Early HIV diagnosis enhances quality-adjusted life expectancy of men who have sex with men living with HIV: A population-based cohort study in Taiwan.

BACKGROUND: Whether early HIV diagnosis is beneficial for HIV patients themselves remains uncertain, given the stigma and social discrimination associated with an HIV diagnosis. This study aimed to measure the impact of early HIV diagnosis on quality-adjusted life expectancy (QALE) in comparison with late HIV diagnosis, from real-world data in Taiwan under universal access to antiretroviral therapy (ART). METHODS: This population-based cohort study included 14,570 men who have sex with men (MSM) in the national HIV registry and a quasi-random sample (n = 127) of MSM patients to measure quality of life using the EQ-5D health utility instrument. We integrated quality of life data into the extrapolated cohort survival curve to estimate the QALE in patients with early versus late HIV diagnosis (≤30 days before AIDS diagnosis). Loss-of-QALE were estimated by comparing the cohort with age-, sex-, and calendar-year-matched referents simulated from vital statistics. Difference-in-differences was estimated to quantify the effect of early HIV diagnosis. RESULTS: Early HIV diagnosis is associated with a loss-of-life expectancy of 3.11 years, with an average health utility of 0.95, in contrast to those diagnosed late (loss-of-life expectancy 8.47 years, with an average health utility of 0.86). After integration of survival and life quality, early HIV diagnosis results in a reduction of loss-of-QALE by 8.28 quality-adjusted life years among MSM living with HIV. CONCLUSIONS: Under universal access to ART, early HIV diagnosis is highly beneficial for people living with HIV themselves, with a net gain of 8.28 healthy life years compared with those diagnosed late.

Characterization of degradation signals at protein C-termini.

Protein termini are critical for protein functions. They are often more accessible than internal regions and thus are frequently subjected to various modifications that affect protein function. Protein termini also contribute to regulating protein lifespan. Recent studies have revealed a series of degradation signals located at protein C-termini, termed C-degrons or C-end degrons. C-degrons have been implicated as underlying a protein quality surveillance system that eliminates truncated, cleaved and mislocalized proteins. Despite the importance of C-degrons, our knowledge of them remains sparse. Here, we describe an established framework for the characterization of C-degrons by Global Protein Stability (GPS) profiling assay, a fluorescence-based reporter system for measuring protein stability in cellulo. Furthermore, we apply an approach that couples GPS with random peptide libraries for unbiased and context-independent characterization of C-degron motifs. Our methodology provides a robust and efficient platform for analyzing the degron potencies of C-terminal peptides, which can significantly accelerate our understanding of C-degrons.

Multi-target regulatory mechanism of Yang Xin Tang - a traditional Chinese medicine against dementia.

BACKGROUND: Yang Xin Tang (YXT) is a traditional Chinese herbal preparation which has been reported to improve cognitive function and memory in patients with dementia. As the underlying mechanism of action of YXT has not been elucidated, we examined the effects of YXT and its major herbal components in regulating gene transcription and molecular targets related to Alzheimer's disease (AD). METHODS: Aqueous and ethanol extracts of YXT and selected herbal components were prepared and validated by standard methods. A series of biochemical and cellular assays were employed to assess the ability of the herbal extracts to inhibit acetylcholinesterase, reduce ß-amyloid aggregation, stimulate the differentiation of neural progenitor cells, suppress cyclooxygenase, and protect neurons against ß-amyloid or N-methyl-D-aspartate-induced cytotoxicity. The effects of YXT on multiple molecular targets were further corroborated by a panel of nine reporter gene assays. RESULTS: Extracts of YXT and two of its constituent herbs, Poria cocos and Poria Sclerotium pararadicis, significantly inhibited ß-amyloid aggregation and ß-amyloid-induced cytotoxicity. A protective effect of the YXT extract was similarly observed against N-methyl-D-aspartate-induced cytotoxicity in primary neurons, and this activity was shared by extracts of Radix Astragali and Rhizoma Chuanxiong. Although the YXT extract was ineffective, extracts of Poria cocos, Poria Sclerotium pararadicis and Radix Polygalae inhibited acetylcholine esterase, with the latter also capable of upregulating choline acetyltransferase. YXT and its components significantly inhibited the activities of the pro-inflammatory cyclooxygenases. Additionally, extracts of YXT and several of its constituent herbs significantly stimulated the phosphorylation of extracellular signal-regulated kinases and cAMP-responsive element binding protein, two molecular targets involved in learning and memory, as well as in the regulation of neurogenesis. CONCLUSIONS: Several constituents of YXT possess multiple regulatory effects on known therapeutic targets of AD that range from ß-amyloid to acetylcholinesterase. The demonstrated neuroprotective and neurogenic actions of YXT lend credence to its use as an alternative medicine for treating AD.

Magnetotransport studies of Fe vacancy-ordered Fe4+δSe5 nanowires.

We studied the electrical transport of Fe4+δSe5 single-crystal nanowires exhibiting √5 × âˆš5 Fe-vacancy order and mixed valence of Fe. Fe4+δSe5 compound has been identified as the parent phase of FeSe superconductor. A first-order metal-insulator (MI) transition of transition temperature T MI ∼ 28 K is observed at zero magnetic fields (B). Colossal positive magnetoresistance emerges, resulting from the magnetic field-dependent MI transition. T MI demonstrates anisotropic magnetic field dependence with the preferred orientation along the c axis. At temperature T < ∼17 K, the state of near-magnetic field-independent resistance, which is due to spin polarized even at zero fields, preserves under magnetic fields up to B = 9 T. The Arrhenius law shift of the transition on the source-drain frequency dependence reveals that it is a nonoxide compound with the Verwey-like electronic correlation. The observation of the magnetic field-independent magnetoresistance at low temperature suggests it is in a charge-ordered state below T ∼ 17 K. The results of the field orientation measurements indicate that the spin-orbital coupling is crucial in √5 × âˆš5 Fe vacancy-ordered Fe4+δSe5 at low temperatures. Our findings provide valuable information to better understand the orbital nature and the interplay between the MI transition and superconductivity in FeSe-based materials.

Mode Dependency of Quantum Decoherence Studied via an Aharonov-Bohm Interferometer.

We investigate the dependence of decoherence on the mode number M in a multiple-mode Aharonov-Bohm (AB) interferometer. The design of the AB interferometer allows us to precisely determine M by the additivity rule of ballistic conductors; meanwhile, the decoherence rate is simultaneously deduced by the variance of the AB oscillation amplitude. The AB amplitude decreases and fluctuates with depopulating M. Moreover, the normalized amplitude exhibits a maximum at a specific M (∼9). Data analysis reveals that the charge-fluctuation-induced dephasing, which depends on the geometry and the charge relaxation resistance of the system, could play an essential role in the decoherence process. Our results suggest that the phase coherence, in principle, can be optimized using a deliberated design and pave one of the ways toward the engineering of quantum coherence.

Cten, a COOH-terminal tensin-like protein with prostate restricted expression, is down-regulated in prostate cancer.

Tensin is a signaling molecule that binds to actin filaments and localizes to focal adhesions. Recently, we have discovered that tensin represents a new gene family with related members that are expressed in a variety of tissues. In this study, we report the identification and characterization of a new COOH-terminal tensin-like molecule, cten. Human cten cDNA encodes a 715 amino acid sequence containing the Src homology 2 and phosphotyrosine-binding domains that are similar to the COOH termini of tensin molecules. Although cten is shorter and does not have the actin-binding domain found in other tensins, analysis of the genomic structure has suggested that cten is related to the tensin gene family. In addition, cten also localizes to focal adhesions. In contrast to other tensin members, cten expression is restricted to prostate and placenta by Northern blot analysis. Furthermore, examination of cten expression in prostate cancer/cell lines has revealed its down-regulation in tumor samples. Our studies have suggested that during evolution, cten has preserved its role in mediating signal transduction at focal adhesions through the Src homology 2 and phosphotyrosine-binding domains but has lost its function in binding to actin filaments. The evolutionary divergence has produced the first focal adhesion protein specifically expressed in the prostate and the placenta, which may be involved in preventing prostate tumor formation.

Inhibitory effects of a luteinizing hormone-releasing hormone agonist on basal and epidermal growth factor-induced cell proliferation and metastasis-associated properties in human epidermoid carcinoma A431 cells.

The purpose of this study was to investigate the effects of a potent LHRH agonist, [D-Trp(6)]LHRH on the basal and EGF-induced cell proliferation and the metastasis-associated properties in A431 human epidermoid carcinoma. [D-Trp(6)]LHRH time-dependently inhibited the basal and EGF-stimulated growth of A431 cancer cells. It is assumed that phosphorylation/dephosphorylation of cellular proteins is highly related to cell growth. This study demonstrates that [D-Trp(6)]LHRH decreased the basal and EGF-induced total cellular kinase activity, particularly the tyrosine phosphorylation of several cellular proteins including the EGFR. In contrast, [D-Trp(6)]LHRH did not cause detectable changes in basal and EGF-stimulated serine/threonine phosphorylation of A431 cellular proteins. The inhibitory effect of [D-Trp(6)]LHRH on A431 cell proliferation was associated with apoptosis as evidenced by the cell morphology and DNA integrity (ladder pattern), the expression of interleukin 1beta-converting enzyme (ICE) and activation of caspase. Furthermore, EGF could rescue the remaining attached A431 cells following [D-Trp(6)]LHRH treatment for 48 hr, which suggests that limited exposure to [D-Trp(6)]LHRH did not channel all cells to irreversible apoptotic process. We also determined the effects of [D-Trp(6)]LHRH on metastasis-associated properties in A431 cells. [D-Trp(6)]LHRH reduced both basal and EGF-stimulated secretion of MMP-9 and MMP-2. In addition, [D-Trp(6)]LHRH suppressed the basal and EGF-induced invasive activity of A431 cells based on an in vitro invasion assay. In conclusion, this study indicates that [D-Trp(6)]LHRH may act partly through activating tyrosine phosphatase activity to inhibit cell proliferation and the metastasis-associated properties of A431 cancer cells. Our work suggests that [D-Trp(6)]LHRH may be therapeutically useful in limiting the tumor growth and metastasis of some neoplasms.