Part A: Antimalarial agents modified at the C-16 position of artemisinin; Part B: Lead optimization of falcipain-2 and falcipain-3 inhibitors

Part A: Antimalarial Agents modified at the C-16 position of Artemisinin. Malaria is a widespread tropical and subtropical parasitic disease which is caused by malarial parasites and transmitted by the infected anopheles mosquitoe. The natural product artemisinin and its derivatives are currently considered the most effective drugs against drug resistant plasmodium falciparum. However, its undesired physicochemical proprieties have limited its usage. In order to improve its effectiveness, scientists around the world have developed novel methodology to synthesize artemisinin derivatives on different positions of the artemisinin skeleton. Previous work in our group has shown that many analogues modified at the C-16 of artemisinin had improved efficacy along with modified physicochemical proprieties. This work focuses on the synthesis of heteroatomic and heterocyclic derivatives of artemisinin with the emphasis on C-16 substituted triazole containing side-chains. Successful synthetic results and subsequent bioassay demonstrated that the compounds have modest antimalarial activity compared to artemisinin and improved water solubility. With these encouraging results in hand, further work is underway to tune the desired physicochemical properties so that plasma half-life and oral bioavailability will be improved. Part B: Lead Optimization of Falcipain-2 and Falcipain-3 Inhibitors. The expanding usage of artemisinin combination therapy casts concern about the potential development of drug resistance to this drug family, thus the search for new drug targets is always needed. Falcipain-2 (FP-II) and falcipain-3 (FP-III) are two cysteine proteases which malarial parasites utilize to degrade hemoglobin to obtain amino acids essential to the parasite. The inhibition of these two enzymes has been shown to have deadly effects on the protozoan life cycle. Recently published crystal structures of FP-II provided an outstanding opportunity for rational drug design and discovery. In the present study, structure-based optimization of virtual screening hits was carried out using scaffold hopping, docking and analogue synthesis. Unfortunately, the biological evaluation of the synthesized compounds against FP-II and FP-III indicated these compounds are inactive. However, the information gained from this exercise could aid further in optimization of this series of compounds

Context-aware Event Forecasting via Graph Disentanglement

Event forecasting has been a demanding and challenging task throughout the entire human history. It plays a pivotal role in crisis alarming and disaster prevention in various aspects of the whole society. The task of event forecasting aims to model the relational and temporal patterns based on historical events and makes forecasting to what will happen in the future. Most existing studies on event forecasting formulate it as a problem of link prediction on temporal event graphs. However, such pure structured formulation suffers from two main limitations: 1) most events fall into general and high-level types in the event ontology, and therefore they tend to be coarse-grained and offers little utility which inevitably harms the forecasting accuracy; and 2) the events defined by a fixed ontology are unable to retain the out-of-ontology contextual information. To address these limitations, we propose a novel task of context-aware event forecasting which incorporates auxiliary contextual information. First, the categorical context provides supplementary fine-grained information to the coarse-grained events. Second and more importantly, the context provides additional information towards specific situation and condition, which is crucial or even determinant to what will happen next. However, it is challenging to properly integrate context into the event forecasting framework, considering the complex patterns in the multi-context scenario. Towards this end, we design a novel framework named Separation and Collaboration Graph Disentanglement (short as SeCoGD) for context-aware event forecasting. Since there is no available dataset for this novel task, we construct three large-scale datasets based on GDELT. Experimental results demonstrate that our model outperforms a list of SOTA methods.Comment: KDD 2023, 9 pages, 7 figures, 4 table

Fine-grained Data Distribution Alignment for Post-Training Quantization

While post-training quantization receives popularity mostly due to its evasion in accessing the original complete training dataset, its poor performance also stems from scarce images. To alleviate this limitation, in this paper, we leverage the synthetic data introduced by zero-shot quantization with calibration dataset and propose a fine-grained data distribution alignment (FDDA) method to boost the performance of post-training quantization. The method is based on two important properties of batch normalization statistics (BNS) we observed in deep layers of the trained network, (i.e.), inter-class separation and intra-class incohesion. To preserve this fine-grained distribution information: 1) We calculate the per-class BNS of the calibration dataset as the BNS centers of each class and propose a BNS-centralized loss to force the synthetic data distributions of different classes to be close to their own centers. 2) We add Gaussian noise into the centers to imitate the incohesion and propose a BNS-distorted loss to force the synthetic data distribution of the same class to be close to the distorted centers. By utilizing these two fine-grained losses, our method manifests the state-of-the-art performance on ImageNet, especially when both the first and last layers are quantized to the low-bit. Code is at \url{https://github.com/zysxmu/FDDA}.Comment: ECCV202

7β-Hydroxy­artemisinin

Crystals of the title compound [systematic name: (3R,6R,7S,8aR,9R,12aR)-7-hydr­oxy-3,6,9-trimethyl­octa­hydro-3,12-ep­oxy[1,2]dioxepino[4,3-i]isochromen-10(3H)-one], C15H22O6, were obtained from microbial transformation of artemisinin by a culture of Cunninghamella elegans. The stereochemistry of the compound is consistent with the spectroscopic findings in previously published works. A weak O—H⋯O hydrogen bond occurs in the crystal structure, together with intermolecular C—H⋯O hydrogen bonds

Ultralow thermal conductivity of single crystalline porous silicon nanowires

Porous materials provide a large surface to volume ratio, thereby providing a knob to alter fundamental properties in unprecedented ways. In thermal transport, porous nanomaterials can reduce thermal conductivity by not only enhancing phonon scattering from the boundaries of the pores and therefore decreasing the phonon mean free path, but also by reducing the phonon group velocity. Here we establish a structure-property relationship by measuring the porosity and thermal conductivity of individual electrolessly etched single crystalline silicon nanowires using a novel electron beam heating technique. Such porous silicon nanowires exhibit extremely low diffusive thermal conductivity (as low as 0.33 Wm-1K-1 at 300K for 43% porosity), even lower than that of amorphous silicon. The origin of such ultralow thermal conductivity is understood as a reduction in the phonon group velocity, experimentally verified by measuring the Young modulus, as well as the smallest structural size ever reported in crystalline Silicon (less than 5nm). Molecular dynamics simulations support the observation of a drastic reduction in thermal conductivity of silicon nanowires as a function of porosity. Such porous materials provide an intriguing platform to tune phonon transport, which can be useful in the design of functional materials towards electronics and nano-electromechanical systems

Reply to: Mobility overestimation in MoS2_2 transistors due to invasive voltage probes

In this reply, we include new experimental results and verify that the observed non-linearity in rippled-MoS$_2$ (leading to mobility kink) is an intrinsic property of a disordered system, rather than contact effects (invasive probes) or other device issues. Noting that Peng Wu's hypothesis is based on a highly ordered ideal system, transfer curves are expected to be linear, and the carrier density is assumed be constant. Wu's model is therefore oversimplified for disordered systems and neglects carrier-density dependent scattering physics. Thus, it is fundamentally incompatible with our rippled-MoS$_2$, and leads to the wrong conclusion

Amorphous 1-D nanowires of calcium phosphate/pyrophosphate : A demonstration of oriented self-growth of amorphous minerals

Amorphous inorganic solids are traditionally isotropic, thus, it is believed that they only grow in a non-preferential way without the assistance of regulators, leading to the morphologies of nanospheres or irregular aggregates of nanoparticles. However, in the presence of (ortho)phosphate (Pi) and pyrophosphate ions (PPi) which have synergistic roles in biomineralization, the highly elongated amorphous nanowires (denoted ACPPNs) form in a regulator-free aqueous solution (without templates, additives, organics, etc). Based on thorough characterization and tracking of the formation process (e.g., Cryo-TEM, spherical aberration correction high resolution TEM, solid state NMR, high energy resolution monochromated STEM-EELS), the microstructure and its preferential growth behavior are elucidated. In ACPPNs, amorphous calcium orthophosphate and amorphous calcium pyrophosphate are distributed at separated but close sites. The ACPPNs grow via either the preferential attachment of ∼2 nm nanoclusters in a 1-dimension way, or the transformation of bigger nanoparticles, indicating an inherent driving force-governed process. We propose that the anisotropy of ACPPNs microstructure, which is corroborated experimentally, causes their oriented growth. This study proves that, unlike the conventional view, amorphous minerals can form via oriented growth without external regulation, demonstrating a novel insight into the structures and growth behaviors of amorphous minerals