Epidemiologic changes of a longitudinal surveillance study spanning 51 years of scrub typhus in mainland China.

Scrub typhus may be one of the world's most prevalent, neglected and serious, but easily treatable, febrile diseases. It has become a significant potential threat to public health in China. In this study we used national disease surveillance data to analyze the incidence and spatial-temporal distribution of scrub typhus in mainland China during 1952-1989 and 2006-2018. Descriptive epidemiological methods and spatial-temporal epidemiological methods were used to investigate the epidemiological trends and identify high-risk regions of scrub typhus infection. Over the 51-year period, a total of 182,991 cases and 186 deaths were notified. The average annual incidence was 0.13 cases/100,000 population during 1952-1989. The incidence increased sharply from 0.09/100,000 population in 2006 to 1.93/100,000 population in 2018 and then exponentially increased after 2006. The incidence was significantly higher in females than males (χ2 = 426.32, P < 0.001). Farmers had a higher incidence of scrub typhus than non-farmers (χ2 = 684.58, P < 0.001). The majority of cases each year were reported between July and November with peak incidence occurring during October each year. The trend surface analysis showed that the incidence of scrub typhus increased gradually from north to south, and from east and west to the central area. The spatial autocorrelation analysis showed that a spatial positive correlation existed in the prevalence of scrub typhus on a national scale, which had the characteristic of aggregated distribution (I = 0.533, P < 0.05). LISA analysis showed hotspots (High-High) were primarily located in the southern and southwestern provinces of China with the geographical area expanding annually. These findings provide scientific evidence for the surveillance and control of scrub typhus which may contribute to targeted strategies and measures for the government.

UPLC-MS/MS Assay for Quantification of Wedelolactone and Demethylwedelolactone in Rat Plasma and the Application to a Preclinical Pharmacokinetic Study.

AIMS AND OBJECTIVE: Wedelolactone and demethylwedelolactone are the two major coumarin constituents of Herba Ecliptae. The objective of this work was to develop and validate a sensitive, rapid, and robust UPLC-MS/MS method for the simultaneous quantification of wedelolactone and demethylwedelolactone in rat plasma. MATERIALS AND METHODS: Wedelolactone and demethylwedelolactone were extracted from rat plasma by protein precipitation with acetonitrile. Electrospray ionization in negative mode and selected reaction monitoring (SRM) were used for wedelolactone and demethylwedelolactone at the transitions m/z 312.8→298.0 and m/z 299.1→270.6, respectively. Chromatographic separation was conducted on a Venusil C18 column (50 mm × 2.1 mm, 5 µm) with isocratic elution of acetonitrile-0.1% formic acid in water (55:45, v/v) at a flow rate of 0.3 mL/min. A linear range was observed over the concentration range of 0.25-100 ng/mL for wedelolactone and demethylwedelolactone. RESULTS: They reached their maximum plasma concentrations (Cmax, 74.9±13.4 ng/mL for wedelolactone and 41.3±9.57 ng/mL for demethylwedelolactone) at the peak time (Tmax) of 0.633 h and 0.800 h, respectively. The AUC0-t value of wedelolactone (260.8±141.8 ng h/mL) was higher than that of demethylwedelolactone (127.4±52.7 ng h/mL) by approximately 2-fold, whereas the terminal elimination half-life (t1/2) of wedelolactone (2.20±0.59 h) showed the approximately same as that of demethylwedelolactone (2.08±0.69 h). CONCLUSION: Based on full validation according to US FDA guidelines, this UPLC-MS/MS method was successfully applied to a pharmacokinetic study in rats.

Influence of Fine Ligand Substitution Modification of the Isocyanidometal Bridge on Metal-to-Metal Charge Transfer Properties in Class II-III Mixed Valence Complexes.

The synthesis and characterization of Class II-III mixed valence complexes have been an interesting topic due to their special intermediate behaviour between localized and delocalized mixed valence complexes. To investigate the influence of the isocyanidometal bridge on metal-to-metal charge transfer (MMCT) properties, a family of new isocyanidometal-bridged complexes and their one-electron oxidation products cis-[Cp(dppe)Fe-CN-Ru(L)2 -NC-Fe(dppe)Cp][PF6 ]n (n=2, 3) (Cp=1,3-cyclopentadiene, dppe=1,2-bis(diphenylphosphino)ethane, L=2,2'-bipyridine (bpy, 1[PF6 ]n ), 5,5'-dimethyl-2,2'-bipyridyl (5,5'-dmbpy, 2[PF6 ]n ) and 4,4'-dimethyl-2,2'-bipyridyl (4,4'-dmbpy, 3[PF6 ]n )) have been synthesized and fully characterized. The experimental results suggest that all the one-electron oxidation products may belong to Class II-III mixed valence complexes, supported by TDDFT calculations. With the change of the substituents of the bipyridyl ligand on the Ru centre from H, 5,5'-dimethyl to 4,4'-dimethyl, the energy of MMCT for the one-electron oxidation complexes changes in the order: 13+ <23+ <33+ , and that for the two-electron oxidation complexes decreases in the order 14+ >34+ >24+ . The potential splitting (ΔE1/2 (2)) between the two terminal Fe centres for N[PF6 ]2 are the largest potential splitting for the cyanido-bridged complexes reported so far. This work shows that the smaller potential difference between the bridging and the terminal metal centres would result in the more delocalized mixed valence complex.

The Role of Metal-Organic Frameworks in Electronic Sensors.

MOFs have a highly ordered self-assembled nanostructure, high surface area, nanoporosity with tunable size and shape, reliable host-guest interactions, and responsiveness to physical and chemical stimuli which can be exploited to address critical issues in sensor applications. On the one hand, the nanoscale pore size of MOFs ranging from less than 1 nm to ≈ 10 nm not only allows the diffusion of small molecules into the pores or through the MOF layer, but also excludes other larger molecules depending on the size, shape, and conformation of MOFs. On the other hand, MOFs with flexible structure exhibit a dynamic response to external stimuli, including guest molecules, temperature, pressure, pH, and light. Due to the unsaturated coordination metal sites and active functional groups, the interaction between certain analytes and active sites results in high selectivity. In this review, we summarize the latest studies on MOF-based electronic sensors in terms of the function of MOFs, discuss challenges, and suggest perspectives.

A Diruthenium-Based Mixed Spin Complex Ru2 5+ (S=1/2)-CN-Ru2 5+ (S=3/2).

An unusual tetra-nuclear linear cyanido-bridged complex [Ru2 (µ-ap)4 -CN-Ru2 (µ-ap)4 ](BPh4 ) (1) (ap=2-anilinopyridinate) has been synthesized and well characterized. The crystallographic data, magnetic measurement, IR, EPR and theoretical calculation results demonstrate that complex 1 is the first example of mixed spin Ru2 5+ -based complex with uncommon electronic configurations of S=1/2 for the cyanido-C bound Ru2 5+ and S=3/2 for the cyanido-N bound Ru2 5+ . This phenomenon can be understood by the theoretical calculation results that from the precursor Ru2 (µ-ap)4 (CN) (S=3/2) to complex 1 the energy gap between π* and δ* orbitals of the cyanido-C bound Ru2 5+ core increases from 0.57 to 1.61 eV due to the enhancement of asymmetrical π back-bonding effect, but that of the cyanido-N bound Ru2 5+ core is essential identical (0.56 eV). Besides, the analysis of UV/Vis-NIR spectra suggests that there exists metal to metal charge transfer (MMCT) from the cyanido-N bound Ru2 5+ (S=3/2) to the cyanido-C bound Ru2 5+ (S=1/2), supported by the TDDFT calculations.

The MMCT excited state of a localized mixed valence cyanido-bridged RuII-Ru-RuII complex.

To investigate MMCT excited states of MV complexes, two symmetrical tetranuclear cyanido-bridged localized MV complexes RuIICNRuIII,III2NCRuII have been designed and synthesized. The ultrafast time-resolved transient absorption (TA) spectroscopy experiment reveals that the MMCT rate of 1 and 2 is 0.18 × 1014 s-1 (τ = 5.7 × 10-14 s) and 0.29 × 1013 s-1 (τ = 3.46 × 10-13 s), respectively, which suggests that the MMCT rate or the lifetime of the MMCT excited state may be controlled by a slight change of the substituent group on the metal center.

Influence of ligand substitution at the donor and acceptor center on MMCT in a cyanide-bridged mixed-valence system.

We detail the rational design of bimetallic cyanide-bridged complexes [TpmRu(LD)(µ-CN)Ru(LP)Cp*][PF6]2 (Tpm = Tris(1-pyrazolyl)methane, LD = 1,10-phenanthroline (phen), 2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (dbpy), LP = bis(diphenylphosphino)methane (dppm), bis(diphenylphosphino)ethane (dppe), Cp* = 1,2,3,4,5-pentamethylcyclopentadiene). The metal-to-metal charge transfer (MMCT) properties of these one-electron oxidized complexes were investigated, suggesting that the substitution of the ancillary ligand provides a strong impetus to systematically tune the MMCT properties. The investigation results indicate that all the mixed-valence complexes belong to Class II mixed-valence complexes, according to the Robin-Day classification.

Different Degrees of Electron Delocalization in Mixed Valence Ru-Ru-Ru Compounds by Cyanido-/Isocyanido-Bridge Isomerism.

The two stable pairs of trimetallic compounds trans-[Cp*(dppe)Ru(µ-NC)Ru(dmap)4 (µ-CN)Ru(dppe)Cp*][PF6 ]n (1[PF6 ]n , n=2, 3; Cp*=1,2,3,4,5-pentamethylcyclopentadiene; dppe=1,2-bis-(diphenylphosphino)ethane; dmap= 4-dimethylaminopyridine) and trans-[Cp*(dppe)Ru(µ-CN)Ru(dmap)4 (µ-NC)Ru(dppe)Cp*][PF6 ]n (2[PF6 ]n , n=2, 3), which demonstrate cyanide/isocyanide isomerism, have been synthesized and fully characterized. 13+ [PF6 ]3 and 23+ [PF6 ]3 are the one-electron oxidation products of 12+ [PF6 ]2 and 22+ [PF6 ]2 , respectively. The results suggest that 1[PF6 ]3 is a class III mixed valence compound, whereas 2[PF6 ]3 might be an unusually symmetrical class II-III mixed valence compound composed of the two asymmetrical delocalized RuIII -NC-RuII mixed valence subunits.

CD24 and Fc fusion protein protects SIVmac239-infected Chinese rhesus macaque against progression to AIDS.

Chronic immune activation and systemic inflammation are underlying causes of acquired immunodeficiency syndrome (AIDS). Products of virus replication and microbial translocation, co-infection or opportunistic pathogens, and danger-associated molecular patterns have been reported to contribute to chronic immune activation and inflammation in human immunodeficiency virus type-1/simian immunodeficiency virus (HIV-1/SIV) infection or other disease. To develop new strategies and therapies for HIV-1/AIDS, we tested if the CD24 and Fc fusion protein (CD24Fc), which interacts with danger-associated molecular patterns and sialic acid binding Ig-like lectin to attenuate inflammation, can protect Chinese rhesus macaques (ChRMs) with SIV infection. We found that CD24Fc treatment decreased weight loss, wasting syndrome, intractable diarrhea, and AIDS morbidity and mortality, while it was well tolerated by SIV-infected animals. Corresponding to the elimination of intractable diarrhea, CD24Fc significantly reduced the expression of IL-6 and indoleamine 2, 3-dioxygenase-1 in peripheral blood mononuclear cell and inflammation in the ileum, colon and rectum based on the reduction of inflammatory cells, pathological scores and expression of inflammatory cytokines. Furthermore, although CD24Fc did not restore CD4+ T cell number or significantly change T cell subsets or CD4+ T cell activation, it maintained low levels of plasma soluble CD14, CD8+ T cell activation, viral load and proviral load in the peripheral blood mononuclear cells and marrow. These results suggested that CD24Fc confers protection to SIV-infected ChRMs against progression to AIDS. It was also implied that CD24Fc may be a potential therapeutic approach for the control of HIV-1/AIDS.

Redox-induced switch between luminescence and magnetism in a trinuclear cyanide-bridged compound.

A trinuclear cyanide-bridged luminescent compound, trans-RuII(DMAP)4(CN)2[(PY5Me2)Mn]2[PF6]4 (1-R), and its oxidation product, ferromagnetic trans-RuIII(DMAP)4(CN)2[(PY5Me2)Mn]2-[PF6]5 (1-O), were synthesized and fully characterized. This is the first example of a molecular material showing a redox-controlled transformation between fluorescence and ferromagnetism.

Accelerated disease progression and robust innate host response in aged SIVmac239-infected Chinese rhesus macaques is associated with enhanced immunosenescence.

The elderly population infected with HIV-1 is often characterized by the rapid AIDS progression and poor treatment outcome, possibly because of immunosenescence resulting from both HIV infection and aging. However, this hypothesis remains to be fully tested. Here, we studied 6 young and 12 old Chinese rhesus macaques (ChRM) over the course of three months after simian immunodeficiency virus (SIV) SIVmac239 infection. Old ChRM showed a higher risk of accelerated AIDS development than did young macaques, owing to rapidly elevated plasma viral loads and decreased levels of CD4+ T cells. The low frequency of naïve CD4+ T cells before infection was strongly predictive of an increased disease progression, whereas the severe depletion of CD4+ T cells and the rapid proliferation of naïve lymphocytes accelerated the exhaustion of naïve lymphocytes in old ChRM. Moreover, in old ChRM, a robust innate host response with defective regulation was associated with a compensation for naïve T cell depletion and a high level of immune activation. Therefore, we suggest that immunosenescence plays an important role in the accelerated AIDS progression in elderly individuals and that SIV-infected old ChRM may be a favorable model for studying AIDS pathogenesis and researching therapies for elderly AIDS patients.

HIV-1 can infect northern pig-tailed macaques (Macaca leonina) and form viral reservoirs in vivo.

Viral reservoirs of HIV-1 are a major obstacle for curing AIDS. The novel animal models that can be directly infected with HIV-1 will contribute to develop effective strategies for eradicating infections. Here, we inoculated 4 northern pig-tailed macaques (NPM) with the HIV-1 strain HIV-1NL4.3 and monitored the infection for approximately 3years (150weeks). The HIV-1-infected NPMs showed transient viremia for about 10weeks after infection. However, cell-associated proviral DNA and viral RNA persisted in the peripheral blood and lymphoid organs for about 3years. Moreover, replication-competent HIV-1 could be successfully recovered from peripheral blood mononuclear cells (PBMCs) during long-term infection. The numbers of resting CD4+ T cells in HIV-1 infected NPMs harboring proviruses fell within a range of 2- to 3-log10 per million cells, and these proviruses could be reactivated both ex vivo and in vivo in response to co-stimulation with the latency-reversing agents JQ1 and prostratin. Our results suggested that NPMs can be infected with HIV-1 and a long-term viral reservoir was formed in NPMs, which might serve asa potential model for HIV-1 reservoir research.

Translocation of microbes and changes of immunocytes in the gut of rapid- and slow-progressor Chinese rhesus macaques infected with SIVmac239.

Human/simian immunodeficiency virus (HIV/SIV) infection can cause severe depletion of CD4(+) T cells in both plasma and mucosa; it also results in damage to the gut mucosa barrier, which makes the condition more conducive to microbial translocation. In this study, we used SIV-infected Chinese rhesus macaques to quantify the extent of microbial translocation and the function of immune cells in the entire gastrointestinal tract and to compare their differences between rapid and slow progressors. The results showed that in the slow progressors, microbial products translocated considerably and deeply into the lamina propria of the gut; the tissue macrophages had no significant differences compared with the rapid progressors, but there was a slightly higher percentage of mucosal CD8(+) T cells and a large amount of extracellular microbial products in the lamina propria of the intestinal mucosa of the slow progressors. The data suggested that although microbial translocation increased markedly, the mucosal macrophages and CD8(+) T cells were insufficient to clear the infiltrated microbes in the slow progressors. Also, therapies aimed at suppressing the translocation of microbial products in the mucosa could help to delay the progression of SIV disease.

High immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected Chinese rhesus macaques.

Chinese rhesus macaques (CRMs) are ideal experimental animals for studying the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and for vaccine research. SHIV89.6 has been reported to be an attenuated virus because, in most cases, SHIV89.6 infection only causes limited alteration of immune cells and tissues, and it has been used commonly for vaccine research. After two serial passages in vivo, SHIV (SHIV-89.6P) induces CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections. However, the pathogenic ability of SHIV89.6 is not well understood. In this study, we found that 6 of 14 SHIV89.6-infected CRMs died within 127 weeks after infection. We found especially high immune activation, low IFN-α expression, and distinctive cytokine expression profiles in the infected and dead (ID) group of monkeys, while there was only few change in the CD4(+) T counts and distribution of T cell subsets in the ID group monkeys. Also, there was a similar dynamic of viral load between infected and surviving (IS) and ID group monkeys. Furthermore, we found various correlations among immune activation, IFN-α expression, and frequencies of cytokine-secreting cells. These results suggest that SHIV89.6 infections have pathogenic potential in CRMs and that high immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected CRMs. This also implies that high immune activation may be relevant to dysfunction of immune cells. It is proposed that high immune activation and dysfunction of immune cells may be good predictors for disease progression and markers for therapy.

Flow cytometric characterizations of leukocyte subpopulations in the peripheral blood of northern pig-tailed macaques (Macaca leonina).

Pig-tailed macaques (Macaca nemistrina group) have been extensively used as non-human primate animal models for various human diseases in recent years, notably for AIDS research due to their sensitivity to HIV-1. Northern pig-tailed macaques (M. leonina) are distributed in China and other surrounding Southeast Asia countries. Although northern pig-tailed macaques have been bred on a large scale as experimental animals since 2012, the reference value of normal levels of leukocytes is not available. To obtain such information, 62 blood samples from male and female healthy northern pig-tailed macaques at different ages were collected. The normal range of major leukocyte subpopulations, such as T lymphocytes, B lymphocytes, natural killer (NK) cells, monocytes, and the expression levels of activation or differentiation related molecules (CD38, HLA-DR, CCR5, CD21, IgD, CD80 and CD86) on lymphocytes were analyzed by flow cytometry. The counts of B cells decreased with age, but those of CD8(+) T cells and NK cells and the frequency of CD38(+)HLA-DR(+)CD4(+) T cells were positively correlated with age. The counts of leukocyte subpopulations were higher in males than those in females except for CD4(+) T cells. Males also showed higher expression levels of IgD and CD21 within B cells. This study provides basic data about the leukocyte subpopulations of northern pig-tailed macaques and compares this species with commonly used Chinese rhesus macaques (M. mulatta), which is meaningful for the biomedical application of northern pig-tailed macaques.