Hippocampal atrophy rate has been correlated with cognitive decline and its genetic modifiers are still unclear. Here we firstly performed a genome-wide association study (GWAS) to identify genetic ...loci that regulate hippocampal atrophy rate. Six hundred and two non-Hispanic Caucasian elders without dementia were included from the Alzheimer's Disease Neuroimaging Initiative cohort. Three single nucleotide polymorphisms (SNPs) (rs4420638, rs56131196, rs157582) in the
-
region were associated with hippocampal atrophy rate at genome-wide significance and 3 additional SNPs (in
and near
gene) reached a suggestive level of significance. Strong linkage disequilibrium between rs4420638 and rs56131196 was found. The minor allele of rs4420638 (G) and the minor allele of rs157582 (T) showed associations with lower Mini-mental State Examination score, higher Alzheimer Disease Assessment Scale-cognitive subscale 11 score and smaller entorhinal volume using both baseline and longitudinal measurements, as well as with accelerated cognitive decline. Moreover, rs56131196 (P = 1.96 × 10
) and rs157582 (P = 9.70 × 10
) were risk loci for Alzheimer's disease. Collectively, rs4420638, rs56131196 and rs157582 were found to be associated with hippocampal atrophy rate. Besides, they were also identified as genetic loci for cognitive decline.
DNA barcoding has greatly facilitated studies of taxonomy, biodiversity, biological conservation, and ecology. Here, we establish a reliable DNA barcoding library for Chinese snakes, unveiling hidden ...diversity with implications for taxonomy, and provide a standardized tool for conservation management. Our comprehensive study includes 1638 cytochrome c oxidase subunit I (COI) sequences from Chinese snakes that correspond to 17 families, 65 genera, 228 named species (80.6% of named species) and 36 candidate species. A barcode gap analysis reveals gaps, where all nearest neighbour distances exceed maximum intraspecific distances, in 217 named species and all candidate species. Three species‐delimitation methods (ABGD, sGMYC, and sPTP) recover 320 operational taxonomic units (OTUs), of which 192 OTUs correspond to named and candidate species. Twenty‐eight other named species share OTUs, such as Azemiops feae and A. kharini, Gloydius halys, G. shedaoensis, and G. intermedius, and Bungarus multicinctus and B. candidus, representing inconsistencies most probably caused by imperfect taxonomy, recent and rapid speciation, weak taxonomic signal, introgressive hybridization, and/or inadequate phylogenetic signal. In contrast, 43 species and candidate species assign to two or more OTUs due to having large intraspecific distances. If most OTUs detected in this study reflect valid species, including the 36 candidate species, then 30% more species would exist than are currently recognized. Several OTU divergences associate with known biogeographic barriers, such as the Taiwan Strait. In addition to facilitating future studies, this reliable and relatively comprehensive reference database will play an important role in the future monitoring, conservation, and management of Chinese snakes.
As a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the ...anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs.
Co-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for cellular PK in co-culture models.
CAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP.
The simple and cost‑effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.
As cognitive function declines with age, identifying factors affecting the trajectory of cognitive decline is an indispensable step toward developing intervention strategies to improve the quality of ...the elderly life.
We performed a genome-wide association study (GWAS) focusing on memory function to explore single nucleotide polymorphisms (SNPs) associated with the rate of memory decline.
Seven hundred and nine eligible non-Hispanic Caucasians from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included for analysis after quality control. GWAS was performed with linear regression. We subsequently tested whether the associations remained significant in subgroup analysis and also examined the impact of SNPs on the longitudinal changes in other neuropsychological measures and amyloid pathology.
We identified rs13374761-A in SLAMF1 gene associated with less memory decline (MAF = 0.071, β= 0.0103, p = 4.14×10-8). Subgroup analysis showed stability of results across groups with different diagnosis at baseline. Rs13374761-A also had protective effects on global cognition (p = 0.024), episodic memory (p = 0.024), and semantic memory (p = 0.042), and exerts protection against a decrease in CSF Aβ42 concentration (p = 0.0463) and an increase in Aβ loading in cerebral cortex (p = 0.00666) among minor allele carriers.
A novel variant in gene SLAMF1 affects the rate of memory decline in the aged population. Given the protective effect of this variant, SLAMF1 should be further investigated as a potential preventive and therapeutic target for monitoring cognition trajectories.
A subgroup of overweight/obese individuals, who had favorable metabolic profiles, was termed as metabolically healthy overweight/obese (MHO). Several studies suggested that MHO individuals were not ...at increased risk of cardiovascular disease and all-course mortality. However, whether MHO is associated with excess risk of Alzheimer's disease (AD) in elders remains unclear. To explore the risk of AD among MHO phenotype and investigate whether MHO associates with neurodegenerative biomarkers of AD, we assessed body mass index-metabolic status phenotypes of 1199 longitudinal elders from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort using the Adult Treatment Panel-III (ATP- III) criteria. MHO subjects were at a significantly decreased risk for AD (adjusted HR=0.73, 95% CI: 0.54-0.97) compared with metabolically healthy normal weight (MHNW) subjects. In multivariable linear regression models, the cross-sectional associations of MHO with cerebrospinal fluid (CSF) biomarkers, brain Aβ load, and cortical structure were explored. MHO was positively correlated with CSF-Aβ (β=0.746, P=0.015), hippocampal volume (β=0.181, P=0.011), and whole brain volume (β=0.133, P=0.004). The MHO phenotype of the elder conferred a decreased risk of AD and its role may be driven by Aβ.
The development of Ru(ii) complexes as luminescent probes has attracted increasing attention in recent decades. In this study, the nanosized polymers of two Ru(ii) complexes Ru(phen)
(dppz)(ClO
)
(1, ...phen = 1,10-phenanthrolin; dppz = dipyrido3,2-
:2',3'-
phenazine) and Ru(phen)
(Br-dppz)(ClO
)
(2, Br-dppz = 11-bromodipyrido3,2-
:2',3'-
phenazine) with oligonucleotides were prepared and investigated as potential tumor-imaging probes. The formation of the nanosized polymers, which had an average width of 125-438 nm and an average height of 3-6 nm, for 1 and 2@oligonucleotides were observed through atomic force microscopy. The emission spectra indicated that the luminescence of 1 and 2 markedly increased after binding to oligonucleotides and double-strand DNA (calf thymus DNA), respectively. Moreover, further studies indicated that 1@oligonucleotides and 2@oligonucleotides can easily enter into tumor cells and selectively highlight the tumor area in the zebrafish bear xenograft tumor (MDA-MB-231). In summary, this study demonstrated that 1@oligonucleotides and 2@oligonucleotides could be developed as potential tumor-imaging luminescent probes for clinical diagnosis and therapy.
•Multidrug-resistant (MDR) Mycobacterium tuberculosis strains of modern Beijing sublineage are prevalent in North China.•Combination of rpoB531-TTG and katG315-ACC favours transmission of modern ...Beijing MDR strains.•Positive epistasis of major resistance mutations depends on the lineage of M. tuberculosis strains.
Mycobacterium tuberculosis Beijing genotype strains increasingly circulate in different world regions, either as historical endemic, e.g. in East Asia, or recently imported, e.g. in South America, and this family is regarded as the most successful lineage of the global tuberculosis (TB) epidemic. Here we analysed the transmission capacity of these strains in the context of their phylogenetic background and drug resistance mutations. The study collection included all multidrug resistant (MDR) strains of Beijing genotype isolated in Beijing Chest Hospital, the largest tertiary TB facility in North China, in 2011–2013 (n = 278). Strains were subjected to NTF/IS6110 and 24-loci MIRU-VNTR analysis. Drug resistance mutations were detected in rpoB, katG, inhA and oxyR–ahpC. A total of 58 and 220 strains were assigned to the ancient and modern Beijing sublineages, respectively. 24-MIRU-VNTR clustering was higher in modern versus ancient Beijing strains (35.9% vs. 12.1%; P < 0.001). After taking into consideration the presence of rpoB and katG mutations, clustering decreased to 15.9% in modern and 0% in ancient strains. The most frequent combination of mutations (rpoB531-TTG and katG315-ACC) was more prevalent in clustered versus non-clustered isolates in the modern sublineage (23/35 vs. 47/185; P < 0.0001). To conclude, a combination of the known low-fitness-cost rpoB531-TTG and katG315-ACC mutations likely facilitates the increased transmission ability of MDR strains of the modern but not ancient Beijing sublineage. Accordingly, positive epistasis of major low-cost drug resistance-conferring mutations is influenced by the phylogenetic background of M. tuberculosis strains.
Age-related changes in visual function and retina structure are very common in aged animals, but the underlying mechanisms of these changes remain unclear. Here we report that the expression of ...interferon regulatory factor 3 (
), a critical immune regulatory factor, is dramatically down-regulated in mouse retinas during aging. To address the role of
in the retina, we examined the structure and function of retinas in young (3-4 months) and old (22-24 months)
mice in comparison to age-matched wildtype (WT) mice. We found that
deletion resulted in impaired electroretinogram (ERG) responses and decreased retinal thickness in both young and old mice. In addition, numerous synapses of the outer plexiform layer (OPL) were found obviously extending into outer nuclear layer (ONL) in
mice, along with a reduction of the average synapse density in the OPL. These changes suggest that
deletion may accelerate retinal senescence. In support of this hypothesis, a number of classic senescence-associated markers were found in remarkably elevated level in
retina, including p53, p16
, inositol-requiring enzyme 1α (IREα), p-H2A.X and promyelocytic leukemia protein (PML). Overall, our results indicate that maintenance normal
levels is necessary for retinal structure and function and suggest that
is an important regulator of retinal senescence.
Venous thromboembolism (VTE) remained common complication following surgical resection of esophageal cancer. In this prospective randomized double-blind placebo-controlled trial (NCT01267305), we aim ...to compare the safety and efficacy between low molecular weight heparin (LMWH) once-daily (QD) and twice-daily (BID) for the prophylaxis of VTE following esophagectomy.
During August 2012 to July 2013, patients underwent esophagectomy were randomly assigned to nadroparin calcium QD (4,100 AxaIU qd + placebo qd, group QD), or nadroparin calcium BID (4,100 AxaIU q12h, group BID) in the prophylaxis of VTE. All patients received thrombelastography (TEG) before and 0/24/48/72 hours after operation. Daily vascular ultrasound of lower extremities was followed during the first 7 postoperative days to confirm the suspected deep venous thrombosis (DVT). Cumulatively postoperative chest drainage at 72 hours after the surgery was collected to identify the difference in volume and red blood cell (RBC) counts between the two groups. Any bleeding events and thromboembolic events were also documented.
A total of 117 patients were enrolled in this study, and 111 eligible patients were randomly assigned (group QD: 55 patients; group BID: 56 patients). Patients' clinical features were close between the two groups. TEG analysis R time, K time, alpha angel and maximum amplitude (MA) before and instantly after operation showed nearly identical results. However, compared with group QD, all TEG measurements of 24/48/72 hours postoperatively showed significantly prolonged R time and K time, and decreased alpha angel in group BID. In ultrasound follow-ups, a total of four cases of DVT (four cases in group QD and no case in group BID) were found in this cohort (7.27% versus 0%, P=0.046), and one case of pulmonary embolism (PE) (in group QD) was observed. The incidence of VTE was lower in group BID (9.09% versus 0%, P=0.032). At 72 hours after surgery, the cumulative volume of chest drainage were close between these two groups (1,001.39±424.58 versus 1,133.61±513.93 mL, P=0.406). RBC counts in chest drainage were also identical between two groups (2.56±1.98)×10(5) versus (2.71±4.67)×10(5), P=0.61. No patient died due to VTE or bleeding events.
For the prophylaxis of VTE, BID LMWH provided more potent efficacy and equal safety when compared to QD LMWH in patients undergoing selective esophagectomy. Further study based on larger population is required to confirm these findings.
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