Search

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4–11 cells at low picomolar concentrations (IC(50) = 3 pM; BRD4 DC(50) = 0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.

Magnetic molecules have shown great potential in quantum information processing due to the chemical tunablity of their quantum behaviors. Chemical derivatives of endohedral nitrogen fullerenes with long coherence time and rich energy levels were synthesized and studied to demonstrate the ability of multiprocessing in quantum information using electron magnetic resonance. After initialization of the 12-levelled spin system, subgroups of spin energy levels coursed by the hyperfine couplings can be selectively manipulated. The cooperatively combining of the parallel calculations enabled quantum error correction, increasing the correct rate by up to 17.82 %. Also, different subgroups of transitions divided by hyperfine coupling can be treated as independent qubits, and multi-task quantum computing were realized by performing Z-gate and X-gate simultaneously, which accelerates the overall gating speed.

Streamflow forecasts at monthly and sub-monthly time scales, e.g. 10-day period, are critical for making decisions to allocate water for different users and mitigate possible flooding. Adaptive forecasting of 10-day streamflow is still challenging, although persistence prediction models sometimes have good performance when streamflow has strong lag-correlation. This study proposes a scheme of proving monthly and sub-monthly flow forecasts at the beginning of the month and updating sub-monthly forecasts subsequently. It examines a principal component regression method to provide monthly average streamflow and sub-monthly, e.g. 10-day, average streamflow forecasts, utilizing gridded precipitation forecasts from climate models and soil moisture estimates from hydrological models. Monthly streamflow forecasts are first obtained. It is then disaggregated to 10-day streamflow based on historical observations using a nonparametric approach. The disaggregated 10-day streamflow forecasts are further improved by incorporating streamflow and soil moisture estimates in the previous 10 days. Hence, sub-monthly flow can be improved adaptively. The proposed approach is demonstrated for monthly and sub-monthly streamflow forecasts in July at the Yangtze River, the largest river in China. The correlation between monthly streamflow forecasts and observation is 0.46 in leave-one-out cross-validation mode. Updated sub-monthly streamflow shows better skill than disaggregated sub-monthly forecasts. To examine the impact of the accuracy of monthly streamflow forecasts on disaggregated 10-day streamflow, synthetic streamflow time series of different level of forecasting skills were examined. Results show that the higher skill of synthetic monthly streamflow forecasts, the lower forecasts error. The value of soil moisture estimates in proving streamflow forecasts is also examined.

A number of watersheds are selected from the Hydro-Climate Data Network over southeastern United States to examine possible changes in hydrological time series, e.g. precipitation, introduced by changing climate. Possible changes in monthly precipitation are examined by three different methods to detect second order stationarity, abrupt changes in the variance and smooth changes in quantiles of the time series. An analysis of second order stationarity shows that precipitation in eight of the 56 watersheds display nonstationary behaviour. Change-point analyses reveal that changes in the long-term variance of monthly precipitation are only detected for a few sites. As a complementary analysis tool, quantile regression aims to detect potential changes of different percentiles of the monthly precipitation over time. Several sites show diverging trends in the quantiles, which implies that the range and thus variance of the data, is increasing. As distinct change-points are not identified, this suggests that the effect is small and cumulative. Results are analysed in detail, and possible explanations are provided. This type of thorough analysis provides a basis for understanding the possible redistribution of water cycle. It also provides implications for water resources management and hydrological engineering facility design and planning.

Vacuum Assisted Resin Transfer Molding (VARTM) hasproven to be a cost effective process for manufactur-ing composite structures compared with prepreg/auto-clave and traditional resin transfer molding (RTM) proc-esses. However, VARTM has not been accomplishedwith high temperature resins (such as polyimides) untilrecently, primarily because no resins had low melt vis-cosity and long melt stability that are required byVARTM. With the recent invention of phenylethynyl ter-minated imides (PETIs), high temperature VARTM hasbeen achieved. Two processing methods, in-plane andthrough-thickness resin flow, were proposed andtested. Both methods are capable of fabricating polyi-mide matrix composites; and the carbon fiber lami-nates yield good fiber-resin interfacial bonding andcomparable mechanical properties to those laminatesfabricated using RTM.

Cellular retinoic acid binding protein (CRABP) is a member of intracellular lipid-binding protein (iLBP), and closely associated with retinoic acid (RA) activity. We have cloned the CRABP gene from silkworm pupae and studied the interaction between Bombyx mori CRABP (BmCRABP) and all-trans retinoic acid (atRA). The MTT assay data indicated that when BmCRABP is overexpressed in Bm5 cells, the cells dramatically resisted to atRA-induced growth inhibition. Conversely, the cells were sensitive to atRA treatment upon knocking down the BmCRABP expression. Subcellular localization revealed that BmCRABP is a cytoplasm protein, even when treated with atRA, the CRABP still remained in the cytoplasm. These data demonstrated that the function of BmCRABP have an effect on the physiological function of atRA.

According to the classical electrodynamics, a new and reasonable method about electrostatic energy decomposition of the solute-solvent system has been proposed in this work by introducing the concept of spring energy. This decomposition in equilibrium solvation gives the clear comprehension for different parts of total electrostatic free energy. Logically extending this cognition to nonequilibrium leads to the new formula of electrostatic free energy of nonequilibrium state. Furthermore, the general solvation shift for light absorption/emission has been reformulated and applied to the ideal sphere case with the monopole approximation and multipole expansion. Solvation shifts in vertical ionizations of atomic ions of some series of main group elements have been investigated with monopole approximation, and the variation tendency of the solvation shift versus atomic number has been discussed. Moreover, the solvation shift in photoionization of nitrate anion in glycol has been investigated by the multipole expansion method.

An advanced cellular automaton model (CA) was designed for earthquake preparation process in a single fault in this paper. By designing the energy exchange between the circumstance and the model by loading and the nonlinear interaction among the cells of the model, we tried to understand the mechanism of seismicity feature. Compared with the cellular automaton models published before, the cellular automaton model in this paper is much closer to the natural seismic preparation system because of the improvement of sampling and the introduction of time-dependent frictional mechanism. The results show that the method of sampling is important for the temporal heterogeneous feature of the man-made seismic catalog and the breaking of each cell and that the events with low magnitude and large magnitude obey respectively remarkably different magnitude-frequency relationships.

Oral submucous fibrosis is a high risk precancerous condition and is suggested to be caused by areca nut chewing. Areca nut chewing is popular in Hunan Province of China, and is more concentrated in Xiangtan City. Two and nine cases of oral submucous fibrosis (OSF) were first noticed in 1984 and 1985 respectively, and an epidemiologic survey was subsequently performed in 1986. The epidermiologic method of cluster sampling was used. The Yuhu District, one of the five urban districts of the Xiangtan City with a population of 100,000 was selected as a whole body in the survey, 57 independent units of various professions were randomly selected as group samples and more than 70% of subjects in each unit were examined. Definite fibrous band on palpation was used as a main diagnostic criterion for OSF. A total of 11046 individuals were examined; among them were 3907 areca nut chewers (35.37%) and 7139 non-chewers (64.63%). 335 cases of OSF were found, comprising a prevalence rate of 3.03%. The disease involved mainly the middle third of the oral cavity. All of the OSF cases were areca nut chewers. No case had been found in non-chewers. Four cases of oral carcinoma were found on the basis of OSF, the malignant transformation rate was 1.19%. The high prevalence of OSF may be due to areca nut chewing plus extensive and heavy use of hot pepper in Xiangtan people. The result supports the role of the areca nut as an etiologic factor in the development of OSF. The low malignant transformation rate of 1.19% compared with the 7.6% in an Indian report may be because Xiangtan people chew areca nut without tobacco.

The fast atom bombardment (FAB) mass spectra of telluronium salts were studied. The spectra exhibit the intact cation (C+) and cluster ions ([M + C]+). The principal fragment ions in the FAB mass spectra of telluronium salts are [RTe]+, [R2Te]+˙, [R2Te − H]+, [RTeR′]+˙, and [RTeR′ + H]+. When the anion was [BPh4]−, interesting cluster ions such as [M + C − BPh3]+ appeared.

The positive-ion fast atom bombardment (FAB) mass spectra of stibonium salts have been studied. The spectra exhibit an abundant intact cation (C + ) and fragment ions resulting from the loss of R,R' or stable neutral species from the cation. The principal fragment ions in the FAB mass spectra of stibonium salts are [R 3 Sb] +. , [R 2 Sb] + , [R 2 SbH 2 ] + , [RSbR'] + , [RSbH] + , [RSb-H] + and [R 2 SbR'] +. . In most cases, [M+C] + cluster ions were detected. When the anion was bromine, the adduct ions [M+(R-H)Sb] + , [C+(R−H)] + and [C+(R'−H)] + were also observed, whereas when the anion was [BPh 4 ] − , interesting cluster ions such as [M=BR'−H)] + and [M+(BR'−3H)] + appeared

The EI mass spectra of seven 1,1′-(3-oxa-pentamethylene)-dicyclopentadienyl lanthanide and yttrium chlorides (1–7), and eleven dicyclopentadienyl lanthanide and yttrium chlorides (8–18) were investigated. Fragmentation patterns of these complexes were studied by using metastable ion measurements. The EI spectra of complexes 1–7 exhibited strong molecular ion peaks, the fragmentation of molecular ions were more complicated. The EI mass spectra of complexes 8–18 supported the dimeric structure under gaseous state. In the spectra of dimers (C5H5)3LN+ observed were resulted from the skeletal rearrangement involving the migration of cyclopentadienyl moiety.