Development of Long-acting Nanoformulated Abacavir ProTides

Combination antiretroviral therapy (cART) for treatment of human immunodeficiency virus (HIV) infection demands life-long regimen adherence. Treatment interruptions lead to a lack of virologic control and the emergence of viral mutations and drug resistance. To address these, our laboratory developed long-acting (LA) parenteral administered nanoformulated abacavir prodrug (NMABC) by formulating myristoylated abacavir (MABC) with poloxamer 407 as stabilizer, which sustained ABC levels for up to 2 weeks with low levels of active drug metabolite (CBV-TP). To more significantly extend the apparent half-life of ABC and improve its antiretroviral activities, we developed second generation long-acting ABC prodrugs by ProTide technologies. This modification can deliver pre-activated nucleoside analog inside the target cells. The work proceeded in defined manner. First, we synthesized then characterized traditional ProTides of ABC, AlaMe, with ProTide technology. The antiretroviral activity (EC50) of AlaMe was 7-fold lower then native ABC. Then, AlaMe loaded and lipid coated PLGA nanoparticle was prepared withna size of 250 nm by thin film hydration (NAlaMe). NAlaMe can be easily taken up and retained by monocyte-derived macrophages (MDM) for weeks and protect MDM against HIV infections. Male BALB/cJ mice were subcutaneously administered 54.3mg/kg ABC equivalents of NAlaMe and ABC. NAlaMe treated mice had higher CBV-TP levels than ABC at 24 and 72 h after administration. These results showed that ProTide technologies can be a useful strategy for the development of second-generation ABC LA. Second, ProTide technology was combined with LA technology. Three ABC ProTides (AlaMe, PheMe and PheC22) were successfully synthesized. AlaMe and PheMe were traditional ProTides. PheC22 possessed a long-chain fatty alcohol moiety. All three ProTides demonstrated improved antiretroviral activities compared to ABC. Nanosuspensions of PheMe (NPheMe) and PheC22 (NPheC22) were formulated using P407 as stabilizer with sizes of 388 and 340 nm, respectively. Cell uptake, retention and antiretroviral activity of NAlaMe, NPheMe, NPheC22 were tested in MDM. NPheC22 had the highest uptake, retention and was able to protect MDM against HIV-1 infection up to 30 days. Combinatorial strategies thus show advantages for the development of second-generation ABC LA.ABC ProTides had long-chain fatty esters were specifically named ABC ProTides LA. Third, we investigated the influence of different combination of amino acid and long-chain fatty alcohol on activities of ABC ProTides LA. Six ABC ProTides LA: AlaC14, AlaC18, AlaC22, PheC14, PheC18 and PheC22 were synthesized and characterized. The EC50 of ABC ProTides were up to 100- or 10-fold lower in MDM or CEM CD4+T cells against HIV infection compared to ABC. CBV-TP was increased by up to 45-fold of 8-fold in MDM or CEM CD4+T cells. Nanosuspension of all six ProTides were formulated using DSPG-mPEG2Kand Tween 80 as stabilizers. The six nanosuspension had sizes range from 220 - 300 nm. Nanosuspensions were taken up, retained and released by MDM and protected MDM against HIV-1 infection more than 28 days. PK studies in rats showed that ProTide nanosuspension provide CBV-TP over a longer time than ABC. NAlaC18 provided clinically relevant CBV-TP levels in rats up to 7 days following a single injection. In conclusion, ProTides and LA technologies were combinationally used to create second generation ABC LA. These works are a step forward in the development of long acting nucleoside reverse transcriptase inhibitors for human use

Differential expression of three galaxin-related genes during settlement and metamorphosis in the scleractinian coral Acropora millepora

BACKGROUND: The coral skeleton consists of CaCO3 deposited upon an organic matrix primarily as aragonite. Currently galaxin, from Galaxea fascicularis, is the only soluble protein component of the organic matrix that has been characterized from a coral. Three genes related to galaxin were identified in the coral Acropora millepora. RESULTS: One of the Acropora genes (Amgalaxin) encodes a clear galaxin ortholog, while the others (Amgalaxin-like 1 and Amgalaxin-like 2) encode larger and more divergent proteins. All three proteins are predicted to be extracellular and share common structural features, most notably the presence of repetitive motifs containing dicysteine residues. In situ hybridization reveals distinct, but partially overlapping, spatial expression of the genes in patterns consistent with distinct roles in calcification. Both of the Amgalaxin-like genes are expressed exclusively in the early stages of calcification, while Amgalaxin continues to be expressed in the adult, consistent with the situation in the coral Galaxea. CONCLUSION: Comparisons with molluscs suggest functional convergence in the two groups; lustrin A/pearlin proteins may be the mollusc counterparts of galaxin, whereas the galaxin-like proteins combine characteristics of two distinct proteins involved in mollusc calcification. Database searches indicate that, although sequences with high similarity to the galaxins are restricted to the Scleractinia, more divergent members of this protein family are present in other cnidarians and some other metazoans. We suggest that ancestral galaxins may have been secondarily recruited to roles in calcification in the Triassic, when the Scleractinia first appeared. Understanding the evolution of the broader galaxin family will require wider sampling and expression analysis in a range of cnidarians and other animals

Multimodality Helps Unimodality: Cross-Modal Few-Shot Learning with Multimodal Models

The ability to quickly learn a new task with minimal instruction - known as few-shot learning - is a central aspect of intelligent agents. Classical few-shot benchmarks make use of few-shot samples from a single modality, but such samples may not be sufficient to characterize an entire concept class. In contrast, humans use cross-modal information to learn new concepts efficiently. In this work, we demonstrate that one can indeed build a better ${\bf visual}$ dog classifier by ${\bf read}$ing about dogs and ${\bf listen}$ing to them bark. To do so, we exploit the fact that recent multimodal foundation models such as CLIP are inherently cross-modal, mapping different modalities to the same representation space. Specifically, we propose a simple cross-modal adaptation approach that learns from few-shot examples spanning different modalities. By repurposing class names as additional one-shot training samples, we achieve SOTA results with an embarrassingly simple linear classifier for vision-language adaptation. Furthermore, we show that our approach can benefit existing methods such as prefix tuning, adapters, and classifier ensembling. Finally, to explore other modalities beyond vision and language, we construct the first (to our knowledge) audiovisual few-shot benchmark and use cross-modal training to improve the performance of both image and audio classification.Comment: CVPR 2023. Project website: https://linzhiqiu.github.io/papers/cross_modal

Economic Dispatch of an Integrated Microgrid Based on the Dynamic Process of CCGT Plant

Intra-day economic dispatch of an integrated microgrid is a fundamental requirement to integrate distributed generators. The dynamic energy flows in cogeneration units present challenges to the energy management of the microgrid. In this paper, a novel approximate dynamic programming (ADP) approach is proposed to solve this problem based on value function approximation, which is distinct with the consideration of the dynamic process constraints of the combined-cycle gas turbine (CCGT) plant. First, we mathematically formulate the multi-time periods decision problem as a finite-horizon Markov decision process. To deal with the thermodynamic process, an augmented state vector of CCGT is introduced. Second, the proposed VFA-ADP algorithm is employed to derive the near-optimal real-time operation strategies. In addition, to guarantee the monotonicity of piecewise linear function, we apply the SPAR algorithm in the update process. To validate the effectiveness of the proposed method, we conduct experiments with comparisons to some traditional optimization methods. The results indicate that our proposed ADP method achieves better performance on the economic dispatch of the microgrid.Comment: This paper has won the Zhang Si-Ying (CCDC) Outstanding Youth Paper Award in the 33 rd Chinese Control and Decision Conference (CCDC 2021

Differential expression of three galaxin-related genes during settlement and metamorphosis in the scleractinian coral Acropora millepora

Background: The coral skeleton consists of CaCO3 deposited upon an organic matrix primarily as aragonite. Currently galaxin, from Galaxea fascicularis, is the only soluble protein component of the organic matrix that has been characterized from a coral. Three genes related to galaxin were identified in the coral Acropora millepora.\ud \ud Results: One of the Acropora genes (Amgalaxin) encodes a clear galaxin ortholog, while the others (Amgalaxin-like 1 and Amgalaxin-like 2) encode larger and more divergent proteins. All three proteins are predicted to be extracellular and share common structural features, most notably the presence of repetitive motifs containing dicysteine residues. In situ hybridization reveals distinct,\ud but partially overlapping, spatial expression of the genes in patterns consistent with distinct roles in calcification. Both of the Amgalaxin-like genes are expressed exclusively in the early stages of\ud calcification, while Amgalaxin continues to be expressed in the adult, consistent with the situation in the coral Galaxea.\ud \ud Conclusion: Comparisons with molluscs suggest functional convergence in the two groups; lustrin A/pearlin proteins may be the mollusc counterparts of galaxin, whereas the galaxin-like proteins combine characteristics of two distinct proteins involved in mollusc calcification. Database searches indicate that, although sequences with high similarity to the galaxins are restricted to the Scleractinia, more divergent members of this protein family are present in other cnidarians and some other metazoans. We suggest that ancestral galaxins may have been secondarily recruited to roles in calcification in the Triassic, when the Scleractinia first appeared. Understanding theevolution of the broader galaxin family will require wider sampling and expression analysis in a\ud range of cnidarians and other animals

Development and Validation of Liquid Chromatography-Mass Spectrometry Method for Determination of Febuxostat in Rat Plasma and its Application

A selective liquid chromatography-mass spectrometry (LC–MS) method for determination of febuxostat in rat plasma was developed and validated. After addition of midazolam as internal standard (IS), protein precipitation by acetonitrile was used as sample preparation, and chromatography involved Agilent SB-C18 column (2.1 x150 mm, 5 μm) using 0.1% formic acid in water and acetonitrile as a mobile phase with gradient elution. Detection involved positive ion mode electrospray ionization (ESI), and selective ion monitoring (SIM) mode was used for quantification of target fragment ions m/z 317 for febuxostat and m/z 326 for midazolam (internal standard, IS). The assay was linear over the range of 10-2000 ng/mL for febuxostat, with a lower limit of quantitation (LLOQ) of 10 ng/mL for febuxostat. Intra- and inter-day RSDs were less than 15% and the accuracies were in the range of 93.8-111.9% for febuxostat. This developed method was successfully applied to determinate of febuxostat in rat plasma for pharmacokinetic study.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Co-Speech Gesture Video Generation via Motion-Decoupled Diffusion Model

Co-speech gestures, if presented in the lively form of videos, can achieve superior visual effects in human-machine interaction. While previous works mostly generate structural human skeletons, resulting in the omission of appearance information, we focus on the direct generation of audio-driven co-speech gesture videos in this work. There are two main challenges: 1) A suitable motion feature is needed to describe complex human movements with crucial appearance information. 2) Gestures and speech exhibit inherent dependencies and should be temporally aligned even of arbitrary length. To solve these problems, we present a novel motion-decoupled framework to generate co-speech gesture videos. Specifically, we first introduce a well-designed nonlinear TPS transformation to obtain latent motion features preserving essential appearance information. Then a transformer-based diffusion model is proposed to learn the temporal correlation between gestures and speech, and performs generation in the latent motion space, followed by an optimal motion selection module to produce long-term coherent and consistent gesture videos. For better visual perception, we further design a refinement network focusing on missing details of certain areas. Extensive experimental results show that our proposed framework significantly outperforms existing approaches in both motion and video-related evaluations. Our code, demos, and more resources are available at https://github.com/thuhcsi/S2G-MDDiffusion.Comment: 22 pages, 8 figures, CVPR 202

Scaling relationships between leaf shape and area of 12 rosaceae species

CITATION: Yu, X., et al. 2019. Scaling relationships between leaf shape and area of 12 rosaceae species. Symmetry, 11(10):1255, doi:10.3390/sym11101255.The original publication is available at https://www.mdpi.comPublisher's versionLeaf surface area (A) and leaf shape have been demonstrated to be closely correlated with photosynthetic rates. The scaling relationship between leaf biomass (both dry weight and fresh weight) and A has been widely studied. However, few studies have focused on the scaling relationship between leaf shape and A. Here, using more than 3600 leaves from 12 Rosaceae species, we examined the relationships of the leaf-shape indices including the left to right side leaf surface area ratio (AR), the ratio of leaf perimeter to leaf surface area (RPA), and the ratio of leaf width to length (RWL) versus A. We also tested whether there is a scaling relationship between leaf dry weight and A, and between PRA and A. There was no significant correlation between AR and A for each of the 12 species. Leaf area was also found to be independent of RWL because leaf width remained proportional to leaf length across the 12 species. However, there was a negative correlation between RPA and A. The scaling relationship between RPA and A held for each species, and the estimated scaling exponent of RPA versus A approached −1/2; the scaling relationship between leaf dry weight and A also held for each species, and 11 out of the 12 estimated scaling exponents of leaf dry weight versus A were greater than unity. Our results indicated that leaf surface area has a strong scaling relationship with leaf perimeter and also with leaf dry weight but has no relationship with leaf symmetry or RWL. Additionally, our results showed that leaf dry weight per unit area, which is usually associated with the photosynthetic capacity of plants, increases with an increasing A because the scaling exponent of leaf dry weight versus A is greater than unity. This suggests that a large leaf surface area requires more dry mass input to support the physical structure of the leaf.https://www.mdpi.com/2073-8994/11/10/125