Hippo Pathway Activity Influences Liver Cell Fate

SummaryThe Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. Employing a combination of lineage tracing, clonal analysis, and organoid culture approaches, we demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level. We also identify the NOTCH-signaling pathway as a functional important effector downstream of the Hippo transducer YAP. Our findings uncover a potent role for Hippo/YAP signaling in controlling liver cell fate and reveal an unprecedented level of phenotypic plasticity in mature hepatocytes, which has implications for the understanding and manipulation of liver regeneration

Towards sustainable sanitation management: Establishing the costs and willingness to pay for emptying and transporting sludge in rural districts with high rates of access to latrines

MOTIVATION: Proper management of fecal sludge has significant positive health and environmental externalities. Most research on managing onsite sanitation so far either simulates the costs of, or the welfare effects from, managing sludge in situ in pit latrines. Thus, designing management strategies for onsite rural sanitation is challenging, because the actual costs of transporting sludge for treatment, and sources for financing these transport costs, are not well understood. METHODS: In this paper we calculate the actual cost of sludge management from onsite latrines, and identify the contributions that latrine owners are willing to make to finance the costs. A spreadsheet-based model is used to identify a cost-effective transport option, and to calculate the cost per household. Then a double-bound contingent valuation method is used to elicit from pit-latrine owners their willingness-to-pay to have sludge transported away. This methodology is employed for the case of a rural subdistrict in Bangladesh called Bhaluka, a unit of administration at which sludge management services are being piloted by the Government of Bangladesh. RESULTS: The typical sludge accumulation rate in Bhaluka is calculated at 0.11 liters/person/day and a typical latrine will need to be emptied approximately once every 3 to 4 years. The costs of emptying and transport are high; approximately USD 13 per emptying event (circa 14% of average monthly income); household contributions could cover around 47% of this cost. However, if costs were spread over time, the service would cost USD 4 per year per household, or USD 0.31 per month per household-comparable to current expenditures of rural households on telecommunications. CONCLUSION: This is one of few research papers that brings the costs of waste management together with financing of that cost, to provide evidence for an implementable solution. This framework can be used to identify cost effective sludge management options and private contributions towards that cost in other (context-specific) administrative areas where onsite sanitation is widespread

NUAK2 is a critical YAP target in liver cancer

Hippo-YAP pathway plays an important role in cancers; however the in vivo relevance of YAP/TAZ target genes is unclear. Here, the authors show that NUAK2 is a target of YAP and participates in a feedback loop to maximize YAP activity. Inhibition of NUAK2 suppresses YAP-driven hepatomegaly and liver cancer growth, offering a new target for cancer therapy

PTX3-based genetic testing for risk of aspergillosis after lung transplant

[Excerpt] We read with interest the article by Wójtowicz et al [1], and would like to comment on it and to share findings from our complementary study. We have recently established genetic variation in the long pentraxin 3 (PTX3) as a major determinant of susceptibility to invasive aspergillosis (IA) after hematopoietic stem cell transplant [2]. Wójtowicz et al are the first to uncover similar findings in solid organ transplant (SOT) recipients, highlighting a potential applicability of these markers in predicting infection across patients with intrinsically different predisposing conditions (...).ESCMID -European Society of Clinical Microbiology and Infectious Diseases(undefined

Restriction of intestinal stem cell expansion and the regenerative response by YAP

A remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signaling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. The mechanisms that counterbalance Wnt-driven proliferation are poorly understood. We demonstrate here that YAP, a protein known for its powerful growth-inducing and oncogenic properties1-2, has an unexpected growth-suppressive function restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells (ISCs) and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signaling independently of the APC/Axin/GSK3β complex partly by limiting the activity of Dishevelled (DVL). DVL signals in the nucleus of ISCs and its forced expression leads to enhanced Wnt signaling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas (CRC) and its expression can restrict the growth of CRC xenografts. Collectively, our work describes a novel mechanistic paradigm for how proliferative signals are counterbalanced in regenerating tissues. Additionally, our findings have important implications for the targeting of YAP in human malignancies

Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity

Specific functions of the immune system are essential to protect us from infections caused by pathogens such as viruses and bacteria. However, as we age, the immune system shows a functional decline that can be attributed in large part to age-associated defects in hematopoietic stem cells (HSCs)-the cells at the apex of the immune cell hierarchy. Here, we find that the Hippo pathway coactivator TAZ is potently induced in old HSCs and protects these cells from functional decline. We identify Clca3a1 as a TAZ-induced gene that allows us to trace TAZ activity in vivo. Using CLCA3A1 as a marker, we can isolate "young-like" HSCs from old mice. Mechanistically, Taz acts as coactivator of PU.1 and to some extent counteracts the gradual loss of PU.1 expression during HSC aging. Our work thus uncovers an essential role for Taz in a previously undescribed fail-safe mechanism in aging HSCs. Immune system function declines with age, a consequence of defects in hematopoietic stem cells (HSCs). Here the authors show that TAZ buffers age-related loss of PU.1 activity to maintain HSC functionality and identify the surface protein Clca3a1 as a marker of "young-like" HSCs, even in old mice

Prevalence of vancomycin-resistant Enterococcus fecal colonization among kidney transplant patients

BACKGROUND: End stage renal disease patients are at risk of Vancomycin-Resistant Enterococcus (VRE) infections. The first reports of VRE isolation were from hemodialysis patients. However, to date, VRE fecal colonization rates as well as associated risk factors in kidney transplant patients have not yet been established in prospective studies. METHODS: We collected one or two stool samples from 280 kidney transplant patients and analysed the prevalence of VRE and its associated risk factors. Patients were evaluated according to the post-transplant period: group 1, less than 30 days after transplantation (102 patients), group 2, one to 6 months after transplantation (73 patients) and group 3, more than 6 months after transplantation (105 patients). RESULTS: The overall prevalence rate of fecal VRE colonization was 13.6% (38/280), respectively 13.7% for Group 1, 15.1% for group 2 and 12.4% for group 3. E. faecium and E. faecalis comprised 50% of all VRE isolates. No immunologic variables were clearly correlated with VRE colonization and no infections related to VRE colonization were reported. CONCLUSION: Fecal VRE colonization rates in kidney transplant patients were as high as those reported for other high-risk groups, such as critical care and hemodialysis patients. This high rate of VRE colonization observed in kidney transplant recipients may have clinical relevance in infectious complications

Broadband terahertz pulse generation driven by an ultrafast thin-disk laser oscillator

We demonstrate broadband THz generation driven by an ultrafast thin-disk laser (TDL) oscillator. By optical rectification of 50-fs pulses at 61 MHz repetition rate in a collinear geometry in crystalline GaP, THz radiation with a central frequency at around 3.4 THz and a spectrum extending from below 1 THz to nearly 7 THz are generated. We realized a spectroscopic characterization of a GaP crystal and a benchmark measurement of the water-vapor absorption spectrum in the THz range. Sub-50-GHz resolution is achieved within a 5 THz bandwidth. Our experiments show the potential of ultrafast TDL oscillators for driving MHz-repetition-rate broadband THz systems