Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. The key cell that prevents albuminuria is the terminally ...differentiated glomerular podocyte. Here we report the evolutionary importance of the enzyme Glycogen Synthase Kinase 3 (GSK3) for maintaining podocyte function in mice and the equivalent nephrocyte cell in Drosophila. Developmental deletion of both GSK3 isoforms (α and β) in murine podocytes causes late neonatal death associated with massive albuminuria and renal failure. Similarly, silencing GSK3 in nephrocytes is developmentally lethal for this cell. Mature genetic or pharmacological podocyte/nephrocyte GSK3 inhibition is also detrimental; producing albuminuric kidney disease in mice and nephrocyte depletion in Drosophila. Mechanistically, GSK3 loss causes differentiated podocytes to re-enter the cell cycle and undergo mitotic catastrophe, modulated via the Hippo pathway but independent of Wnt-β-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney function.
Background
The aim of this study was to assess the immune profile within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), and to investigate the prognostic value of intratumoral ...infiltrating immune/inflammatory cells (IICs) in patients after surgery.
Methods
Eighteen phenotypic markers representing 11 types of IIC and the protein products of genes TP53, CDKN2A/p16 and SMAD4/DPC4 were assessed by immunohistochemistry of specimens from patients with pancreatic cancer. The expression of IICs and the mutational status of the genes were correlated with tumour recurrence and survival, and results were validated in an independent cohort.
Results
CD15+ neutrophils, CD20+ B cells and CD206+ tumour‐associated macrophages were seen frequently in tumours, and their presence was associated with reduced survival in a cohort of 79 patients. Expression of CD4+ T helper cells, CD8+ cytotoxic T lymphocytes and CD117+ mast cells was associated with a favourable prognosis. A weighted Cox regression recurrence‐predictive model was constructed that showed good correlation of IICs and gene mutations. A combination of CD15, CD206, CD117 and Smad4 expression was independently associated with overall (hazard ratio (HR) 3·63, 95 per cent c.i. 2·18 to 6·04; P < 0·001) and recurrence‐free (HR 2·93, 1·81 to 4·75; P < 0·001) survival. These findings were validated in an independent cohort (151 patients) and in 54 tissue samples obtained by preoperative endoscopic ultrasound‐guided fine‐needle aspiration.
Conclusion
PDAC has a unique immunosuppressive phenotype that is associated with characteristic gene mutations, disease recurrence and survival after pancreatectomy.
Surgical relevance
The immune microenvironment plays a critical role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is associated with mutations in major driver genes, including KRAS, TP53, CDKN2A/p16 and SMAD4/DPC4.
This study shows that the microenvironment of PDAC has a unique immunosuppressive phenotype, which may be driven by oncogene mutations. Patients with PDAC with a highly immunosuppressive profile tended to have poor postoperative survival. A model including three intratumoral infiltrating immune markers (CD15+, CD206+ and CD117+) and a SMAD4 mutation can be used to predict recurrence and survival in patients after surgery for PDAC.
Immunosuppressive phenotype has poor prognosis
High Phase-Space-Density Gas of Polar Molecules Ni, K.-K; Ospelkaus, S; de Miranda, M.H.G ...
Science (American Association for the Advancement of Science),
10/2008, Letnik:
322, Številka:
5899
Journal Article
Recenzirano
Odprti dostop
A quantum gas of ultracold polar molecules, with long-range and anisotropic interactions, not only would enable explorations of a large class of many-body physics phenomena but also could be used for ...quantum information processing. We report on the creation of an ultracold dense gas of potassium-rubidium (⁴⁰K⁸⁷Rb) polar molecules. Using a single step of STIRAP (stimulated Raman adiabatic passage) with two-frequency laser irradiation, we coherently transfer extremely weakly bound KRb molecules to the rovibrational ground state of either the triplet or the singlet electronic ground molecular potential. The polar molecular gas has a peak density of 10¹² per cubic centimeter and an expansion-determined translational temperature of 350 nanokelvin. The polar molecules have a permanent electric dipole moment, which we measure with Stark spectroscopy to be 0.052(2) Debye (1 Debye = 3.336 x 10⁻³⁰ coulomb-meters) for the triplet rovibrational ground state and 0.566(17) Debye for the singlet rovibrational ground state.
The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n=18), we used an μ-opioid ...receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids have a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well being in the social environment.
Abstract
Twisted two-dimensional van der Waals (vdW) heterostructures have unlocked a new means for manipulating the properties of quantum materials. The resulting mesoscopic moiré superlattices are ...accessible to a wide variety of scanning probes. To date, spatially-resolved techniques have prioritized electronic structure visualization, with lattice response experiments only in their infancy. Here, we therefore investigate lattice dynamics in twisted layers of hexagonal boron nitride (hBN), formed by a minute twist angle between two hBN monolayers assembled on a graphite substrate. Nano-infrared (nano-IR) spectroscopy reveals systematic variations of the in-plane optical phonon frequencies amongst the triangular domains and domain walls in the hBN moiré superlattices. Our first-principles calculations unveil a local and stacking-dependent interaction with the underlying graphite, prompting symmetry-breaking between the otherwise identical neighboring moiré domains of twisted hBN.
With the aim of gathering temporal trends on bacterial epidemiology and resistance from multiple laboratories in China, the CHINET surveillance system was organized in 2005. Antimicrobial ...susceptibility testing was carried out according to a unified protocol using the Kirby-Bauer method or automated systems. Results were analyzed according to Clinical and Laboratory Standards Institute (CLSI) 2014 definitions. Between 2005 and 2014, the number of bacterial isolates ranged between 22 774 and 84 572 annually. Rates of extended-spectrum β-lactamase production among Escherichia coli isolates were stable, between 51.7 and 55.8%. Resistance of E. coli and Klebsiella pneumoniae to amikacin, ciprofloxacin, piperacillin/tazobactam and cefoperazone/sulbactam decreased with time. Carbapenem resistance among K. pneumoniae isolates increased from 2.4 to 13.4%. Resistance of Pseudomonas aeruginosa strains against all of antimicrobial agents tested including imipenem and meropenem decreased with time. On the contrary, resistance of Acinetobacter baumannii strains to carbapenems increased from 31 to 66.7%. A marked decrease of methicillin resistance from 69% in 2005 to 44.6% in 2014 was observed for Staphylococcus aureus. Carbapenem resistance rates in K. pneumoniae and A. baumannii in China are high. Our results indicate the importance of bacterial surveillance studies.
Transversus abdominis plane (TAP) block is an alternative to spinal morphine for analgesia after Caesarean section but there are few data on its comparative efficacy. We compared the analgesic ...efficacy of the TAP block with and without spinal morphine after Caesarean section in a prospective, randomized, double-blinded placebo-controlled trial.
Eighty patients were randomized to one of four groups to receive (in addition to spinal anaesthesia) either spinal morphine 100 µg (SM) or saline (SS) and a postoperative bilateral TAP block with either bupivacaine (TLA) 2 mg kg−1 or saline (TS).
Pain on movement and early morphine consumption were lowest in groups receiving spinal morphine and was not improved by TAP block. The rank order of median pain scores on movement at 6 h was: SMTLA (20 mm)<SMTS (27.5 mm)<SSTS (51.5 mm)<SSTLA (52.0 mm) (P<0.05, highest vs lowest). The rank order of median morphine consumption at 6 h was: SMTS (4.0 mg)<SMTLA (5.0 mg)<SSTLA (8.0 mg)<SSTS (12.0 mg) and at 24 h was: SMTLA (5.0 mg)<SMTS (6.0 mg)<SSTS (9.5 mg)<SSTLA (15.0 mg) (P<0.05, highest vs lowest). Sedation scores and patient satisfaction did not differ between groups. Anti-emetic use and pruritus were highest in the SMTLA group.
Spinal morphine—but not TAP block—improved analgesia after Caesarean section. The addition of TAP block with bupivacaine 2 mg kg−1 to spinal morphine did not further improve analgesia.
Summary
Aiming to identify pleiotropic genomic loci for bone mineral density and bone size, we performed a bivariate GWAS in five discovery samples and replicated in two large-scale samples. We ...identified 2 novel loci at 2q37.1 and 6q26. Our findings provide insight into common genetic architecture underlying both traits.
Introduction
Bone mineral density (BMD) and bone size (BS) are two important factors that contribute to the development of osteoporosis and osteoporotic fracture. Both BMD and BS are highly heritable and they are genetically correlated. In this study, we aim to identify pleiotropic loci associated with BMD and BS.
Methods
We conducted a bivariate genome-wide association (GWA) analysis of hip BMD and hip BS in 6180 participants from 5 samples, followed by in silico replication in the UK Biobank study of BMD (
N
= 426,824) and the deCODE study of BS (
N
= 28,954), respectively.
Results
SNPs from 2 genomic loci were significant at the genome-wide significance (GWS) level (
p
lt; 5 × 10
−8
) in the discovery samples and were successfully replicated in the replication samples (2q37.1, lead SNP rs7575512, discovery
p
= 1.49 × 10
−10
, replication
p
= 0.05; 6q26, lead SNP rs1040724, discovery
p
= 1.95 × 10
−8
, replication
p
= 0.03). Functional annotations suggested functional relevance of the identified variants to bone development.
Conclusion
Our findings provide insight into the common genetic architecture underlying BMD and BS, and enhance our understanding of the potential mechanism of osteoporosis fracture.
The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of ...radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance.
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