Demographic dynamics and molecular evolution of the rare and endangered subsect. Gerardianae of Pinus: insights from chloroplast genomes and mitochondrial DNA markers.

MAIN CONCLUSION: The divergence of subsect. Gerardianae was likely triggered by the uplift of the Qinghai-Tibetan Plateau and adjacent mountains. Pinus bungeana might have probably experienced expansion since Last Interglacial period. Historical geological and climatic oscillations have profoundly affected patterns of nucleotide variability, evolutionary history, and species divergence in numerous plants of the Northern Hemisphere. However, how long-lived conifers responded to geological and climatic fluctuations in East Asia remain poorly understood. Here, based on paternally inherited chloroplast genomes and maternally inherited mitochondrial DNA markers, we investigated the population demographic history and molecular evolution of subsect. Gerardianae (only including three species, Pinus bungeana, P. gerardiana, and P. squamata) of Pinus. A low level of nucleotide diversity was found in P. bungeana (π was 0.00016 in chloroplast DNA sequences, and 0.00304 in mitochondrial DNAs). The haplotype-based phylogenetic topology and unimodal distributions of demographic analysis suggested that P. bungeana probably originated in the southern Qinling Mountains and experienced rapid population expansion since Last Interglacial period. Phylogenetic analysis revealed that P. gerardiana and P. squamata had closer genetic relationship. The species divergence of subsect. Gerardianae occurred about 27.18 million years ago (Mya) during the middle to late Oligocene, which was significantly associated with the uplift of the Qinghai-Tibetan Plateau and adjacent mountains from the Eocene to the mid-Pliocene. The molecular evolutionary analysis showed that two chloroplast genes (psaI and ycf1) were under positive selection, the genetic lineages of P. bungeana exhibited higher transition and nonsynonymous mutations, which were involved with the strongly environmental adaptation. These findings shed light on the population evolutionary history of white pine species and provide striking insights for comprehension of their species divergence and molecular evolution.

Discovery of cinnamamide/ester triazole hybrids as potential treatment for Alzheimer's disease.

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.

Whole-genome sequencing of clinical isolates of Citrobacter Europaeus in China carrying blaOXA-48 and blaNDM-1.

OBJECTIVE: To analyze the clinical infection characteristics and genetic environments of resistance genes in carbapenem-resistant Citrobacter europaeus using whole-genome sequencing. METHODS: The susceptibility of two clinical isolates of C. europaeus (WF0003 and WF1643) to 24 antimicrobial agents was assessed using the BD Phoenix™ M50 System and Kirby-Bauer (K-B) disk-diffusion method. Whole-genome sequencing was performed on the Illumina and Nanopore platforms, and ABRicate software was used to predict resistance and virulence genes of carbapenem-resistant C. europaeus. The characteristics of plasmids carrying carbapenem-resistance genes and their genetic environments were analyzed. Single nucleotide polymorphisms were used to construct a phylogenetic tree to analyze the homology of these two C. europaeus strains with ten strains of C. europaeus in the NCBI database. RESULTS: The two strains of carbapenem-resistant C. europaeus are resistant to various antimicrobial agents, particularly carbapenems and ß-lactams. WF0003 carries blaNDM- 1, which is located on an IncX3 plasmid that has high homology to the pNDM-HN380 plasmid. blaNDM- 1 is located on a truncated Tn125. It differs from Tn125 by the insertion of IS5 in the upstream ISAba125 and the deletion of the downstream ISAba125, which is replaced by IS26. WF1643 carries blaOXA- 48 in a Tn1999 transposon on the IncL/M plasmid, carrying only that single drug resistance gene. Homology analysis of these two strains of C. europaeus with ten C. europaeus strains in the NCBI database revealed that the 12 strains can be classified into three clades, with both WF0003 and WF1643 in the B clade. CONCLUSION: To the best of our knowledge, this is the first study to report an IncX3 plasmid carrying blaNDM- 1 in C. europaeus in China. C. europaeus strains harboring carbapenem-resistance genes are concerning in relation to the spread of antimicrobial resistance, and the presence of carbapenem-resistance genes in C. europaeus should be continuously monitored.

Total body water percentage and 3rd space water are novel risk factors for training-related lower extremity muscle injuries in young males.

PURPOSE: To identify the risk factors for training-related lower extremity muscle injuries in young males by a non-invasive method of body composition analysis. METHODS: A total of 282 healthy young male volunteers aged 18 - 20 years participated in this cohort study. Injury location, degree, and injury rate were adjusted by a questionnaire based on the overuse injury assessment methods used in epidemiological studies of sports injuries. The occurrence of training injuries is monitored and diagnosed by physicians and treated accordingly. The body composition was measured using the BodyStat QuadScan 4000 multifrequency Bio-impedance system at 5, 50, 100 and 200 kHz to obtain 4 impedance values. The Shapiro-Wilk test was used to check whether the data conformed to a normal distribution. Data of normal distribution were shown as mean ± SD and analyzed by t-test, while those of non-normal distribution were shown as median (Q1, Q3) and analyzed by Wilcoxon rank sum test. The receiver operator characteristic curve and logistic regression analysis were performed to investigate risk factors for developing training-related lower extremity injuries and accuracy. RESULTS: Among the 282 subjects, 78 (27.7%) developed training injuries. Lower extremity training injuries revealed the highest incidence, accounting for 23.4% (66 cases). These patients showed higher percentages of lean body mass (p = 0.001), total body water (TBW, p = 0.006), extracellular water (p = 0.020) and intracellular water (p = 0.010) as well as a larger ratio of basal metabolic rate/total weight (p = 0.006), compared with those without lower extremity muscle injuries. On the contrary, the percentage of body fat (p = 0.001) and body fat mass index (p = 0.002) were lower. Logistic regression analysis showed that TBW percentage > 65.35% (p = 0.050, odds ratio = 3.114) and 3rd space water > 0.95% (p = 0.045, odds ratio = 2.342) were independent risk factors for lower extremity muscle injuries. CONCLUSION: TBW percentage and 3rd space water measured with bio-impedance method are potential risk factors for predicting the incidence of lower extremity muscle injuries in young males following training.

Analysis of resistance genes of carbapenem-resistant Providencia rettgeri using whole genome sequencing.

OBJECTIVE: This study aimed to investigate the clinical infection characteristics and analyze the resistance gene carrying status of carbapenem-resistant Providencia rettgeri via whole genome sequencing (WGS). METHODS: Carbapenem-resistant P. rettgeri were collected from clinical patients between January 2020 and December 2021, and their susceptibility to 19 antimicrobial drugs was determined using the VITEK 2 Compact system and Kirby-Bauer (KB) disk diffusion method. The Illumina platform was used to perform WGS of the P. rettgeri isolates, and the resistance genes carried by the Carbapenem-resistant P. rettgeri strains were detected via ABRicate software. The phylogenetic tree was constructed by thirty-four strains including twenty-eight strains downloaded from NCBI database and the carbapenem-resistant six P. rettgeri strains in this study. Which based on genomic single nucleotide polymorphism (SNP) to understand the affinities of the carbapenem-resistant P. rettgeri strains. RESULTS: Six carbapenem-resistant P. rettgeri strains were isolated from five different clinical departments using the blood, urine, sputum, and secretion specimens. These infected patients are middle-aged and elderly people with a history of severe trauma, tumors, hypertension, and various other underlying diseases, and invasive procedures. Antimicrobial sensitivity testing showed that all strains presented resistance to ampicillin-sulbactam, ceftazidime, ciprofloxacin, levofloxacin, and ertapenem, whereas they exhibited full susceptibility to cefepime and amikacin. Most strains demonstrated high resistance to ß-lactams, aminoglycosides, and sulfonamides. Thirty-five resistance genes were identified by ABRicate. All carbapenem-resistant P. rettgeri strains carried aminoglycoside, fluoroquinolone, chloramphenicol, rifampicin, sulfonamide, and ß-lactam resistance genes, and most importantly, all strains possessed the carbapenem resistance gene blaNDM-1. The six P. rettgeri strains in this study and the 28 carbapenem-resistant P. rettgeri strains from the NCBI database were divided into four evolutionary groups. The WF3643, WF3849, WF3822, and WF3821 strains in this study were in the same evolutionary group (clade A), while the closely related WF3099 and WF3279 strains were in different evolutionary groups (clade B and clade D), respectively. The WF3099 strain was distantly related to the other five strains. CONCLUSION: Carbapenem-resistant P. rettgeri strains were mostly isolated from middle-aged and older patients with a history of surgery or serious underlying diseases, and they were found to cause multisystem infections. All Carbapenem-resistant P. rettgeri strains in this study carried blaNDM-1 and multiple antimicrobial drug resistance genes. Furthermore, the P. rettgeri strains in this study were closely related, suggesting the possibility of nosocomial infections. Therefore, our study highlights the need for research on P. rettgeri to control the spread of these nosocomial infections.

The hybridization origin of the Chinese endemic herb genus Notopterygium (Apiaceae): Evidence from population genomics and ecological niche analysis.

Hybridization is recognized as a major force in species evolution and biodiversity formation, generally leading to the origin and differentiation of new species. Multiple hybridization events cannot easily be reconstructed, yet they offer the potential to study a number of evolutionary processes. Here, we used nuclear expressed sequence tag-simple sequence repeat and large-scale single nucleotide polymorphism variation data, combined with niche analysis, to investigate the putative independent hybridization events in Notopterygium, a group of perennial herb plants endemic to China. Population genomic analysis indicated that the four studied species are genetically well-delimited and that N. forrestii and N. oviforme have originated by hybridization. According to Approximate Bayesian Computation, the best-fit model involved the formation of N. forrestii from the crossing of N. franchetii and N. incisum, with N. forrestii further backcrossing to N. franchetii to form N. oviforme. The niche analyses indicated that niche divergence [likely triggered by the regional climate changes, particularly the intensification of East Asian winter monsoon, and tectonic movements (affecting both Qinghai-Tibetan Plateau and Qinling Mountains)] may have promoted and maintained the reproductive isolation among hybrid species. N. forrestii shows ecological specialization with respect to their parental species, whereas N. oviforme has completely shifted its niche. These results suggested that the climate and environmental factors together triggered the two-step hybridization of the East Asia herb plants. Our study also emphasizes the power of genome-wide SNPs for investigating suspected cases of hybridization, particularly unravelling old hybridization events.

Lipid Microparticles Show Similar Efficacy With Lipid Nanoparticles in Delivering mRNA and Preventing Cancer.

PURPOSE: Messenger RNA (mRNA) has shown great promise for vaccine against both infectious diseases and cancer. However, mRNA is unstable and requires a delivery vehicle for efficient cellular uptake and degradation protection. So far, lipid nanoparticles (LNPs) represent the most advanced delivery platform for mRNA delivery. However, no published studies have compared lipid microparticles (LMPs) with lipid nanoparticles (LNPs) in delivering mRNA systematically, therefore, we compared the impact of particle size on delivery efficacy of mRNA vaccine and subsequent immune responses. METHODS: Herein, we prepared 3 different size lipid particles, from nano-sized to micro-sized, and they loaded similar amounts of mRNA. These lipid particles were investigated both in vitro and in vivo, followed by evaluating the impact of particle size on inducing cellular and humoral immune responses. RESULTS: In this study, all mRNA vaccines showed a robust immune response and lipid microparticles (LMPs) show similar efficacy with lipid nanoparticles (LNPs) in delivering mRNA and preventing cancer. In addition, immune adjuvants, either toll like receptors or active molecules from traditional Chinese medicine, can improve the efficacy of mRNA vaccines. CONCLUSIONS: Considering the efficiency of delivery and endocytosis, besides lipid nanoparticles with size smaller than 150 nm, lipid microparticles (LMPs) also have the potential to be an alternative and promising delivery system for mRNA vaccines.

Influence of COVID-19 pandemic on the virus spectrum in children with respiratory infection in Xuzhou, China: a long-term active surveillance study from 2015 to 2021.

BACKGROUND: To investigate the impact of the coronavirus disease 2019 (COVID-19) outbreak on the prevalence of respiratory viruses among pediatric patients with acute respiratory infections in Xuzhou from 2015-2021. METHODS: Severe acute respiratory infection (SARI) cases in hospitalized children were collected from 2015-2021 in Xuzhou, China. Influenza virus(IFV), respiratory syncytial virus (RSV), human parainfluenza virus type 3(hPIV-3), human rhinovirus (hRV), human adenovirus(hAdV), human coronavirus(hCoV) were detected by real-time fluorescence polymerase chain reaction(RT-qPCR), and the results were statistically analyzed by SPSS 23.0 software. RESULTS: A total of 1663 samples with SARI were collected from 2015-2021, with a male-to-female ratio of 1.67:1 and a total virus detection rate of 38.5% (641/1663). The total detection rate of respiratory viruses decreased from 46.2% (2015-2019) to 36% (2020-2021) under the control measures for COVID-19 (P < 0.01). The three viruses with the highest detection rates changed from hRV, RSV, and hPIV-3 to hRV, RSV, and hCoV. The epidemic trend of hPIV-3 and hAdV was upside down before and after control measures(P < 0.01); however, the epidemic trend of RV and RSV had not changed from 2015 to 2021(P > 0.05). After the control measures, the detection rate of hPIV-3 decreased in all age groups, and the detection rate of hCoV increased in all except the 1 ~ 3 years old group. CONCLUSIONS: Implementing control measures for COVID-19 outbreak curbed the spread of respiratory viruses among children as a whole. However, the epidemic of RV and RSV was not affected by the COVID-19 control policy.

The interaction between obesity and visceral hypersensitivity.

Obesity has been a worldwide problem associated with numerous chronic diseases such as cardiovascular disease, type 2 diabetes, and metabolic disorders. It may also play a role in visceral hypersensitivity, contributing to irritable bowel syndrome. (i) Adipose tissue secretes various inflammatory mediators, causing intestinal hyperpermeability and nerve endings activation. (ii) Obesity and gastrointestinal microbiota could affect each other, and microbial metabolites can increase sensitivity of the colon. (iii) Vitamin D deficiency contributes to both fat accumulation and disruption of the intestinal mucosal barrier. (iv) Brain-gut axis may be another bridge from obesity to visceral hypersensitivity.

Effects of nano-titanium dioxide on calcium homeostasis in vivo and in vitro: a systematic review and meta-analysis.

With the extensive application of titanium dioxide nanoparticles (TiO2 NPs), their impacts on calcium homeostasis have aroused extensive attention from scholars. However, there are still some controversies in relevant reports. Therefore, a systematic review was performed followed by a meta-analysis to explore whether TiO2 NPs could induce the imbalance in calcium homeostasis in vivo and in vitro through Revman5.4 and Stata15.0 in this research. Fourteen studies were included through detailed database retrieval and literature screening. Results indicated that the calcium levels were significantly increased and the activity of Ca2+-ATPase was significantly decreased by TiO2 NPs in vivo and in vitro. Subgroup analysis of the studies in vivo showed that TiO2 NPs exposure caused a significant increase in calcium levels in rats, exposure to large-sized TiO2 NPs (>10 nm) and long-term (>30 days) exposure could significantly increase calcium levels, and the activity of Ca2+-ATPase showed a concentration-dependent downward trend. Subgroup analysis of the studies in vitro revealed that intracellular calcium levels increased significantly in animal cells, exposure to small-sized TiO2 NPs (≤10 nm) and high concentration (>10 µg/mL) exposure could induce a significant increase in Ca2+ concentration, and the activity of Ca2+-ATPase also showed a concentration-dependent downward trend. This research showed that the physicochemical properties of TiO2 NPs and the experimental scheme could affect calcium homeostasis.

[Variation and interaction mechanism between active components in Rheum officinale and rhizosphere soil microorganisms under drought stress].

To explore the changes and the reaction mechanisms between soil microecological environment and the content of secon-dary metabolites of plants under water deficit, this study carried out a pot experiment on the 3-leaf stage seedlings of Rheum officinale to analyze their response mechanism under different drought gradients(normal water supply, mild, moderate, and severe drought). The results indicated that the content of flavonoids, phenols, terpenoids, and alkaloids in the root of R. officinale varied greatly under drought stresses. Under mild drought stress, the content of substances mentioned above was comparatively high, and the content of rutin, emodin, gallic acid, and(+)-catechin hydrate in the root significantly increased. The content of rutin, emodin, and gallic acid under severe drought stress was significantly lower than that under normal water supply. The number of species, Shannon diversity index, richness index, and Simpson index of bacteria in the rhizosphere soil were significantly higher than those in blank soil, and the number of microbial species and richness index decreased significantly with the aggravation of drought stresses. In the context of water deficit, Cyanophyta, Firmicutes, Actinobacteria, Chloroflexi, Gemmatimonadetes, Streptomyces, and Actinomyces were the dominant bacteria in the rhizosphere of R. officinale. The relative content of rutin and emodin in the root of R. officinale was positively correlated with the relative abundance of Cyanophyta and Firmicutes, and the relative content of(+)-catechin hydrate and(-)-epicatechin gallate was positively correlated with the relative abundance of Bacteroidetes and Firmicutes. In conclusion, appropriate drought stress can increase the content of secondary metabolites of R. officinale from physiological induction and the increase in the association with beneficial microbe.

A Multiple-Target Simultaneous Detection Method for Immunosorbent Assay and Immunospot Assay.

Enzyme-linked immunosorbent assay (ELISA) is one of the most common methods in biological studies, and enzyme-linked immunospot (ELISpot) is a method to measure specific cell numbers by detecting protein secretion at a single-cell level. However, these two current methods can only detect one signal at one time and the sensitivity is not high enough to test low-concentration samples, which are major shortcomings in systematically analyzing the samples of interest. Herein, we demonstrated fluorescence-based oligo-linked immunosorbent assay (FOLISA) and fluorescence-based oligo-linked immunospot (FOLISPOT), which utilized DNA-barcoded antibodies to provide a highly multiplexed method with signal amplification. Signal amplification and simultaneous multiple-target detection were achieved by DNA complementary pairing and modular orthogonal DNA concatemers. By comparing FOLISA with traditional ELISA and comparing FOLISPOT with traditional ELISPOT, we found that the detection sensitivities of FOLISA and FOLISPOT are much higher than those of traditional ELISA and ELISPOT. The detection limit of ELISA is around 3 pg/mL, and the detection limit of FOLISA is below 0.06 pg/mL. FOLISPOT can detect more spots than ELISPOT and can detect targets that are undetectable for ELISPOT. Furthermore, FOLISA and FOLISPOT allowed sequential detection of multiple targets by using a single dye or multiple dyes in one round and sequential detection in multiple rounds. Thus, FOLISA and FOLISPOT enabled simultaneous detection of a large number of targets, significantly improved the detection sensitivity, and overcame the shortcomings of ELISA and ELISPOT. Overall, FOLISA and FOLISPOT presented effective and general platforms for rapid and multiplexed detection of antigens or antibodies with high sensitivity, either in laboratory tests or potentially in clinic tests.

Identification of an IRES within the coding region of the structural protein of human rhinovirus 16.

As an alternative mechanism for cap-dependent (m7GpppN) translation, internal ribosome entry site (IRES)-dependent translation has been observed in the 5' untranslated regions (5' UTR) and coding regions of a number of viral and eukaryotic mRNAs. In this study, a series of 5' terminal truncated structural protein genes that were fused with GFP was used to screen for potential IRESs, and IRESs were identified using a bicistronic luciferase vector or GFP expression vector possessing a hairpin structure. Our results revealed that a putative IRES was located between nt 1982 and 2281 in the VP3 coding region of the human rhinovirus 16 (HRV16) genomes. We also demonstrated that effective IRES-initiated protein expression in vitro did not occur through splicing sites or cryptic promoters. We confirmed that thapsigargin (TG), an inducer of endoplasmic reticulum stress (ERS), facilitated increased IRES activity in a dose-dependent manner. Additionally, the secondary structure of the IRES was predicted online using the RNAfold web server.

Antimicrobial Resistance and Molecular Characterization of Gene Cassettes from class 1 Integrons in Carbapenem-resistant Escherichia coli strains.

OBJECTIVE: To investigate the distribution of class 1 integrons and their variable regional molecular characteristics, as well as the diversity of promoter and drug sensitivity of CR-Eco (carbapenem-resistant E. coli) strains. METHOD: A total of 117 CR-Eco strains, collected between 2012.01 and 2019.12, underwent fully automated bacterial identification and sensitization using VITEK-2 Compact and supplemented by K-B assay. PCR was employed to screen for class 1 integrase genes and integron variable regions, while the promoter type and variable region gene cassette characteristics were determined by sequencing analysis. RESULTS: The positive rate of the class 1 integron of the CR-Eco strains was 83.70% (92/117) herein. Moreover, class 1 integrase-positive strains exhibited statistically significant resistance to aztreonam, ceftazidime, ciprofloxacin, ceftriaxone, gentamicin, meropenem, and trimethoprim-sulfamethoxazole compared to integron-negative strains (P < 0.05). Variable regions were observed in 77 of the 92 class 1 integrase-positive strains. In addition, seven gene cassettes were detected, namely dfrA17-aadA5, aadA22, dfrA12-aadA2, dfrA12, dfrA17, dfrA27 and aadA. Finally, five types of class 1 integron variable region promoters were identified in those 77 strains, including PcW, PcH1, PcWTGN-10, PcH1TGN-10, and P2, which were detected in 48, 18, 8, 2, and 1 strains, respectively. CONCLUSION: The primary integrator variable region gene cassettes of this class were dfrA and aadA. The integron-positive strains displayed simultaneous high resistance to multiple antimicrobial drugs. The integrator variable region promoters of the CR-Eco strains are primarily weak and can potentially form and spread drug resistance.

Transcriptomic analysis reveals that coxsackievirus B3 Woodruff and GD strains use similar key genes to induce FoxO signaling pathway activation in HeLa cells.

Coxsackievirus B3 (CVB3) is a major cause of viral myocarditis in humans. Although there have been studies on CVB3 infection and pathogenesis, the precise disease mechanism is still not clear. In this study, we used RNA-seq technology to compare the transcriptomic profile of virus-infected HeLa cells to that of uninfected cells to identify key genes involved in host-virus interaction. For this, two CVB3 strains, CVB3 Woodruff, an experimental strain, and GD16-69/GD/CHN/2016, a clinical strain, were selected to examine the common mechanisms underlying their infection. Transcriptomic profiles revealed increased expression of the cell cycle genes CCNG2, GADD45B, PIM1, RBM15, KLF10, and RIOK3 and decreased expression of CYBA. The autophagy-related genes ATG12 and YOD1 were found to be upregulated, while the expression of SOD2 and XPO1 increased slightly in infected cells, and only a minor change was observed in GABARAP expression. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed the FoxO signaling pathway to be enriched and showed a close interaction with differentially expressed genes (DEGs) in the protein-protein interaction network. DEGs associated with related pathways such as cell cycle, autophagy, and oxidative stress resistance were also confirmed by qRT-PCR. In summary, the FoxO signaling pathway was activated during infection with both CVB3 strains and was found to have a regulatory role in downstream pathways such as cell cycle, autophagy, oxidative stress resistance, and the antiviral immune response.

Burden of chronic kidney disease and its risk-attributable burden in 137 low-and middle-income countries, 1990-2019: results from the global burden of disease study 2019.

BACKGROUND: Chronic kidney disease (CKD) is a global public health concern, but its disease burden and risk-attributable burden in CKD has been poorly studied in low - and middle-income countries (LMICs). This study aimed to estimate CKD burden and risk-attributable burden in LMICs from 1990 to 2019. METHODS: Data were collected from the Global Burden of Disease (GBD) Study 2019, which measure CKD burden using the years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs) and calculate percentage contributions of risk factors to age-standardized CKD DALY using population attributable fraction (PAF) from 1990 to 2019. Trends of disease burden between 1990 and 2019 were evaluated using average annual percent change (AAPC). The 95% uncertainty interval (UI) were calculated and reported for YLDs, YLLs, DALYs and PAF. RESULTS: In 2019, LICs had the highest age-standardized DALY rate at 692.25 per 100,000 people (95%UI: 605.14 to 785.67), followed by Lower MICs (684.72% (95%UI: 623.56 to 746.12)), Upper MICs (447.55% (95%UI: 405.38 to 493.01)). The age-standardized YLL rate was much higher than the YLD rate in various income regions. From 1990 to 2019, the age-standardized DALY rate showed a 13.70% reduction in LICs (AAPC = -0.5, 95%UI: - 0.6 to - 0.5, P < 0.001), 3.72% increment in Lower MICs (AAPC = 0.2, 95%UI: 0.0 to 0.3, P < 0.05). Age-standardized YLD rate was higher in females than in males, whereas age-standardized rates of YLL and DALY of CKD were all higher in males than in females in globally and LMICs. Additionally, the YLD, YLL and DALY rates of CKD increased with age, which were higher in aged≥70 years in various income regions. In 2019, high systolic blood pressure, high fasting plasma glucose, and high body-mass index remained the major causes attributable age-standardized CKD DALY. From 1990 to 2019, there were upward trends in the PAF of age-standardized DALY contributions of high fasting plasma glucose, high systolic blood pressure, and high body-mass index in Global, LICs, Lower MICs and Upper MICs. The greatest increase in the PAF was high body-mass index, especially in Lower MICs (AAPC = 2.7, 95%UI: 2.7 to 2.8, P < 0.001). The PAF of age-standardized DALY for high systolic blood pressure increased the most in Upper MICs (AAPC = 0.6, 95%UI: 0.6 to 0.7, P < 0.001). CONCLUSIONS: CKD burden remains high in various income regions, especially in LICs and Lower MICs. More effective and targeted preventive policies and interventions aimed at mitigating preventable CKD burden and addressing risk factors are urgently needed, particularly in geographies with high or increasing burden.

Phylogenetic relationships and molecular evolution of woody forest tree family Aceraceae based on plastid phylogenomics and nuclear gene variations.

The forest tree family Aceraceae is widespread in the northern hemisphere and it has ecological and economic importance. However, the phylogenetic relationships and classifications within the family are still controversial due to transitional intraspecific morphological characteristics and introgression hybridization among species. In this study, we determined the evolutionary relationships and molecular evolution of Aceraceae based on plastid phylogenomics and two nuclear gene variations. Phylogenetic analysis based on the plastid genomes suggested that Aceraceae species can be divided into two larger sub-clades corresponding to the two genera Acer and Dipteronia. Conjoint analysis of the plastid and nuclear gene sequences supported the classification with two genera in the family. Molecular dating showed that the two genera diverged 60.2 million years ago, which is generally consistently with previously reported results. Divergence hotspots and positively selected genes identified in the plastid genomes could be useful genetic resources in Aceraceae.

TGF-ß/Alk5 signaling prevents osteoarthritis initiation via regulating the senescence of articular cartilage stem cells.

Osteoarthritis (OA) is the most common joint disease. The surface of joint cartilage is a defensive and first affected structure of articular cartilage (AC) during the pathogenesis of OA. Alk5 signaling is critical for maintaining AC homeostasis, however, the role and underlying mechanism for the involvement of Alk5 signaling in the phenotypes of articular cartilage stem cells (ACSCs) at the surface of AC is still unclear. The role of Alk5 in OA development was explored using an ACSCs-specific Alk5-deficient (cKO) mouse model. Alterations in cartilage structure were evaluated histologically. Senescence was detected by SA-ß-gal, while reactive oxygen species (ROS), MitoTracker, and LysoTracker staining were used to detect changes related to senescence. In addition, mice were injected intra-articularly with ganciclovir to limit the detrimental roles of senescent cells (SnCs). Alk5 cKO mice showed a decreased number of the slow-cell cycle cells and less lubricant secretion at the surface accompanied with drastically accelerated cartilage degeneration under ageing and surgically induced OA conditions. Further studies showed that Alk5 deficient ACSCs exhibited senescence-like manifestations including decreased proliferation and differentiation, more SA-ß-gal-positive cells and ROS production, as well as significantly swollen mitochondria and lysosome breakdown. We further found that local limitation of the detrimental roles of SnCs can attenuate the development of posttraumatic OA. Taken together, our findings suggest that Alk5 signaling acts as an important regulator of the SnCs in the superficial layer during AC maintenance and OA initiation.

Identification of cryptic putative IRESs within the ORF encoding the nonstructural proteins of the human rhinovirus 16 genome.

Internal ribosome entry site (IRES)-dependent translation is a mechanism distinct from 5' cap-dependent translation. IRES elements are located mainly in the 5' untranslated regions (UTRs) of viral and eukaryotic mRNAs. However, IRESs are also found in the coding regions of some viral and eukaryotic genomes to initiate the translation of some functional truncated isoforms. Here, five putative IRES elements of human rhinovirus 16 (HRV16) were identified in the coding region of the nonstructural proteins P2 and P3 through fusion with green fluorescent protein (GFP) expression vectors and bicistronic vectors with a hairpin structure. These five putative IRESs were located at nucleotide positions 4286-4585, 5002-5126, 6245-6394, 6619-6718, and 6629-6778 in the HRV16 genome. The functionality of the five IRESs was confirmed by their ability to initiate GFP expression in vitro. This suggests that an alternative mechanism might be used to increase the efficiency of replication of HRV16.

Constructing High-Fidelity Phenotype Knowledge Graphs for Infectious Diseases With a Fine-Grained Semantic Information Model: Development and Usability Study.

BACKGROUND: Phenotypes characterize the clinical manifestations of diseases and provide important information for diagnosis. Therefore, the construction of phenotype knowledge graphs for diseases is valuable to the development of artificial intelligence in medicine. However, phenotype knowledge graphs in current knowledge bases such as WikiData and DBpedia are coarse-grained knowledge graphs because they only consider the core concepts of phenotypes while neglecting the details (attributes) associated with these phenotypes. OBJECTIVE: To characterize the details of disease phenotypes for clinical guidelines, we proposed a fine-grained semantic information model named PhenoSSU (semantic structured unit of phenotypes). METHODS: PhenoSSU is an "entity-attribute-value" model by its very nature, and it aims to capture the full semantic information underlying phenotype descriptions with a series of attributes and values. A total of 193 clinical guidelines for infectious diseases from Wikipedia were selected as the study corpus, and 12 attributes from SNOMED-CT were introduced into the PhenoSSU model based on the co-occurrences of phenotype concepts and attribute values. The expressive power of the PhenoSSU model was evaluated by analyzing whether PhenoSSU instances could capture the full semantics underlying the descriptions of the corresponding phenotypes. To automatically construct fine-grained phenotype knowledge graphs, a hybrid strategy that first recognized phenotype concepts with the MetaMap tool and then predicted the attribute values of phenotypes with machine learning classifiers was developed. RESULTS: Fine-grained phenotype knowledge graphs of 193 infectious diseases were manually constructed with the BRAT annotation tool. A total of 4020 PhenoSSU instances were annotated in these knowledge graphs, and 3757 of them (89.5%) were found to be able to capture the full semantics underlying the descriptions of the corresponding phenotypes listed in clinical guidelines. By comparison, other information models, such as the clinical element model and the HL7 fast health care interoperability resource model, could only capture the full semantics underlying 48.4% (2034/4020) and 21.8% (914/4020) of the descriptions of phenotypes listed in clinical guidelines, respectively. The hybrid strategy achieved an F1-score of 0.732 for the subtask of phenotype concept recognition and an average weighted accuracy of 0.776 for the subtask of attribute value prediction. CONCLUSIONS: PhenoSSU is an effective information model for the precise representation of phenotype knowledge for clinical guidelines, and machine learning can be used to improve the efficiency of constructing PhenoSSU-based knowledge graphs. Our work will potentially shift the focus of medical knowledge engineering from a coarse-grained level to a more fine-grained level.