New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention and Cure.

Previously, we showed that substitution of HIV-1 Env residue 375-Ser by bulky aromatic residues enhances binding to rhesus CD4 and enables primary HIV-1 Envs to support efficient replication as simian-human immunodeficiency virus (SHIV) chimeras in rhesus macaques (RMs). Here, we test this design strategy more broadly by constructing SHIVs containing ten primary Envs corresponding to HIV-1 subtypes A, B, C, AE and AG. All ten SHIVs bearing wildtype Env375 residues replicated efficiently in human CD4+ T cells, but only one replicated efficiently in primary rhesus cells. This was a subtype AE SHIV that naturally contained His at Env375. Replacement of wildtype Env375 residues by Trp, Tyr, Phe or His in the other nine SHIVs led to efficient replication in rhesus CD4+ T cells in vitro and in vivo Nine SHIVs containing optimized Env375 alleles were grown large-scale in primary rhesus CD4+ T cells to serve as challenge stocks in preclinical prevention trials. These virus stocks were genetically homogeneous, native-like in Env antigenicity and tier-2 neutralization sensitivity, and transmissible by rectal, vaginal, penile, oral or intravenous routes. To facilitate future SHIV constructions, we engineered a simplified second-generation design scheme and validated it in RMs. Overall, our findings demonstrate that SHIVs bearing primary Envs with bulky aromatic substitutions at Env375 consistently replicate in RMs, recapitulating many features of HIV-1 infection in humans. Such SHIVs are efficiently transmitted by mucosal routes common to HIV-1 infection and can be used to test vaccine efficacy in preclinical monkey trials.ImportanceSHIV infection of Indian rhesus macaques is an important animal model for studying HIV-1 transmission, prevention, immunopathogenesis and cure. Such research is timely, given recent progress with active and passive immunization and novel approaches to HIV-1 cure. Given the multifaceted roles of HIV-1 Env in cell tropism and virus entry, and as a target for neutralizing and non-neutralizing antibodies, Envs selected for SHIV construction are of paramount importance. Until recently, it has been impossible to strategically design SHIVs bearing clinically relevant Envs that replicate consistently in monkeys. This changed with the discovery that bulky aromatic substitutions at residue Env375 confer enhanced affinity to rhesus CD4. Here, we show that 10 new SHIVs bearing primary HIV-1 Envs with residue 375 substitutions replicated efficiently in RMs and could be transmitted efficiently across rectal, vaginal, penile and oral mucosa. These findings suggest an expanded role for SHIVs as a model of HIV-1 infection.

Synthesis, Characterization of NR@SiO2/PNIPAm-co-Ppa Composite Nanogel and Study On Its Application in Photodynamic Therapy.

In the present study, a novel composite nanogel based on fluorescence resonance energy transfer (FRET) and its application for photodynamic therapy is reported. First of all, nanoparticles of silica doped with Nile Red (NR) were prepared by Stöber method, then they were decorated by γ-methacryloxypropyltrimethoxysilane (MPS) to prepare MPS decorated NR@SiO2 nanoparticles, and finally they were copolymerized with N-isopropylacrylamide (NIPAm) and Pyropheophorbide-a (Ppa) by free radical copolymerization, and composite nanogel of NR@SiO2/PNIPAm-co-Ppa was fabricated. The microstructure of the as-prepared nanogel was characterized by Fourier transform infrared spectrum (FTIR), photoluminescence (PL), UV-Visible spectrophotometer (UV-Vis), dynamic light scattering (DLS) and transmission electron microscopy (TEM). PL spectrum indicated that, under irradiation of visible light source, energy can be transferred from NR to Ppa. UV-Vis spectrum demonstrated that aggregation of Ppa is prevented efficiently and Ppa exists as "monomer" state in the composite nanogel. Under irradiation of laser, singlet oxygen (1O2) can be produced efficiently by excited nanogel. The in vitro cytotoxicity test showed that HeLa cells can be killed by the composite nanogel.

Value of ambroxol in the treatment of asthmatic bronchitis.

OBJECTIVE: To investigate the clinical effect of ambroxol in the treatment of asthmatic bronchitis. METHODS: One hundred and twenty patients with asthmatic bronchitis who were admitted to our hospital from June 2017 to August 2018 were selected as the research subjects and divided into a control group and an observation group according to random number table method, 60 in each group. The control group was treated with conventional treatment, while the observation group was treated with ambroxol in addition to conventional treatment. The therapeutic effect, disappearance time of symptoms and signs and the recovery of pulmonary function were compared between the two groups. RESULTS: The total effective rate of the observation group was 96.7%, and that of the control group was 73.3%. The control effect of the observation group was significantly better than that of the control group, showing a significant difference (P<0.05). The disappearance time of symptoms of the observation group was shorter than that of the control group, and the recovery of pulmonary function was better; the differences were statistically significant (P<0.05). CONCLUSION: For asthmatic bronchitis patients, addition of ambroxol to conventional treatment can improve the therapeutic effect, shorten the disappearance time of clinical signs and symptoms, and promote the recovery of patients, which is worth clinical application.

Pharmacokinetic Characterizations of Ginsenoside Ocotillol, RT5 and F11, the Promising Agents for Alzheimer's Disease from American Ginseng, in Rats and Beagle Dogs.

BACKGROUND: Ocotillol, RT5 and F11, the main active components of ocotillol type ginsenosides, have attracted a lot of attention due to their beneficial effects on neurodegenerative disease models of Alzheimer's disease. Pharmacokinetic (PK) is a bridge linking the herbal medicines and their pharmacological responses. However, few data are available regarding PK behaviors of ocotillol type ginsenosides. METHODS: The liquid chromatography-tandem mass spectrometry methods were developed and validated to calculate the concentrations of 3 ginsenosides in different biological matrices. Rat and beagle dog plasma samples were deproteinized with methanol and separated on Shim-pack GIST C18 column. All of the analytes were detected in positive ion mode using multiple reaction monitoring. RESULTS: The methods showed good linearity (r > 0.996) in the established concentration range. All validated data, such as specificity, intra- and inter-day precision, accuracy, extraction recovery, matrix effect, and stability were within required limits. The values of Cmax and AUC(0-t) indicated ocotillol type ginsenosides had low systemic exposure and poor absorption into blood. T1/2 and MRT(0-t) demonstrated the elimination process of ocotillol type ginsenosides might be slow. Double peaks were observed in the mean plasma concentration versus time profiles of ocotillol, RT5, and F11 after oral intake. CONCLUSIONS: This was the first PK investigation of the ocotillol type ginsenosides in rats and beagle dogs. The results we found here were helpful to our understanding of the absorption mechanism of ocotillol type ginsenosides and provided the scientific basis for further pre-clinical research.

Costunolide enhances sensitivity of K562/ADR chronic myeloid leukemia cells to doxorubicin through PI3K/Akt pathway.

Costunolide, a sesquiterpene lactone, a small molecular monomer extracted from Inula helenium, has been reported to possess antiproliferative effects on several cancer cell lines. The current study was designed to evaluate the effect of costunolide on sensitivity of K562/ADR chronic myeloid leukemia cells to doxorubicin. The antiproliferative effect of costunolide was assessed by CCK-8 assay. Flow cytometry and Western blot were used to examine the mechanisms of antileukemia action. Costunolide dramatically enhanced doxorubicin-induced antiproliferative activity against K562/ADR cells through inhibition of PI3K/Akt pathway, activation of caspases 3, cleavage of poly (ADP-ribose) polymerase, and downregulation of p-glycoprotein expression. These results demonstrate that costunolide may be a potent therapeutic agent against CML.

Orbicular-Donor-Acceptor System in N-doped Nanographene for Highly Efficient NIR-II Photothermal Therapy.

Developing stable and efficient photothermal agents (PTAs) for the second near-infrared window (NIR-II, 1 000-1700 nm) photothermal therapy (PTT) is highly desirable but remains challenging. Herein, a facile strategy to prepare NIR-II nano-PTA based on the ionic N-doped nanographene hexapyrrolohexaazacoronene (HPHAC) is reported featuring a specific orbicular-donor-acceptor (O-D-A) structure. Oxidizing HPHAC 1 to dication 12+ causes a substantial decrease in its band gap, leading to a shift in absorption from the confined UV region to a broad absorption range that reaches up to 1400 nm. The dication 12+ exhibits global aromaticity and excellent stability. Theoretical investigation demonstrates that the strong NIR-II absorption of 12+ is attributed to a distinct inner-to-outer intramolecular charge transfer. Encapsulating 12+ with amphiphilic polymers results in water-soluble 12+ NPs with retained optical characteristics. The 12+ NPs exhibit exceptional biocompatibility, intense photoacoustic responses, and a high photothermal conversion efficiency of 72% under the 1064 nm laser irradiation, enabling efficient PTT of cancer cells. The "O-D-A" system on HPHAC, which is created by a simple redox approach, provides a novel strategy to construct efficient NIR-II photothermal materials through molecular engineering of nanographenes.

Density functional study of organocatalytic cross-aldol reactions between two aliphatic aldehydes: insight into their functional differentiation and origins of chemo- and stereoselectivities.

The chemo-, diastereo-, and enantioselectivities in proline and axially chiral amino sulfonamide-catalyzed direct aldol reactions between two enolizable aldehydes with different electronic nature have been studied with the aid of density functional theory (DFT) method. The potential energy profiles for the enamine formation between each aliphatic aldehyde and the catalyst confirm that two subject catalysts can successfully differentiate between 3-methylbutanal as an enamine component and α-chloroaldehydes as a carbonyl component. Transition states associated with the stereochemistry-determining C-C bond-forming step with the enamine intermediate addition to the aldehyde acceptor for proline and chiral amino sulfonamide-promoted aldol reactions are reported. DFT calculations not only provide a good explanation for the formation of the sole cross-aldol product between two aliphatic aldehydes both bearing α-methylene protons but also well reproduce the opposite syn vs anti diastereoselectivities in the chiral amino sulfonamide and proline-catalyzed aldol reactions.

Neonatal SHIV infection in rhesus macaques elicited heterologous HIV-1-neutralizing antibodies.

Infants and children infected with human immunodeficiency virus (HIV)-1 have been shown to develop neutralizing antibodies (nAbs) against heterologous HIV-1 strains, characteristic of broadly nAbs (bnAbs). Thus, having a neonatal model for the induction of heterologous HIV-1 nAbs may provide insights into the mechanisms of neonatal bnAb development. Here, we describe a neonatal model for heterologous HIV-1 nAb induction in pathogenic simian-HIV (SHIV)-infected rhesus macaques (RMs). Viral envelope (env) evolution showed mutations at multiple sites, including nAb epitopes. All 13 RMs generated plasma autologous HIV-1 nAbs. However, 8/13 (62%) RMs generated heterologous HIV-1 nAbs with increasing potency over time, albeit with limited breadth, and mapped to multiple nAb epitopes, suggestive of a polyclonal response. Moreover, plasma heterologous HIV-1 nAb development was associated with antigen-specific, lymph-node-derived germinal center activity. We define a neonatal model for heterologous HIV-1 nAb induction that may inform future pediatric HIV-1 vaccines for bnAb induction in infants and children.

Preparation, stimuli-response performance of HPC-PMAA/PpIX nanogels and their application in photodynamic therapy.

In the present study, a novel nanogel of HPC-PMAA/PpIX with thermo- and pH sensitive performance and its application in cancer photodynamic therapy is reported. HPC-PMAA/PpIX nanogels were prepared by free radical polymerization method with HPC as template, hydroxypropyl cellulose (HPC), methyl acrylic acid (MAA), protoporphyrin IX (PpIX) and N,N'-methylene bisacrylamide (BIS) as raw materials. The as-prepared nanogels were characterized by Fourier transform infrared (FTIR), photoluminescence (PL) and UV-visible spectrophotometer (UV-vis), dynamic light scattering (DLS) and transmission electron microscopy (TEM). PL and UV-vis spectra demonstrate that PpIX is incorporated into HPC-PMAA by covalent bonds, and its aggregation is prevented. Moreover, the as-prepared nanogels can be dispersed in water over 1 week, significant singlet oxygen can be produced under irradiation of laser. With tumor cell of HepG2 as model cell, the nanogels are biocompatible with cell viability of >85% even at high concentrations of the PpIX in vitro. In addition, the HPC-PMAA/PpIX nanogels show photo-dependent toxicity in the concentration range of 10 µg/mL of PpIX, suggesting that HPC-PMAA/PpIX nanogels have potential for the treatment of photodynamic therapy (PDT).

Modulation of Host Antiviral Innate Immunity by African Swine Fever Virus: A Review.

African swine fever (ASF), caused by African swine fever virus (ASFV), is a highly contagious and fatal disease found in swine. However, the viral proteins and mechanisms responsible for immune evasion are poorly understood, which has severely hindered the development of vaccines. This review mainly focuses on studies involving the innate antiviral immune response of the host and summarizes the latest studies on ASFV genes involved in interferon (IFN) signaling and inflammatory responses. We analyzed the effects of candidate viral proteins on ASFV infection, replication and pathogenicity and identified potential molecular targets for novel ASFV vaccines. These efforts will contribute to the construction of novel vaccines and wonder therapeutics for ASF.

Wearable Near-Field Communication Sensors for Healthcare: Materials, Fabrication and Application.

The wearable device industry is on the rise, with technology applications ranging from wireless communication technologies to the Internet of Things. However, most of the wearable sensors currently on the market are expensive, rigid and bulky, leading to poor data accuracy and uncomfortable wearing experiences. Near-field communication sensors are low-cost, easy-to-manufacture wireless communication technologies that are widely used in many fields, especially in the field of wearable electronic devices. The integration of wireless communication devices and sensors exhibits tremendous potential for these wearable applications by endowing sensors with new features of wireless signal transferring and conferring radio frequency identification or near-field communication devices with a sensing function. Likewise, the development of new materials and intensive research promotes the next generation of ultra-light and soft wearable devices for healthcare. This review begins with an introduction to the different components of near-field communication, with particular emphasis on the antenna design part of near-field communication. We summarize recent advances in different wearable areas of near-field communication sensors, including structural design, material selection, and the state of the art of scenario-based development. The challenges and opportunities relating to wearable near-field communication sensors for healthcare are also discussed.

Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth.

Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution very similar to those in humans, including conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2 apex mode of recognition like that of human broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.

A Self-Quenching System Based on Bis-Naphthalimide: A Dual Two-Photon-Channel GSH Fluorescent Probe.

A single fluorescent signal output often does not satisfy the detection accuracy requirements for bioactive compounds in biological systems. It is of great interest to develop a dual-channel turn-on fluorescence sensing system for self-validated detection. Herein, we report a self-quenching nanoparticle composed of dual two-photon dyes of naphthalimides, displaying almost no fluorescence at both channels, owing to aggregation-caused quenching (ACQ). A dual two-photon-channel fluorescent probe for GSH was further developed by inserting a disulfide bond between two naphthalimides. Upon treatment with GSH, the disulfide bond was cleaved, and two napthalimide fluorophores were separated, leading to turn-on fluorescence at both channels. This dual-two-photon-channel design strategy can be easily extended to other analytes, simply by changing the linker molecules, which creates new opportunities to accurately monitor various biological processes in living cells.

A hybrid flower pollination algorithm based modified randomized location for multi-threshold medical image segmentation.

Multi-threshold image segmentation is a powerful image processing technique that is used for the preprocessing of pattern recognition and computer vision. However, traditional multilevel thresholding methods are computationally expensive because they involve exhaustively searching the optimal thresholds to optimize the objective functions. To overcome this drawback, this paper proposes a flower pollination algorithm with a randomized location modification. The proposed algorithm is used to find optimal threshold values for maximizing Otsu's objective functions with regard to eight medical grayscale images. When benchmarked against other state-of-the-art evolutionary algorithms, the new algorithm proves itself to be robust and effective through numerical experimental results including Otsu's objective values and standard deviations.