Bile acid interactions with cholangiocytes

Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter （ASBT） （also referred to as Ibat; gene name Slc10a2） is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified （t-ASBT, multidrug resistance （MDR）3, an unidentified anion exchanger system and organic solute transporter （Ost） heteromeric transporter, Ostα- Ostβ. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3＇, 5＇monophosphate （cAMP）-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C （PKC）, phosphoinositide 3-kinase （PI3K）, mitogenactivated protein （MAP） kinase and extracellular signalregulated protein kinase （ERK） intracellular signals. Bile acids significantly alter cholangiocyte secretion,proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals,and in some instances trigger opposing effects on cholangiocyte secretion, proliferation and survival. Based upon these concepts and observations, the cholangiocyte has been proposed to be the principle target cell for bile acids in the liver.

Integrated circulating tumor DNA and T cell repertoire predict radiotherapeutic response and outcome in non-small cell lung cancer patients with brain metastasis

Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor cells,circulating tumor DNA(ctDNA)is widely distributed in various body fluids,including peripheral blood and cerebrospinal fluid(CSF),as an alternative biomarker for tumor-associated analysis[1].Fortunately,genomic alterations of blood ctDNA and CSF ctDNA have been proven as prognostic markers in non-small cell lung cancer(NSCLC)patients with brain metastasis[2,3].

Assessing the capacity of biochar to stabilize copper and lead in contaminated sediments using chemical and extraction methods

Because of its high adsorption capacity, biochar has been used to stabilize metals when remediating contaminated soils; to date, however, it has seldom been used to remediate contaminated sediment. A biochar was used as a stabilization agent to remediate Cu-and Pb-contaminated sediments, collected from three locations in or close to Beijing. The sediments were mixed with a palm sawdust gasified biochar at a range of weight ratios(2.5%, 5%, and 10%) and incubated for 10, 30, or 60 days. The performance of the different treatments and the heavy metal fractions in the sediments were assessed using four extraction methods, including diffusive gradients in thin films, the porewater concentration, a sequential extraction, and the toxicity characteristic leaching procedure. The results showed that biochar could enhance the stability of heavy metals in contaminated sediments. The degree of stability increased as both the dose of biochar and the incubation time increased. The sediment p H and the morphology of the metal crystals adsorbed onto the biochar changed as the contact time increased. Our results showed that adsorption,metal crystallization, and the p H were the main controls on the stabilization of metals in contaminated sediment by biochar.

Impacts of n-alkane concentration on soil bacterial community structure and alkane monooxygenase genes abundance during bioremediation processes

Petroleum hydrocarbons,mainly consisting of n-alkanes and polycyclic aromatic hydrocarbons(PAHs),are considered as priority pollutants and biohazards in the environment,eventually affecting the ecosystem and human health.Though many previous studies have investigated the change of bacterial community and alkane degraders during the degradation of petroleum hydrocarbons,there is still lack of understanding on the impacts of soil alkane contamination level.In the present study,microcosms with different n-alkane contamination(1%,3%and 5%)were set up and our results indicated a complete alkane degradation after 30 and 50 days in 1%-and 3%-alkane treatments,respectively.In all the treatments,alkanes with medium-chain length(C_(11)-C_(14))were preferentially degraded by soil microbes,followed by C27-alkane in 3%and 5%treatments.Alkane contamination level slightly altered soil bacterial community,and the main change was the presence and abundance of dominant alkane degraders.Thermogemmatisporaceae,Gemmataceae and Thermodesulfovibrionaceae were highly related to the degradation of C_(14)-and C_(27)-alkanes in 5%treatment,but linked to alkanes with medium-chain(C11-C18)in 1%treatment and C21-alkane in 3%treatment,respectively.Additionally,we compared the abundance of three alkane-monooxygenase genes,e.g.,alk_A,alk_P and alk_R.The abundance of alk_R gene was highest in soils,and alk_P gene was more correlated with alkane degradation efficiency,especially in 5%treatment.Our results suggested that alkane contamination level showed non-negligible effects on soil bacterial communities to some extents,and particularly shaped alkane degraders and degrading genes significantly.This study provides a better understanding on the response of alkane degraders and bacterial communities to soil alkane concentrations,which affects their biodegradation process.

ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers

Background:Limited by difficulties in early detection and availabilities of effective treatments,pancreatic cancer is a highly malignant disease with poor prognosis.Nuclear receptors are a family of ligand‐dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development,including cancer.In this study,we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor(LXR)agonist GW3965 in pancreatic cancer.Methods:Soft‐agar colony formation assay,xenograft tumors,Oligonucleotide microarray,Reverse transcription real‐time polymerase chain reaction,Western immunoblotting and Immunohistochemistry were used in this study.Results:We demonstrated pleotropic in vitro activities of GW3965 in pancreatic cell lines MIA PaCa‐2 and BXPC3 including reduction of cell viability,inhibition of cell proliferation,stimulation of cell death,and suppression of colony formation,which translated to significant inhibition of xenograft tumor growth in vitro.By mapping the gene expression profiles,we identified the up‐regulations of 188 and the down‐regulations of 92 genes common to both cell lines following GW3965 treatment.Genes responsive to GW3965 represent a variety of biological pathways vital for multiple cellular functions.Specifically,we identified that the activating transcription factor 4/thioredoxin‐interacting protein/regulated in development and DNA damage responses 1/mechanistic target of rapamycin(ATF4/TXNIP/REDD1/mTOR)signaling critically controls GW3965‐mediated regulation of cell proliferation/death.The significance of the ATF4/TXNIP/REDD1/mTOR pathway was further supported by associated expressions in xenograft tumors as well as human pancreatic cancer samples.Conclusions:This study provides the pre‐clinical evidence that LXR agonist is a promising therapy for pancreatic cancer.

All-conjugated amphiphilic diblock copolymers for improving morphology and thermal stability of polymer/nanocrystals hybrid solar cells

Herein, the ability to optimize the morphology and photovoltaic performance of poly（3-hexylthiophene） （P3HT）/ZnO hybrid bulk-heterojunction solar cells via introducing all-conjugated amphiphilic P3HT-based block copolymer （BCP）, poly（3- hexylthiophene）-block-poly（3-triethylene glycol-thiophene） （P3HT-b-P3TEGT）, as polymeric additives is demonstrated. The results show that the addition of P3HT-b-P3TEGT additives can effectively improve the compatibility between P3HT and ZnO nanocrystals, increase the crystalline and ordered packing of P3HT chains, and form optimized hybrid nanomorphology with stable and intimate hybrid interface. The improvement is ascribed to the P3HT-b-P3TEGT at the P3HT/ZnO interface that has strong coordination interactions between the TEG side chains and the polar surface of ZnO nanoparticles. All of these are favor of the efficient exciton dissociation, charge separation and transport, thereby, contributing to the improvement of the efficiency and thermal stability of solar cells. These observations indicate that introducing all-conjugated amphiphilic BCP additives can be a promising and effective protocol for high-performance hybrid solar cells.

The Effect of Adrenal Replacement Therapy on Rates of Fungal Colonization and Mortality in Critically Ill Patients Awaiting Liver Transplantation

Background: The effect of adrenal replacement therapy (ART) with hydrocortisone on critical endpoints such as infection and mortality in critically ill patients with cirrhosis remains unclear. We evaluated our indications for ART in patients with cirrhosis with clinical symptoms of adrenal insufficiency (AI), and examined the rate of peri-transplant fungal colonization and mortality associated with ART. Methods: Seventy-eight patients with cirrhosis admitted to our institution's surgical intensive care unit (ICU) over a 4-year period met criteria for AI by vasopressor requirement and baseline cortisol levels. Outcomes included disposition at 90-days, fungal colonization, and fungal infection in the presence or absence of ART. Results: In total, 56 patients received hydrocortisone (HC+) while 22 did not (HC-). The HC+ and HC- groups had comparable median Model for End-stage Liver Disease (MELD) scores (26.5 vs. 25, respectively;p=0.93), median ICU lengths of stay (23 vs. 20 days, respectively;p=0.54) and median cortisol levels (18μg/dL for both, p=0.87). Fungal cultures (FC) from blood, urine or bronchoalveolar lavage/sputum were positive for 44% of HC+, and 40.9%of HC-(p=0.77) had mortality rates between HC+and HC-groups that were not significantly different (60.7%vs. 50%, respectively;p=0.39;α=0.05). The 90-day outcomes for HC+ vs. HC- (39.3% vs. 50% discharged, respectively;p=0.39;α=0.05) and those surviving to transplant (17.9%vs. 36.4%, respectively;p=0.08;α=0.05) were not signifi-cantly different between the two groups.Conclusion:In this small single-center series, we found that steroid administration for AI does not affect the rate of fungal colonization/infection or mortality. Further prospective stu-dies are required to determine the utility of ART and factors affecting the rate of FC and mortality in these patients.