Impaired end joining induces cardiac atrophy in a Hutchinson-Gilford progeria mouse model.

Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of cardiovascular complications. Although vascular pathologies have been reported, whether HGPS patients exhibit cardiac dysfunction and its underlying mechanism is unclear, rendering limited options for treating HGPS-related cardiomyopathy. In this study, we reported a cardiac atrophy phenotype in the LmnaG609G/G609G mice (hereafter, HGPS mice). Using a GFP-based reporter system, we demonstrated that the efficiency of nonhomologous end joining (NHEJ) declined by 50% in HGPS cardiomyocytes in vivo, due to the attenuated interaction between γH2AX and Progerin, the causative factor of HGPS. As a result, genomic instability in cardiomyocytes led to an increase of CHK2 protein level, promoting the LKB1-AMPKα interaction and AMPKα phosphorylation, which further led to the activation of FOXO3A-mediated transcription of atrophy-related genes. Moreover, inhibiting AMPK enlarged cardiomyocyte sizes both in vitro and in vivo. Most importantly, our proof-of-concept study indicated that isoproterenol treatment significantly reduced AMPKα and FOXO3A phosphorylation in the heart, attenuated the atrophy phenotype, and extended the mean lifespan of HGPS mice by ~21%, implying that targeting cardiac atrophy may be an approach to HGPS treatment.

Metal-free synthesis of difluoro/trifluoromethyl carbinol-containing chromones via tandem cyclization of o-hydroxyaryl enaminones.

We herein propose a HFIP-promoted tandem cyclization reaction for the synthesis of difluoro/trifluoromethyl carbinol-containing chromones from o-hydroxyphenyl enaminones at room temperature. This protocol provides a facile and efficient approach to access diverse difluoro/trifluoromethylated carbinols in good to excellent yields. In addition, gram-scale and synthetic derivatization experiments have also been performed.

The Potential Role of Timosaponin-AIII in Cancer Prevention and Treatment.

Cancer, as one of the leading causes of death worldwide, has challenged current chemotherapy drugs. Considering that treatments are expensive, alongside the resistance of tumor cells to anticancer drugs, the development of alternative medicines is necessary. Anemarrhena asphodeloides Bunge, a recognized and well-known medicinal plant for more than two thousand years, has demonstrated its effectiveness against cancer. Timosaponin-AIII (TSAIII), as a bioactive steroid saponin isolated from A. asphodeloides, has shown multiple pharmacological activities and has been developed as an anticancer agent. However, the molecular mechanisms of TSAIII in protecting against cancer development are still unclear. In this review article, we provide a comprehensive discussion on the anticancer effects of TSAIII, including proliferation inhibition, cell cycle arrest, apoptosis induction, autophagy mediation, migration and invasion suppression, anti-angiogenesis, anti-inflammation, and antioxidant effects. The pharmacokinetic profiles of TSAII are also discussed. TSAIII exhibits efficacy against cancer development. However, hydrophobicity and low bioavailability may limit the application of TSAIII. Effective delivery systems, particularly those with tissue/cell-targeted properties, can also significantly improve the anticancer effects of TSAIII.

1,1,1,3,3,3-Hexafluoro-2-Propanol-Promoted Friedel-Crafts Reaction: Metal-Free Synthesis of C3-Difluoromethyl Carbinol-Containing Imidazo[1,2-a]pyridines at Room Temperature.

A facile and efficient method has been developed for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature via the HFIP-promoted Friedel-Crafts reaction of difluoroacetaldehyde ethyl hemiacetal and imidazo[1,2-a]pyridines. This strategy could be applied to the direct C(sp2)-H hydroxydifluoromethylation of imidazo[1,2-a]pyridines and afford a series of novel difluoromethylated carbinols in good to satisfactory yields with 29 examples. Furthermore, gram-scale and synthetic transformation experiments have also been achieved, demonstrating its potential applicable value in organic synthesis. This green protocol has several advantages, including being transition metal- and oxidant-free, being carried out at room temperature, having high efficiency, and having a wide substrate scope.

Insights into the Molecular Competitive Adsorption Mechanism of CH4/CO2 in a Kerogen Matrix in the Presence of Moisture, Salinity, and Ethane.

Carbon dioxide (CO2) injection in shale and coal seam gas reservoirs has become one of the most popular ways to promote methane (CH4) production. However, geological factors affecting the CO2 enhanced gas recovery (CO2-EGR) projects have not been studied in great depth, including underground moisture, subsurface water salinity, and other gases accompanying CH4. Thus, a hybrid methodology of molecular dynamics (MD) and grand canonical Monte Carlo (GCMC) simulation is employed to reveal the gas adsorption and displacement mechanisms at a fundamental molecular level. This study generates a type II-D kerogen matrix as the adsorbent. The simulation environment includes 0-5 wt % moisture content, 0-6 mol/L NaCl saline, and 0-5 wt % C2H6 for up to 30 MPa at 308, 338, and 368 K. The impressions of moisture, C2H6, and salinity on gas adsorption and competitive adsorption characteristics are analyzed and discussed. On the basis of the simulation results, the preloaded H2O molecules negatively influence CH4 adsorption, leading to a 44.9% reduction at 5 wt % moisture content. Additionally, 6 mol/L NaCl within 5 wt % moisture content exhibits a further 9.8% reduction on the basis of the moisture effect. C2H6 presents a more noticeable negative impact, of which 5 wt % results in a 73.2% reduction in CH4 adsorption. Moreover, the competitive process indicator, preferential selectivity SCO2/CH4, is analyzed and discussed in the presence of the mentioned factors. Moisture positively influences SCO2/CH4, salinity promotes SCO2/CH4, and C2H6 develops SCO2/CH4. These factors would encourage the displacement processes of CH4 by CO2 injection. This study provides essential information for better gas resource estimation and gas recovery improvement in unconventional systems.

The Key Roles of GSK-3ß in Regulating Mitochondrial Activity.

Glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine protein kinase, has been reported to show essential roles in molecular pathophysiology of many diseases. Mitochondrion is a dynamic organelle for producing cellular energy and determining cell fates. Stress-induced translocated GSK-3ß may interact with mitochondrial proteins, including PI3K-Akt, PGC-1α, HK II, PKCε, components of respiratory chain, and subunits of mPTP. Mitochondrial pool of GSK-3ß has been implicated in mediation of mitochondrial functions. GSK-3ß exhibits the regulatory effects on mitochondrial biogenesis, mitochondrial bioenergetics, mitochondrial permeability, mitochondrial motility, and mitochondrial apoptosis. The versatile functions of GSK-3ß might be associated with its wide range of substrates. Accumulative evidence demonstrates that GSK-3ß inactivation may be potentially developed as the promising strategy in management of many diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Intensive efforts have been made for exploring GSK-3ß inhibitors. Natural products provide us a great source for screening new lead compounds in inactivation of GSK-3ß. The key roles of GSK-3ß in mediation of mitochondrial functions are discussed in this review.

Quality analysis and assessment of representative sea buckthorn fruits in northern China.

Sea buckthorn (SB) primarily grows in northern China and is rich in nutritional components, making it popular among consumers. This study aims to select suitable SB varieties for processing by analyzing physicochemical components, color, taste, and volatile compounds. The results showed that the physicochemical content of Chinese SB from Gansu were as follows: total soluble solids 13.50 ± 0.37°Brix, titratable acidity 6.46 ± 0.39 %, ascorbic acid 578 mg/100 g, polyphenols 517 mg/100 g, and flavonoids 194 mg/100 g, which were higher than those of the other four SB samples; the content of organic acids was relatively abundant. Taste analysis via electronic tongue indicated that Chinese SB had the highest ANS (sweetness) value and the lowest SCS (bitterness) value, exhibiting the richest flavor. Gas chromatography-mass spectrometry analysis showed that Gansu Chinese SB had a rich variety of volatile components, totaling 74. In summary, Gansu Chinese SB is a variety suitable for processing.

Geniposide alleviates cholesterol-induced endoplasmic reticulum stress and apoptosis in osteoblasts by mediating the GLP-1R/ABCA1 pathway.

BACKGROUND: Cholesterol (CHO) is an essential component of the body. However, high CHO levels in the body can damage bone mass and promote osteoporosis. CHO accumulation can cause osteoblast apoptosis, which has a negative effect on bone formation. The pathogenesis of osteoporosis is a complicate process that includes oxidative stress, endoplasmic reticulum (ER) stress, and inflammation. Geniposide (GEN) is a natural compound with anti-osteoporotic effect. However, the roles of GEN in osteopathogenesis are still unclear. Our previous studies demonstrated that GEN could reduce the accumulation of CHO in osteoblasts and the activation of ER stress in osteoblasts. However, the molecular mechanism of GEN in inhibiting CHO-induced apoptosis in osteoblasts needs to be further investigated. METHODS: MC3T3-E1 cells were treated with osteogenic induction medium (OIM). Ethanol-solubilized cholesterol (100 µM) was used as a stimulator, and 10 µM and 25 µM geniposide was added for treatment. The alterations of protein expression were detected by western blot, and the cell apoptosis was analyzed by a flow cytometer. RESULTS: CHO promoted osteoblast apoptosis by activating ER stress in osteoblasts, while GEN alleviated the activation of ER stress and reduced osteoblast apoptosis by activating the GLP-1R/ABCA1 pathway. Inhibition of ABCA1 or GLP-1R could eliminate the protective activity of GEN against CHO-induced ER stress and osteoblast apoptosis. CONCLUSION: GEN alleviated CHO-induced ER stress and apoptosis in osteoblasts by mediating the GLP-1R/ABCA1 pathway.

Prospective policy analysis-a critical interpretive synthesis review.

Most policy analysis methods and approaches are applied retrospectively. As a result, there have been calls for more documentation of the political-economy factors central to health care reforms in real-time. We sought to highlight the methods and previous applications of prospective policy analysis (PPA) in the literature to document purposeful use of PPA and reflect on opportunities and drawbacks. We used a critical interpretive synthesis (CIS) approach as our initial scoping revealed that PPA is inconsistently defined in the literature. While we found several examples of PPA, all were researcher-led, most were published recently and few described mechanisms for engagement in the policy process. In addition, methods used were often summarily described and reported on relatively short prospective time horizons. Most of the studies stemmed from high-income countries and, across our sample, did not always clearly outline the rationale for a PPA and how this analysis was conceptualized. That only about one-fifth of the articles explicitly defined PPA underscores the fact that researchers and practitioners conducting PPA should better document their intent and reflect on key elements essential for PPA. Despite a wide recognition that policy processes are dynamic and ideally require multifaceted and longitudinal examination, the PPA approach is not currently frequently documented in the literature. However, the few articles reported in this paper might overestimate gaps in PPA applications. More likely, researchers are embedded in policy processes prospectively but do not necessarily write their articles from that perspective, and analyses led by non-academics might not make their way into the published literature. Future research should feature examples of testing and refining the proposed framework, as well as designing and reporting on PPA. Even when policy-maker engagement might not be feasible, real-time policy monitoring might have value in and of itself.

Effects of Pulsed Electric Field and High-Pressure Processing Treatments on the Juice Yield and Quality of Sea Buckthorn.

Sea buckthorn juice has high nutritional value and a rich flavor that consumers enjoy. Traditional sea buckthorn thermal processing (TP) technology has problems such as low juice yield, poor quality, and poor flavor. Sea buckthorn berries are processed using a technique combining pulsed electric field (PEF) and high-pressure processing (HPP) to increase juice yield and study its impact on the quality and volatile aroma of sea buckthorn juice. Results have show that, compared with TP, under the condition of PEF-HPP, the juice yield of sea buckthorn significantly increased by 11.37% (p > 0.05); TP and PEF-HPP treatments could effectively kill microorganisms in sea buckthorn juice, but the quality of sea buckthorn juice decreased significantly after TP treatment (p > 0.05), whereas PEF-HPP coupling technology could maximally retain the nutrients of sea buckthorn juice while inhibiting enzymatic browning to improve color, viscosity, and particle size. The flavor of sea buckthorn juice is analyzed using electronic nose (E-nose) and gas chromatography-ion mobility spectrometer (GC-IMS) techniques, and it has been shown that PEF-HPP retains more characteristic volatile organic compounds (VOCs) of sea buckthorn while avoiding the acrid and pungent flavors produced by TP, such as benzaldehyde, (E)-2-heptenal, and pentanoic acid, among others, which improves the sensory quality of sea buckthorn juice. PEF-HPP technology is environmentally friendly and efficient, with significant economic benefits. Research data provide information and a theoretical basis for the sea buckthorn juice processing industry.

Triclocarban disrupts the activation and differentiation of human CD8+ T cells by suppressing the vitamin D receptor signaling.

Triclocarban (TCC) is a widely applied environmental endocrine-disrupting chemical (EDC). Similar to most of EDCs, TCC potentially damages the immunity of various species. However, whether and how TCC impacts the adaptive immunity in mammals has yet to be determined. Herein, we discovered that TCC disrupts the activation and differentiation of CD8+ T cells in primary human peripheral blood samples, purified CD8+ T cells, and in mice in vivo. Mechanistically, TCC might block the activation of the vitamin D receptor (VDR) and reduce the synthesis of cholesterol, a precursor of vitamin D, resulting in inhibition of VDR signaling due to the suppression of both its ligand and the receptor itself by TCC. Our findings elucidate the hazard and potential mechanisms of TCC in mammalian adaptive immunity and highlighted VDR as a potential therapeutic target for the immunodeficiency caused by TCC.

Single-cell dissection reveals promotive role of ENO1 in leukemia stem cell self-renewal and chemoresistance in acute myeloid leukemia.

BACKGROUND: Quiescent self-renewal of leukemia stem cells (LSCs) and resistance to conventional chemotherapy are the main factors leading to relapse of acute myeloid leukemia (AML). Alpha-enolase (ENO1), a key glycolytic enzyme, has been shown to regulate embryonic stem cell differentiation and promote self-renewal and malignant phenotypes in various cancer stem cells. Here, we sought to test whether and how ENO1 influences LSCs renewal and chemoresistance within the context of AML. METHODS: We analyzed single-cell RNA sequencing data from bone marrow samples of 8 relapsed/refractory AML patients and 4 healthy controls using bioinformatics and machine learning algorithms. In addition, we compared ENO1 expression levels in the AML cohort with those in 37 control subjects and conducted survival analyses to correlate ENO1 expression with clinical outcomes. Furthermore, we performed functional studies involving ENO1 knockdown and inhibition in AML cell line. RESULTS: We used machine learning to model and infer malignant cells in AML, finding more primitive malignant cells in the non-response (NR) group. The differentiation capacity of LSCs and progenitor malignant cells exhibited an inverse correlation with glycolysis levels. Trajectory analysis indicated delayed myeloid cell differentiation in NR group, with high ENO1-expressing LSCs at the initial stages of differentiation being preserved post-treatment. Simultaneously, ENO1 and stemness-related genes were upregulated and co-expressed in malignant cells during early differentiation. ENO1 level in our AML cohort was significantly higher than the controls, with higher levels in NR compared to those in complete remission. Knockdown of ENO1 in AML cell line resulted in the activation of LSCs, promoting cell differentiation and apoptosis, and inhibited proliferation. ENO1 inhibitor can impede the proliferation of AML cells. Furthermore, survival analyses associated higher ENO1 expression with poorer outcome in AML patients. CONCLUSIONS: Our findings underscore the critical role of ENO1 as a plausible driver of LSC self-renewal, a potential target for AML target therapy and a biomarker for AML prognosis.

TMF inhibits extracellular matrix degradation by regulating the C/EBPß/ADAMTS5 signaling pathway in osteoarthritis.

Osteoarthritis (OA) is a chronic joint disease, characterized by degenerative destruction of articular cartilage. Chondrocytes, the unique cell type in cartilage, mediate the metabolism of extracellular matrix (ECM), which is mainly constituted by aggrecan and type II collagen. A disintegrin and metalloproteinase with thrombospondin 5 (ADAMTS5) is an aggrecanase responsible for the degradation of aggrecan in OA cartilage. CCAAT/enhancer binding protein ß (C/EBPß), a transcription factor in the C/EBP family, has been reported to mediate the expression of ADAMTS5. Our previous study showed that 5,7,3',4'-tetramethoxyflavone (TMF) could activate the Sirt1/FOXO3a signaling in OA chondrocytes. However, whether TMF protected against ECM degradation by down-regulating C/EBPß expression was unknown. In this study, we found that aggrecan expression was down-regulated, and ADAMTS5 expression was up-regulated. Knockdown of C/EBPß could up-regulate aggrecan expression and down-regulate ADAMTS5 expression in IL-1ß-treated C28/I2 cells. TMF could compromise the effects of C/EBPß on OA chondrocytes by activating the Sirt1/FOXO3a signaling. Conclusively, TMF exhibited protective activity against ECM degradation by mediating the Sirt1/FOXO3a/C/EBPß pathway in OA chondrocytes.

Modeling Consumer Acceptance and Usage Behaviors of m-Health: An Integrated Model of Self-Determination Theory, Task-Technology Fit, and the Technology Acceptance Model.

Although mobile health (m-health) has great potential to reduce the cost of medical care and improve its quality and efficiency, it is not widely accepted by consumers. In addition, there is still a lack of comprehensive insight into m-health acceptance, especially among consumers with different demographic characteristics. This study aimed to explore the factors affecting consumers' acceptance and usage behaviors of m-health and to examine whether their roles differ by demographic characteristics. A comprehensive m-health acceptance model was proposed by integrating factors from the Self-Determination Theory, Task-Technology Fit, and Technology Acceptance Model. Survey data were collected from 623 Chinese adults with at least 6 months of m-health usage experience and analyzed using structural equation modeling techniques. Multi-group analyses were performed to assess whether the model relationships were different across gender, age, and usage experience. The results indicated that relatedness and competence were significant motivational antecedents of perceived ease of use. Task-technology fit and the perceived ease of use significantly affected the perceived usefulness. The perceived ease of use and perceived usefulness were significant determinants of consumer usage behaviors of m-health and together explained 81% of its variance. Moreover, the relationships among autonomy, perceived usefulness, and usage behaviors of m-health were moderated by gender. Consumer usage behaviors of m-health were affected by factors such as self-motivation (i.e., relatedness and competence), technology perceptions (i.e., perceived ease of use and perceived usefulness), and task-technology fit. These findings provide a theoretical underpinning for future research on m-health acceptance and provide empirical evidence for practitioners to promote the better design and use of m-health for healthcare activities.

Advances in the interaction between endoplasmic reticulum stress and osteoporosis.

The endoplasmic reticulum (ER) is the main site for protein synthesis, folding, and secretion, and accumulation of the unfolded/misfolded proteins in the ER may induce ER stress. ER stress is an important participant in various intracellular signaling pathways. Prolonged- or high-intensity ER stress may induce cell apoptosis. Osteoporosis, characterized by imbalanced bone remodeling, is a global disease caused by many factors, such as ER stress. ER stress stimulates osteoblast apoptosis, increases bone loss, and promotes osteoporosis development. Many factors, such as the drug's adverse effects, metabolic disorders, calcium ion imbalance, bad habits, and aging, have been reported to activate ER stress, resulting in the pathological development of osteoporosis. Increasing evidence shows that ER stress regulates osteogenic differentiation, osteoblast activity, and osteoclast formation and function. Various therapeutic agents have been developed to counteract ER stress and thereby suppress osteoporosis development. Thus, inhibition of ER stress has become a potential target for the therapeutic management of osteoporosis. However, the in-depth understanding of ER stress in the pathogenesis of osteoporosis still needs more effort.

Advances in the roles of ATF4 in osteoporosis.

Osteoporosis (OP) is characterized by reduced bone mass, decreased strength, and enhanced bone fragility fracture risk. Activating transcription factor 4 (ATF4) plays a role in cell differentiation, proliferation, apoptosis, redox balance, amino acid uptake, and glycolipid metabolism. ATF4 induces the differentiation of bone marrow mesenchymal stem cells (BM-MSCs) into osteoblasts, increases osteoblast activity, and inhibits osteoclast formation, promoting bone formation and remodeling. In addition, ATF4 mediates the energy metabolism in osteoblasts and promotes angiogenesis. ATF4 is also involved in the mediation of adipogenesis. ATF4 can selectively accumulate in osteoblasts. ATF4 can directly interact with RUNT-related transcription factor 2 (RUNX2) and up-regulate the expression of osteocalcin (OCN) and osterix (Osx). Several upstream factors, such as Wnt/ß-catenin and BMP2/Smad signaling pathways, have been involved in ATF4-mediated osteoblast differentiation. ATF4 promotes osteoclastogenesis by mediating the receptor activator of nuclear factor κ-B (NF-κB) ligand (RANKL) signaling. Several agents, such as parathyroid (PTH), melatonin, and natural compounds, have been reported to regulate ATF4 expression and mediate bone metabolism. In this review, we comprehensively discuss the biological activities of ATF4 in maintaining bone homeostasis and inhibiting OP development. ATF4 has become a therapeutic target for OP treatment.

Geniposide stimulates autophagy by activating the GLP-1R/AMPK/mTOR signaling in osteoarthritis chondrocytes.

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degeneration. Autophagy is associated with chondrocyte homeostasis and exhibits a role in protecting against OA pathogenesis. Geniposide (GEN), an iridoid glycoside extracted from Eucommia ulmoides Oliv, acts as an activator of GLP-1R, which can stimulate autophagy. The AMPK/mTOR signaling pathway participates in the mediation of autophagy, and GLP-1R may act as an upstream factor of AMPK. However, whether GEN mediates the autophagic responses by activating the GLP-1R/AMPK/mTOR signaling pathway in OA chondrocytes is still unclear. In the current study, attenuated autophagy in MIA-induced rat OA models was observed, as shown by up-regulated expression of p62 and down-regulated expression of Beclin-1 and LC3-II/I. GEN stimulated autophagy and protected OA cartilage by up-regulating GLP-1R expression. In addition, GEN could enhance AMPK phosphorylation and down-regulate mTOR expression in IL-1ß-treated C28/I2 cells. Inhibition of AMPK or activation of mTOR could reverse the stimulatory effects of GEN on autophagy. Furthermore, a GLP-1R inhibitor Exendin 9-39 could eliminate the chondroprotective effects of GEN by suppressing the AMPK/mTOR signaling pathway. Conclusively, Geniposide exhibits protective effects against osteoarthritis development by stimulating autophagy via activating the GLP-1R/AMPK/mTOR signaling pathway.

Loss of the receptors ER, PR and HER2 promotes USP15-dependent stabilization of PARP1 in triple-negative breast cancer.

Poly(ADP-ribose) polymerase 1 (PARP1) is essential for the progression of several types of cancers. However, whether and how PARP1 is stabilized to promote genomic stability in triple-negative breast cancer (TNBC) remains unknown. Here, we demonstrated that the deubiquitinase USP15 interacts with and deubiquitinates PARP1 to promote its stability, thereby stimulating DNA repair, genomic stability and TNBC cell proliferation. Two PARP1 mutations found in individuals with breast cancer (E90K and S104R) enhanced the PARP1-USP15 interaction and suppressed PARP1 ubiquitination, thereby elevating the protein level of PARP1. Importantly, we found that estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) inhibited USP15-mediated PARP1 stabilization through different mechanisms. ER bound to the USP15 promoter to suppress its expression, PR suppressed the deubiquitinase activity of USP15, and HER2 abrogated the PARP1-USP15 interaction. The specific absence of these three receptors in TNBC results in high PARP1 levels, leading to increases in base excision repair and female TNBC cell survival.

Traditional Chinese medicine etiology and pathogenesis of acquired immune deficiency syndrome in simian immunodeficiency virus-infected Chinese rhesus macaques.

OBJECTIVE: To investigate the traditional Chinese Medicine (TCM) etiology and pathogenesis of acquired immune deficiency syndrome (AIDS) by 18-month observation of Chinese rhesus macaques infected with simian immunodeficiency virus (SIV) mac239. METHODS: Thirty-five healthy Chinese rhesus macaques were divided into a model group (n = 30) and a control group (n = 5). The model was established by inoculating monkeys intravenously with SIVmac239. Changes in TCM symptoms after SIV infection within 18 months were then observed and recorded. Routine blood tests, SIV viral load, T-lymphocyte subsets, plasma triiodothyronine (T3), tetraiodothyronine (T4), adrenocorticotropic hormone (ACTH) and cortisol (Cor) were tested periodically during the experiment. RESULTS: During the acute infection period of SIV, model monkeys temporarily showed clinical symptoms such as diarrhea, dysphoria and slight weight loss. Decrease percentages of CD4+ T-lymphocytes were observed but levels of T3, T4, Cor, and ACTH were relatively unchanged. Monkeys in the model group during the early and middle periods of infection showed no obvious symptoms, except few monkeys exhibited transient diarrhea and reduced food intake. All variables at this stage showed normal fluctuations. In the middle period model group monkeys showed chronic and persistent diarrhea, weight loss, reduced food intake and low levels of T3 and Cor. In the late period, symptoms including emaciation, weight loss, listlessness, crouching in corners and low levels of T3 appeared. CONCLUSION: The results suggest that the rhesus monkey SIV/SAIDS model can be applied to research on TCM etiology and pathogenesis of AIDS. According to this model, the etiology of disease is the SIV virus. The pathogenesis manifests as the invasion of SIV virus, incubation of the virus, balance between virus and healthy "Qi", damage to spleen and kidney as the disease progressed, exhaustion of vitality and finally the failure of five zang and six fu organs.

A two-subpopulation model that reflects heterogeneity of large dense core vesicles in exocytosis.

Exocytosis of large dense core vesicles is responsible for hormone secretion in neuroendocrine cells. The population of primed vesicles ready to release upon cell excitation demonstrates large heterogeneity. However, there are currently no models that clearly reflect such heterogeneity. Here, we develop a novel model based on single vesicle release events from amperometry recordings of PC12 cells using carbon fiber microelectrode. In this model, releasable vesicles can be grouped into two subpopulations, namely, SP1 and SP2. SP1 vesicles replenish quickly, with kinetics of ~0.0368 s-1, but likely undergo slow fusion pore expansion (amperometric signals rise at ~2.5 pA/ms), while SP2 vesicles demonstrate slow replenishment (kinetics of ~0.0048 s-1) but prefer fast dilation of fusion pore, with an amperometric signal rising rate of ~9.1 pA/ms. Phorbol ester enlarges the size of SP2 partially via activation of protein kinase C and conveys SP1 vesicles into SP2. Inhibition of Rho GTPase-dependent actin rearrangement almost completely depletes SP2. We also propose that the phorbol ester-sensitive vesicle subpopulation (SP2) is analogous to the subset of superprimed synaptic vesicles in neurons. This model provides a meticulous description of the architecture of the readily releasable vesicle pool and elucidates the heterogeneity of the vesicle priming mechanism.