The histone methyltransferase G9a is overexpressed in a variety of cancer types, including pancreatic adenocarcinoma, and promotes tumor invasiveness and metastasis. We recently reported the ...discovery of BRD4770, a small-molecule inhibitor of G9a that induces senescence in PANC-1 cells. We observed that the cytotoxic effects of BRD4770 were dependent on genetic background, with cell lines lacking functional p53 being relatively resistant to compound treatment. To understand the mechanism of genetic selectivity, we used two complementary screening approaches to identify enhancers of BRD4770. The natural product and putative BH3 mimetic gossypol enhanced the cytotoxicity of BRD4770 in a synergistic manner in p53-mutant PANC-1 cells but not in immortalized non-tumorigenic pancreatic cells. The combination of gossypol and BRD4770 increased LC3-II levels and the autophagosome number in PANC-1 cells, and the compound combination appears to act in a BNIP3 (B-cell lymphoma 2 19-kDa interacting protein)-dependent manner, suggesting that these compounds act together to induce autophagy-related cell death in pancreatic cancer cells.
To investigate whether lipid-related or body mass index (BMI)-related common genetic polymorphisms modulate the associations between serum lipid levels, BMI and disability progression in multiple ...sclerosis (MS).
The association between disability progression (annualised Expanded Disability Status Scale (EDSS) change over 5 years, ΔEDSS) and lipid-related or BMI-related genetic polymorphisms was evaluated in a longitudinal cohort (n=184), diagnosed with MS. We constructed a cumulative genetic risk score (CGRS) of associated polymorphisms (p<0.05) and examined the interactions between the CGRS and lipid levels (measured at baseline) in predicting ΔEDSS. All analyses were conducted using linear regression.
Five lipid polymorphisms (rs2013208, rs9488822, rs17173637, rs10401969 and rs2277862) and one BMI polymorphism (rs2033529) were nominally associated with ΔEDSS. The constructed lipid CGRS showed a significant, dose-dependent association with ΔEDSS (p
=1.4×10
), such that participants having ≥6 risk alleles progressed 0.38 EDSS points per year faster compared with those having ≤3. This CGRS model explained 16% of the variance in ΔEDSS. We also found significant interactions between the CGRS and lipid levels in modulating ΔEDSS, including high-density lipoprotein (HDL; p
=0.005) and total cholesterol:high-density lipoprotein ratio (TC:HDL; p
=0.030). The combined model (combination of CGRS and the lipid parameter) explained 26% of the disability variance for HDL and 27% for TC:HDL.
In this prospective cohort study, both lipid levels and lipid-related polymorphisms individually and jointly were associated with significantly increased disability progression in MS. These results indicate that these polymorphisms and tagged genes might be potential points of intervention to moderate disability progression.
Loss of E-cadherin marks a defect in epithelial integrity and polarity during tissue injury and fibrosis. Whether loss of E-cadherin plays a causal role in fibrosis is uncertain. α3β1 Integrin has ...been identified to complex with E-cadherin in cell-cell adhesion, but little is known about the details of their cross talk. Herein, E-cadherin gene ( Cdh1 ) was selectively deleted from proximal tubules of murine kidney by Sglt2Cre . Ablation of E-cadherin up-regulated α3β1 integrin at cell-cell adhesion. E-cadherin–deficient proximal tubular epithelial cell displayed enhanced transforming growth factor-β1–induced α-smooth muscle actin (α-SMA) and vimentin expression, which was suppressed by siRNA silencing of α3 integrin, but not β1 integrin. Up-regulation of transforming growth factor-β1–induced α-SMA was mediated by an α3 integrin-dependent increase in integrin-linked kinase (ILK). Src phosphorylation of β-catenin and consequent p-β-catenin-Y654/p-Smad2 transcriptional complex underlies the transcriptional up-regulation of ILK. Kidney fibrosis after unilateral ureteric obstruction or ischemia reperfusion was increased in proximal tubule E-cadherin–deficient mice in comparison to that of E-cadherin intact control mice. The exacerbation of fibrosis was explained by the α3 integrin-dependent increase of ILK, β-catenin nuclear translocation, and α-SMA/proximal tubular–specific Cre double positive staining in proximal tubular epithelial cell. These studies delineate a nonconventional integrin/ILK signaling by α3 integrin–dependent Src/p-β-catenin-Y654/p-Smad2–mediated up-regulation of ILK through which loss of E-cadherin leads to kidney fibrosis.
During cardiopulmonary bypass (CPB), pulmonary ischemia/reperfusion (I/R) injury can cause acute lung injury (ALI). Our previous research confirmed that abnormal high-mobility group box 1 (HMGB1) ...release after CPB was closely related to ALI. However, the mechanism underlying the HMGB1-mediated induction of ALI after CPB is unclear. Our previous study found that HMGB1 binds Toll-like receptor 4 (TLR4), leading to lung injury, but direct evidence of a role for these proteins in the mechanism of CPB-induced lung injury has not been shown. We examined the effects of inhibiting HMGB1 or reducing TLR4 expression on CPB-induced lung injury in rats administered anti-HMBG1 antibody or TLR4 short-hairpin RNA (shTLR4), respectively. In these rat lungs, we studied the histologic changes and levels of interleukin- (IL-) 1β, tumour necrosis factor- (TNF-) α, HMGB1, and TLR4 after CPB. After CPB, the lung tissues from untreated rats showed histologic features of injury and significantly elevated levels of IL-1β, TNF-α, HMGB1, and TLR4. Treatment with anti-HMGB1 attenuated the CPB-induced morphological inflammatory response and protein levels of IL-1β, TNF-α, HMGB1, and TLR4 in the lung tissues and eventually alleviated the ALI after CPB. Treatment with shTLR4 attenuated the CPB-induced morphological inflammatory response and protein levels of IL-1β, TNF-α, and TLR4 in the lung tissues and eventually alleviated the ALI after CPB, but could not alleviate the HMGB1 protein levels induced by CPB. In summary, the present study demonstrated that the HMGB1/TLR4 pathway mediated the development of ALI induced by CPB.
This study enhances an existing global hydrological model (GHM), Xanthos, by adding a new water management module that distinguishes between the operational characteristics of irrigation, hydropower, ...and flood control reservoirs. We remapped reservoirs in the Global Reservoir and Dam (GRanD) database to the 0.5∘ spatial resolution in Xanthos so that a single lumped reservoir exists per grid cell, which yielded 3790 large reservoirs. We implemented unique operation rules for each reservoir type, based on their
primary purposes. In particular, hydropower reservoirs have been treated as
flood control reservoirs in previous GHM studies, while here, we determined
the operation rules for hydropower reservoirs via optimization that maximizes long-term hydropower production. We conducted global simulations
using the enhanced Xanthos and validated monthly streamflow for 91 large river basins, where high-quality observed streamflow data were available. A
total of 1878 (296 hydropower, 486 irrigation, and 1096 flood control and
others) out of the 3790 reservoirs are located in the 91 basins and are part of our reported results. The Kling–Gupta efficiency (KGE) value (after adding the new water management) is ≥ 0.5 and ≥ 0.0 in 39 and 81 basins, respectively. After adding the new water management module, model performance improved for 75 out of 91 basins and worsened for only 7. To measure the relative difference between explicitly representing hydropower reservoirs and representing hydropower reservoirs as flood control reservoirs (as is commonly done in other GHMs), we use the normalized root mean square error (NRMSE) and the coefficient of determination (R2). Out of the 296 hydropower reservoirs, the NRMSE is
> 0.25 (i.e., considering 0.25 to represent a moderate difference) for over 44 % of the 296 reservoirs when comparing both the simulated reservoir releases and storage time series between the two simulations. We suggest that correctly representing hydropower reservoirs in GHMs could have important implications for our understanding and management of freshwater resource challenges at regional-to-global scales. This enhanced global water management modeling framework will allow the analysis of future global reservoir development and management from a coupled human–earth system perspective.
Abstract
Gamma rays from HESS J1849−000, a middle-aged TeV pulsar wind nebula (PWN), are observed by the Tibet air shower array and the muon detector array. The detection significance of gamma rays ...reaches 4.0
σ
and 4.4
σ
levels above 25 TeV and 100 TeV, respectively, in units of the Gaussian standard deviation
σ
. The energy spectrum measured between 40 TeV <
E
< 320 TeV for the first time is described with a simple power-law function of
dN
/
dE
=
(
2.86
±
1.44
)
×
10
−
16
(
E
/
40
TeV
)
−
2.24
±
0.41
TeV
−
1
cm
−
2
s
−
1
. The gamma-ray energy spectrum from the sub-TeV (
E
< 1 TeV) to sub-PeV (100 TeV <
E
< 1 PeV) ranges, including the results of previous studies, can be modeled with the leptonic scenario, i.e., inverse Compton scattering by high-energy electrons accelerated by the PWN of PSR J1849−0001. On the other hand, the gamma-ray energy spectrum can also be modeled with the hadronic scenario in which gamma rays are generated from the decay of neutral pions produced by collisions between accelerated cosmic-ray protons and the ambient molecular cloud found in the gamma-ray-emitting region. The cutoff energy of cosmic-ray protons
E
p,cut
is estimated as
log
10
(
E
p
,
cut
/
TeV
)
=
3.73
−
0.66
+
2.98
, suggesting that protons are accelerated up to the PeV energy range. Our study thus proposes that HESS J1849−000 should be further investigated as a new candidate as a Galactic PeV cosmic-ray accelerator, or “PeVatron.”
Many common, biologically important polysaccharides contain pyranose rings made of five carbon atoms and one oxygen atom. They occur in a variety of cellular structures, where they are often ...subjected to considerable tensile stress. The polysaccharides are thought to respond to this stress by elastic deformation, but the underlying molecular rearrangements allowing such a response remain poorly understood. It is typically assumed, however, that the pyranose ring structure is inelastic and locked into a chair-like conformation. Here we describe single-molecule force measurements on individual polysaccharides that identify the pyranose rings as the structural unit controlling the molecule's elasticity. In particular, we find that the enthalpic component of the polymer elasticity of amylose, dextran and pullulan is eliminated once their pyranose rings are cleaved. We interpret these observations as indicating that the elasticity of the three polysaccharides results from a force-induced elongation of the ring structure and a final transition from a chair-like to a boat-like conformation. We expect that the force-induced deformation of pyranose rings reported here plays an important role in accommodating mechanical stresses and modulating ligand binding in biological systems.
The
Saccharomyces genome-deletion project created >5900 ‘molecularly barcoded’ yeast knockout mutants (YKO mutants). The YKO mutant collections have facilitated large-scale analyses of a multitude of ...mutant phenotypes. For example, both synthetic genetic array (SGA) and synthetic-lethality analysis by microarray (SLAM) methods have been used for synthetic-lethality screens. Global analysis of synthetic lethality promises to identify cellular pathways that ‘buffer’ each other biologically. The combination of global synthetic-lethality analysis, together with global protein–protein interaction analyses, mRNA expression profiling and functional profiling will, in principle, enable construction of a cellular ‘wiring diagram’ that will help frame a deeper understanding of human biology and disease.
A golden age for heavy-quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The ...early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the
B
-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations at BESIII, the LHC, RHIC, FAIR, the Super Flavor and/or Tau–Charm factories, JLab, the ILC, and beyond. The list of newly found conventional states expanded to include
h
c
(1
P
),
χ
c
2
(2
P
),
, and
η
b
(1
S
). In addition, the unexpected and still-fascinating
X
(3872) has been joined by more than a dozen other charmonium- and bottomonium-like “
XYZ
” states that appear to lie outside the quark model. Many of these still need experimental confirmation. The plethora of new states unleashed a flood of theoretical investigations into new forms of matter such as quark–gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of
,
, and
bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. Lattice QCD has grown from a tool with computational possibilities to an industrial-strength effort now dependent more on insight and innovation than pure computational power. New effective field theories for the description of quarkonium in different regimes have been developed and brought to a high degree of sophistication, thus enabling precise and solid theoretical predictions. Many expected decays and transitions have either been measured with precision or for the first time, but the confusing patterns of decays, both above and below open-flavor thresholds, endure and have deepened. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark–gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.
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