The structural basis of actinomycin D–bindinginduces nucleotide flipping out, a sharp bendand a left-handed twist in CGG triplet repeats

The potent anticancer drug actinomycin D (ActD)functions by intercalating into DNA at GpC sites,thereby interrupting essential biological processesincluding replication and transcription. Certainneurological diseases are correlated with the expansionof (CGG)n trinucleotide sequences, whichcontain many contiguous GpC sites separated by asingle G:G mispair. To characterize the binding ofActD to CGG triplet repeat sequences, the structuralbasis for the strong binding of ActD to neighbouringGpC sites flanking a G:G mismatch has beendetermined based on the crystal structure of ActDbound to ATGCGGCAT, which contains a CGGtriplet sequence. The binding of ActD molecules toGCGGC causes many unexpected conformationalchanges including nucleotide flipping out, a sharpbend and a left-handed twist in the DNA helix via atwo site-binding model. Heat denaturation, circulardichroism and surface plasmon resonance analysesshowed that adjacent GpC sequences flanking aG:G mismatch are preferred ActD-binding sites. Inaddition, ActD was shown to bind the hairpin conformationof (CGG)16 in a pairwise combination andwith greater stability than that of other DNAintercalators. Our results provide evidence of apossible biological consequence of ActD bindingto CGG triplet repeat sequences

DEVELOPMENT OF RATIONAL COMBINATION THERAPY WITH PARP INHIBITORS AND KINASE INHIBITORS IN TNBC

Poly (ADP-ribose) polymerase inhibitors (PARPi) emerge as potential targeting drugs for BRCA-deficient cancers including triple negative breast cancer (TNBC). However, it has been reported that a subgroup of patients even with BRCA mutation fails to respond to PARPi in multiple clinical trials. In this study, we identified c-Met, a tyrosine kinase, phosphorylates PARP1 at Y907 and that the phosphorylation increases PARP1 activity, thereby rendering cancer cells resistant to PARPi. The combination of c-Met inhibitors (METi) and PARPi has a synergistic effect for c-Met overexpressed TNBC in vitro and in vivo. In addition to c-Met, through functional analysis, we found casein kinase 2 (CK2) is another potential PARP1 regulator. The combination of a CK2 inhibitor (CK2i) and PARPi synergistically attenuates DNA damage repair, cell cycle, cell proliferation and xenograft tumor growth. Similar to the c-Met-PARP1 axis, CK2 interacts with PARP1 in the nucleus. Moreover, CK2 can phosphorylate PARP1 in vitro, implicating that similar to c-Met, CK2 regulates PARP1 activity through direct phosphorylation. Together, phosphorylation of PARP1 may be used as biomarkers to guide the combinational treatment of PARPi and corresponding kinase inhibitors. Our study not only has revealed a new mechanism of PARPi resistance but also provided a marker-guided combination therapeutic strategy to stratify TNBC patients who do not respond to PARPi

Optimization Study of Small-Scale Solar Membrane Distillation Desalination Systems (s-SMDDS)

[[abstract]]Membrane distillation (MD), which can utilize low-grade thermal energy, has been extensively studied for desalination. By incorporating solar thermal energy, the solar membrane distillation desalination system (SMDDS) is a potential technology for resolving energy and water resource problems. Small-scale SMDDS (s-SMDDS) is an attractive and viable option for the production of fresh water for small communities in remote arid areas. The minimum cost design and operation of s-SMDDS are determined by a systematic method, which involves a pseudo-steady-state approach for equipment sizing and dynamic optimization using overall system mathematical models. Two s-SMDDS employing an air gap membrane distillation module with membrane areas of 11.5 m2 and 23 m2 are analyzed. The lowest water production costs are $5.92/m3 and$5.16/m3 for water production rates of 500 kg/day and 1000 kg/day, respectively. For these two optimal cases, the performance ratios are 0.85 and 0.91; the recovery ratios are 4.07% and 4.57%. The effect of membrane characteristics on the production cost is investigated. For the commercial membrane employed in this study, the increase of the membrane mass transfer coefficient up to two times is beneficial for cost reduction.[[notice]]補正完畢[[incitationindex]]SCI[[incitationindex]]EI[[booktype]]電子

Ultrafine MnFeO4 powder preparation by combusting the coprecipitate with and without Mg2+ or Zn2+ additives

[[abstract]]Ultrafine MnFe2O4 powder with its crystallites less than 100 nm was prepared using a combustion process. The coprecipitates containing the stoichiometric amount of Mn2+ and Fe3+ to form MnFe2O4 were prepared by dissolving the required metallic nitrates in de-ionized water and adding NH4OH to adjust the pH of the solutions to 9. The collected dried precipitates were then heated up to predetermined temperatures and then quickly contacted with the acetone spray. Upon contacting with the heated precipitates, the acetone spray was ignited. The combustion of acetone caused the precipitates to form crystalline MnFe2O4 without chemical segregation. The crystallinity of MnFe2O4 powder so obtained depended on the ignition temperature of acetone spray. MnFe2O4 powder obtained at acetone ignition temperature of 773 K had higher crystallinity than that obtained at acetone ignition temperature of 523 K. The presence of a small amount of Mg2+ or Zn2+ in the composition of the coprecipitates promoted the mobility of constituent ions of the combusted powder and resulted in bigger MnFe2O4 crystallites at a lower acetone ignition temperature.[[incitationindex]]SCI[[incitationindex]]EI[[booktype]]紙本[[booktype]]電子

Syndrome-based Fusion Rules in Heterogeneous Distributed Quickest Change Detection

In this paper, the heterogeneous distributed quickest change detection (HetDQCD) with 1-bit non-anonymous feedback is studied. The concept of syndromes is introduced and the family of syndrome-based fusion rules is proposed, which encompasses all deterministic fusion rules as special cases. Through the Hasse diagram of syndromes, upper and lower bounds on the second-order performance of expected detection delay as a function of average run length to false alarm are provided. An interesting instance, the weighted voting rule previously proposed in our prior work, is then revisited, for which an efficient pruning method for breadth-first search in the Hasse diagram is proposed to analyze the performance. This in turn assists in the design of the weight threshold in the weighted voting rule. Simulation results corroborate that our analysis is instrumental in identifying a proper design for the weighted voting rule, demonstrating consistent superiority over both the anonymous voting rule and the group selection rule in HetDQCD

Structural and cognitive deficits in chronic carbon monoxide intoxication: a voxel-based morphometry study

BACKGROUND: Patients with carbon monoxide (CO) intoxication may develop ongoing neurological and psychiatric symptoms that ebb and flow, a condition often called delayed encephalopathy (DE). The association between morphologic changes in the brain and neuropsychological deficits in DE is poorly understood. METHODS: Magnetic resonance imaging and neuropsychological tests were conducted on 11 CO patients with DE, 11 patients without DE, and 15 age-, sex-, and education-matched healthy subjects. Differences in gray matter volume (GMV) between the subgroups were assessed and further correlated with diminished cognitive functioning. RESULTS: As a group, the patients had lower regional GMV compared to controls in the following regions: basal ganglia, left claustrum, right amygdala, left hippocampus, parietal lobes, and left frontal lobe. The reduced GMV in the bilateral basal ganglia, left post-central gyrus, and left hippocampus correlated with decreased perceptual organization and processing speed function. Those CO patients characterized by DE patients had a lower GMV in the left anterior cingulate and right amygdala, as well as lower levels of cognitive function, than the non-DE patients. CONCLUSIONS: Patients with CO intoxication in the chronic stage showed a worse cognitive and morphologic outcome, especially those with DE. This study provides additional evidence of gray matter structural abnormalities in the pathophysiology of DE in chronic CO intoxicated patients

Dynamics of Rapidly Rotating Bose-Einstein Quantum Droplets

The work theoretically investigates the dynamics of trapped rapidly rotating Bose-Einstein droplets governed by the modified Gross-Pitaevskii equation with the inclusion of Lee-Huang-Yang nonlinear interaction. Mimicking the quantum Hall systems, the stationary properties of droplets are obtained by minimizing the energy functional established based on the Laughlin-like wavefunction including Landau-Level mixing. By tuning the particle-particle interaction and rotation speed, the preference of the formation of the center-of-mass state, vortex state, and off-centered vortex state can be distinguished on the phase diagram. Under fast rotations, the highly-spiral phase portraits reveal that the emergence of huge vortices with high angular momentum would stabilize the droplets against centrifugal depletion. By solving Euler-Lagrange equations, the periodicity and stability of each phase's breathing and trajectory during long-time evolution are analyzed. As a signature of superfluids, the generation of nonuniform persistent currents of multiple topological charges is also a direct reflection of dynamic breathing induced by the Landau-Level mixing effect