Several studies based on 16SrDNA analysis have revealed certain unique characteristics of gut microbiome in centenarians. We established a prospective cohort of fecal microbiota and conducted the ...first metagenomics-based study among centenarians. The objective was to explore the dynamic changes of gut microbiota in healthy centenarians and centenarians approaching end of life and to unravel the characteristics of aging-associated microbiome. Seventy-five healthy centenarians residing in three regions of Hainan participated in follow-up surveys and collection of fecal samples at intervals of 3 months. Data pertaining to dietary status, health status scores, cause of disease and death, and fecal specimens were collected for 15 months. Twenty participants died within 20 months during the follow-up period. The median survival time was 8-9 months (range, 1-17) and the mortality rate was 14.7% per year. The health status scores before death were significantly lower than those at 3 months before the end of the follow-up period median score: 3 (range, 1-5), P < 0.05. At this time, the participants mainly exhibited symptoms of anorexia and reduced dietary intake and physical activity. Metagenomics sequencing and analysis were carried out to characterize the gut microbiota changes in the centenarians during their transition from healthy status to death. Anosim analysis showed a significant change in gut microbiota from 7 months prior to death (R = 0.10, P = 0.02). All participants were grouped with 7 months before death as cut-off; no significant difference in α diversity was found between the two groups (P = 0.45). Semi-supervised monitoring and log rank sum analysis revealed significant changes in the abundance of ten bacterial species before death; of these, eight species were significantly reduced (Akkermansia muciniphila, Alistipes finegoldii, Alistipes shahii, Bacteroides faecis, Bacteroides intestinalis, Butyrivibrio crossotus, Bacteroides stercoris, and Prevotella stercorea) while two were significantly increased before death (Bifidobacterium longum and Ruminococcus bromii). Compared to centenarians in northern Italy, Hainan centenarians exhibited unique characteristics of gut microbiome. The abundance of ten bacterial species showed significant changes starting from 7 months before death. We speculate that these changes might occur before the clinical symptoms of deterioration in health status.
Sex differences in health status and life expectancy are widely accepted to exist. The mechanisms underlying it are still poorly understood. In this study, we aimed to clarify the influences and ...contributions of sex on the gut microbiome in healthy centenarians and to explore the different roles played by the gut microbiome in healthy aging between the sexes.
Taking covariates of different dimensions into account (social demographics, anthropometry, the activities of daily living, dietary structure, mental state, blood tests, lifestyle and disease history), our data showed that sex was one of the most significant covariates affecting the gut microbiome of healthy centenarians at both the species and Kyoto Encyclopedia of Genes and Genomes Orthology (KO) levels. The beta diversity between the sexes were significantly different (Adonis test: p = 0.011, R
= 0.031), and the male centenarians had a greater alpha diversity than the females (Simpson and Shannon test: P<0.05). At the species level, we identified 31 species enriched in males and 7 species enriched in females. The composition and function patterns of the microbiome varied between the sexes. Further functional analysis showed that males' gut microbiome exhibited greater resistance to oxidative stress compared to females. In contrast to men, the species associated with healthy aging dominated among healthy female centenarians, while the species associated with unhealthy aging were relatively rare.
The present study reveals that the gut microbiome structure and resistance to oxidative stress in healthy centenarians differ between the sexes and provides new insights into the possible sex-specific role of the gut microbiome in healthy aging.
We previously confirmed that a strain of Lactobacillus oris isolated from the fecal samples of healthy Hainan centenarian having potent lipid-lowering ability in HepG2 cells; and this study was to ...investigate the effect of the stain on non-alcoholic fatty liver in mice in vivio. The Lactobacillus oris strain isolated from Hainan centenarian fecal samples were frozen stored in our laboratory. Thirty ob/ob mice (10 in each group) were orally gavaged with Lactobacillus oris (Lactobacillus, 5 × 10
cfu), mixed probiotics (Mixed, 5 × 10
cfu, a mixture with known lipid-lowering ability), or culture medium (Control) respectively. Lactobacillus oris isolated from fecal samples of Hainan centenarians showed significantly in vivo lipid lowering ability compared with the controls, and the ability was comparable with mixed probiotics strains in mice The possible mechanisms of lipid-lowering of probiotics and Lactobacillus oris may be associated with HMGR inhibition to suppress the synthesis of endogenous cholesterol; bile acids reabsorption, and intestinal FXR-FGF15 signaling pathways promoting the cholesterol conversion into bile acids secretion.
The gut microbes play important roles in human longevity and the gut microbiota profile of centenarians shows some unique features from young adults. Nowadays, most microbial studies on longevity are ...commonly based on metagenomic sequencing which may lose information about the functional microbes with extremely low abundance. Here, we combined in-depth metagenomic sequencing and large-scale culturomics to reveal the unique gut microbial structure of a Chinese longevity population, and to explore the possible relationship between intestinal microbes and longevity. Twenty-five healthy Hainan natives were enrolled in the study, including 12 centenarians and 13 senior neighbors. An average of 51.1 Gb raw sequencing data were obtained from individual fecal sample. We assembled 1778 non-redundant metagenomic assembled genomes (MAGs), 33.46% of which cannot be classified into known species. Comparison with the ordinary people in Hainan province, the longevous cohort displayed significantly decreased abundance of butyrate-producing bacteria and largely increased proportion of Escherichia coli, Desulfovibrio piger and Methanobrevibacter smithii. These species showed a constant change with aging. We also isolated 8,030 strains from these samples by large-scale culturomics, most of which belonged to 203 known species as identified by MALDI-TOF. Surprisingly, only 42.17% of the isolated species were also detected by metagenomics, indicating obvious complementarity between these two approaches. Combination of two complement methods, in-depth metagenomic sequencing and culturomics, provides deeper insights into the longevity-related gut microbiota. The uniquely enriched gut microbes in Hainan extreme decades population may help to promote health and longevity.
Direct digital synthesis (DDS) technology is widely used in test and measurement instruments, and DDS technology can easily synthesize various types of waveforms with high frequency switching speed, ...flexible waveform editing, and high frequency resolution. However, the internal timing characteristics of the waveform, such as pulse edge time, pulse width, and ramp symmetry, need the waveform samples rewritten into the waveform memory to achieve changes. The timing resolution of the waveform is also limited by the capacity of the waveform memory and the waveform sample rate, which is difficult to further improve. In this paper, we proposes a method for synthesizing pulses, squares and ramps with high timing resolution based on a combination of real-time computation and DDS. The timing resolution of the synthesized waveform is no longer limited by the waveform memory capacity and waveform sample rate. And the timing resolution of the waveform can be hundreds or thousands of times of the sampling period. Also, since the waveform samples are calculated in real time based on waveform parameters, it is easy to realize various modulations such as pulse width modulation (PWM), frequency modulation (FM), and amplitude modulation (AM). In the case of multi-channel output, high-resolution interchannel delay control can be achieved by precisely adjusting the waveform phases. A experimental prototype based on this method was designed. The prototype has four waveform output channels, each with a 2.5 GSPS waveform sample rate, and realizes a variety of waveform synthesis and modulation including pulse, square and ramp. The timing resolution can reach 0.1 ps, including interchannel delay, pulse edge time, pulse width, duty cycle and ramp symmetry.
Direct digital frequency synthesis (DDFS) technology is widely used in modern nanoscale CMOS integrated devices, but it suffers from large waveform distortion and timing jitter in applications. In ...order to achieve high frequency resolution with limited waveform memory capacity, the phase of the waveform is usually truncated to switch waveform phases. The truncation of the phase causes the synthesized waveform to produce spurious and loses waveform details during phase switching, resulting in waveform distortion. In this paper, we propose a waveform distortion correction method that combines jitter injection and FIR digital filter using Farrow structure. Based on the waveform real-time computation technique, jitters are injected into the waveform time parameter to break the harmonic components caused by non-integer multiples of the sampling rate and waveform frequency. Using this approach, waveform spurious is further suppressed. The waveform distortion correction is achieved by design functions which complement the waveform distortion features. The complementary functions are then combined as Farrow filter coefficients by polynomial fitting. In this paper, a pulse waveform with 0.2 ps timing resolution is generated at 1 GSPS sampling rate by real-time computation technique. And then the waveform distortion correction method based on the proposed jitter injection combined with Farrow structure reduces the deterministic jitter from more than 600 ps to less than 20 ps, and the random jitter from more than 60 ps rms to less than 25 ps rms. The accuracy of timing parameters such as rise time, fall time, and pulse width is improved from ±500 ps to ±50 ps.
In the field of automatic test systems, direct digital synthesis (DDS) technology plays a crucial role with features such as fast frequency switching speed, high-frequency resolution, and flexible ...waveforms. However, the timing resolution of the pulse waveform generated by DDS technology is limited by the storage depth of waveform memory and sampling rate. DDS generates a maximum 1 clock cycle jitter in the pulse waveform as the frequency tune word (FTW) changes driven by the sampling clock, and the pulse width modulation (PWM) of the pulse waveform is not possible with DDS technology. In this paper, a parallel pulse waveform synthesis method based on real-time computation is proposed. The pulse waveform generated by this method has a timing resolution that far exceeds the sampling period including rising time resolution, falling time resolution, pulse width resolution, and delay resolution. Since the pulse parameters such as rising time, falling time, and pulse width can be independently adjusted with phase continuity, and the waveform samples are generated by real-time computation, the method can easily implement PWM and various modulations. The waveform samples computed in real-time correspond precisely to their theoretical phases with extremely low phase truncation error, thus jitter is greatly reduced and the timing resolution can be significantly improved. In this paper, based on the real-time computation of waveform samples, the sampling rate is increased eight times by parallelizing the computation. Each computing channel is run at 156.25 MHz, and the sampling rate of 1.25 GSPS waveform samples is achieved by running in parallel with eight channels. Finally, the pulse waveform is generated with a timing resolution of 0.2 ps, which theoretically requires a sampling rate of 5 TSPS to achieve.
The combination of a chemotherapeutic drug with a multidrug resistance (MDR) modulator has emerged as a promising strategy for treating MDR cancer. To ensure two drugs could be simultaneously ...delivered to tumor region at the optimum ratio, and the MDR modulator could be released earlier and faster than the chemotherapeutic drug to inactivate P-glycoprotein (P-gp) and subsequently inhibit the pumping out of the chemotherapeutic drug, a smart pH-sensitive polymeric micelles system with high drug loading and precise drug ratio was designed and prepared by conjugating doxorubicin (DOX) to poly(styrene-co-maleic anhydride) (SMA) derivative with adipic dihydrazide (ADH) through a acid-cleavable hydrazone bond, and then encapsulating disulfiram (DSF), a P-gp inhibitor as well as an apoptosis inducer, into the micelles formed by the self-assembly of SMA-ADH-DOX (SAD) conjugate. The pH-sensitive polymeric micelles system enabled a temporal release of two drugs: encapsulated DSF was released fast to inhibit the activity of P-gp and restore cell apoptotic signaling pathways, while conjugated DOX was released in a sustained and pH-dependent manner and highly accumulated in drug resistant cells to exert therapeutic effect, due to the inactivation of P-gp by DSF. The smart co-delivery system was very effective in enhancing the cytotoxicity by increasing the intracellular accumulation of DOX and promoting the apoptotic response, and showed the most effective inhibitory effect on the growth of drug-resistant breast cancer xenografts as compared to other combinations of both drugs. In a word, this smart co-delivery system has significant promise for the clinical therapy of MDR cancer.
Posterior segment diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) are vital factor that seriously threatens human vision health and quality of life, the ...treatment of which poses a great challenge to ophthalmologists and ophthalmic scientists. In particular, ocular posterior drug delivery in a non-invasive manner is highly desired but still faces many difficulties such as rapid drug clearance, limited permeability and low drug accumulation at the target site. At present, many novel non-invasive topical ocular drug delivery systems are under development aiming to improve drug delivery efficiency and biocompatibility for better therapy of posterior segment oculopathy. The purpose of this review is to present the challenges in the noninvasive treatment of posterior segment diseases, and to propose strategies to tackle these bottlenecks. First of all, barriers to ocular administration were introduced based on ocular physiological structure and behavior, including analysis and discussion on the influence of ocular structures on noninvasive posterior segment delivery. Thereafter, various routes of posterior drug delivery, both invasive and noninvasive, were illustrated, along with the respective anatomical obstacles that need to be overcome. The widespread and risky application of invasive drug delivery, and the need to develop non-invasive local drug delivery with alternative to injectable therapy were described. Absorption routes through topical administration and strategies to enhance ocular posterior drug delivery were then discussed. As a follow-up, an up-to-date research advances in non-invasive delivery systems for the therapy of ocular fundus lesions were presented, including different nanocarriers, contact lenses, and several other carriers. In conclusion, it seems feasible and promising to treat posterior oculopathy via non-invasive local preparations or in combination with appropriate devices.
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