonly present in nanostructures. Here, we investigated for the first time the exciton spectra evolution in bent ZnO microwires along the radial direction via high spatial/energy resolution cathodeluminescence spectroscopy at 5.5 K. Our experiments show that the exciton peak splits into multi fine peaks towards the compressive part while retains one peak in the tensile part and the emission peak displays a continuous blue-shift from tensile to compressive edges. In combination with first-principles calculations, we show that the observed NBE emission splitting is due to the valence band splitting and the absence of peak splitting in the tensile part maybe due to the highly localized holes in the A band and the carrier density distribution across the microwire. Our studies may pave the way to design nanophotonic and electronic devices using bent ZnO nanowires
Laparoscopic cholecystectomy for melanoma metastatic to the gallbladder: is it an adequate surgical procedure? Report of a case and review of the literature
<p>Abstract</p> <p>Background</p> <p>Only 2% to 4% of patients with melanoma will be diagnosed with gastrointestinal metastasis during the course of their disease. The most common sites of gastrointestinal metastases from melanoma include the small bowel (35%–67%), colon (9%–15%) and stomach (5%–7%), with a median survival of 6–10 months after surgery, and 18% survival at five years. Metastatic melanoma to the gallbladder is extremely rare and it is associated with a very poor prognosis.</p> <p>Case presentation</p> <p>We report a case of a 54-year old man presented to observation with diagnosis of 6.1 mm thick, Clark's level IV, ulcerated melanoma of the trunk, developing in the course of the disease metastatic involvement of the gallbladder as first site of recurrence, treated by laparoscopic cholecystectomy. To date only few cases of patients with metastatic melanoma of the gallbladder treated by this surgical procedure have been reported in literature.</p> <p>Conclusion</p> <p>Gallbladder metastasis represents a rare event as a first site of recurrence. It must be considered a possible expression of systemic disease also despite radiological absence of other metastatic lesions. Laparoscopic approach has a possible therapeutic role, but open surgery has also a concomitant diagnostic purpose because gives the possibility of manual exploration of abdominal cavity, useful particularly to reveal bowel metastatic lesions, not easily identifiable by preoperative imaging examinations.</p
The RNA-binding protein Sam68 regulates expression and transcription function of the androgen receptor splice variant AR-V7.
Castration-resistant (CR) prostate cancer (PCa) partly arises due to persistence of androgen receptor (AR) transcriptional activity in the absence of cognate ligand. An emerging mechanism underlying the CRPCa phenotype and predicting response to therapy is the expression of the constitutively-active AR-V7 splice variant generated by AR cryptic exon 3b inclusion. Here, we explore the role of the RNA-binding protein (RBP) Sam68 (encoded by KHDRBS1), which is over-expressed in clinical PCa, on AR-V7 expression and transcription function. Using a minigene reporter, we show that Sam68 controls expression of exon 3b resulting in an increase in endogenous AR-V7 mRNA and protein expression in RNA-binding-dependent manner. We identify a novel protein-protein interaction between Sam68 and AR-V7 mediated by a common domain shared with full-length AR, and observe these proteins in the cell nucleoplasm. Using a luciferase reporter, we demonstrate that Sam68 co-activates ligand-independent AR-V7 transcriptional activity in an RNA-binding-independent manner, and controls expression of the endogenous AR-V7-specific gene target UBE2C. Our data suggest that Sam68 has separable effects on the regulation of AR-V7 expression and transcriptional activity, through its RNA-binding capacity. Sam68 and other RBPs may control expression of AR-V7 and other splice variants as well as their downstream functions in CRPCa
Murine Gamma Herpesvirus 68 Hijacks MAVS and IKKβ to Abrogate NFκB Activation and Antiviral Cytokine Production
Upon viral infection, mitochondrial antiviral signaling (MAVS) protein serves as a key adaptor to promote cytokine production. We report here that murine gamma herpesvirus 68 (γHV68), a model virus for oncogenic human gamma herpesviruses, subverts cytokine production via the MAVS adaptor. During early infection, γHV68 hijacks MAVS and IKKβ to induce the site-specific phosphorylation of RelA, a crucial subunit of the transcriptionally active NFκB dimer, which primes RelA for the proteasome-mediated degradation. As such, γHV68 efficiently abrogated NFκB activation and cytokine gene expression. Conversely, uncoupling RelA degradation from γHV68 infection promoted NFκB activation and elevated cytokine production. Loss of MAVS increased cytokine production and immune cell infiltration in the lungs of γHV68-infected mice. Moreover, exogenous expression of the phosphorylation- and degradation-resistant RelA variant restored γHV68-induced cytokine production. Our findings uncover an intricate strategy whereby signaling via the upstream MAVS adaptor is intercepted by a pathogen to nullify the immediate downstream effector, RelA, of the innate immune pathway
Avoiding Loss of Catalytic Activity of Pd Nanoparticles Partially Embedded in Nanoditches in SiC Nanowires
Nanoditches from selective etching of periodically twinned SiC nanowires were employed to hinder the migration and coalescence of Pd nanoparticles supported on the nanowires, and thus to improve their catalytic stability for total combustion of methane. The results show that the etched Pd/SiC catalyst can keep the methane conversion of almost 100% while the unetched one has an obvious decline in the catalytic activity from 100 to 82% after ten repeated reaction cycles. The excellent catalytic stability originates from the limitation of the nanoditches to the migration and growth of Pd nanoparticles
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