Comprehensive risk factor predictions for 3-year survival among HIV-associated and disseminated cryptococcosis involving lungs and central nervous system.

BACKGROUND: The global mortality rate resulting from HIV-associated cryptococcal disease is remarkably elevated, particularly in severe cases with dissemination to the lungs and central nervous system (CNS). Regrettably, there is a dearth of predictive analysis regarding long-term survival, and few studies have conducted longitudinal follow-up assessments for comparing anti-HIV and antifungal treatments. METHODS: A cohort of 83 patients with HIV-related disseminated cryptococcosis involving the lung and CNS was studied for 3 years to examine survival. Comparative analysis of clinical and immunological parameters was performed between deceased and surviving individuals. Subsequently, multivariate Cox regression models were utilized to validate mortality predictions at 12, 24, and 36 months. RESULTS: Observed plasma cytokine levels before treatment were significantly lower for IL-1RA (p < 0.001) and MCP-1 (p < 0.05) when in the survivor group. Incorporating plasma levels of IL-1RA, IL-6, and high-risk CURB-65 score demonstrated the highest area under curve (AUC) value (0.96) for predicting 1-year mortality. For 1-, 2- and 3-year predictions, the single-factor model with IL-1RA demonstrated superior performance compared to all multiple-variate models (AUC = 0.95/0.78/0.78). CONCLUSIONS: IL-1RA is a biomarker for predicting 3-year survival. Further investigations to explore the pathogenetic role of IL-1RA in HIV-associated disseminated cryptococcosis and as a potential therapeutic target are warranted.

Lung cancer-derived exosomal miR-132-3p contributed to interstitial lung disease development.

PURPOSE: Interstitial lung diseases (ILDs) have high morbidity and mortality and poor prognosis. The significance of microRNAs (miRNAs) was highlighted in ILDs development. Currently, we attempted to confirm the functions of lung cancer-derived exosomal miR-132-3p and reveal the underlying mechanism. METHOD: Characteristics of exosomes were verified by transmission electron microscope (TEM), nanoparticle tracking analysis, and Western blot assay. Exosome uptake for the normal human lung fibroblasts (NHLF) was assessed using a PKH67 staining assay. MTT and colony formation assays were applied to examine the proliferation abilities of NHLF. The interaction between miR-132-3p and sprouty1 (SPRY1) was confirmed by a luciferase reporter assay. RESULTS: Lung cancer-derived exosomes promoted normal human lung fibroblast activation. Exosome inhibitor GW4869 reversed the effects of Exo on NHLF. Subsequently, miR-132-3p in lung cancer-derived exosomes activated the normal human lung fibroblast and promoted interstitial lung disease development ex vivo. Next, SPRY1 was verified to be the binding protein of miR-132-3p, and sh-SPRY1 abrogated the effects of the miR-132-3p inhibitor on NHLF. CONCLUSION: Exosomal miR-132-3p from A549 cells accelerated the development of interstitial lung disease through binding to SPRY1, which might serve as an important target for ILDs.

Plant biomass responses to elevated CO2 are mediated by phosphorus uptake.

Elevated atmospheric CO2 concentrations [CO2] potentially alter carbon (C) and phosphorus (P) cycles in terrestrial ecosystems. Although numerous field experiments and a few meta-analyses have been conducted, it is still largely unclear how the P cycle affects plant biomass responses under elevated [CO2] globally. Here, we conducted a global synthesis by analyzing 111 studies on the responses of above- and belowground P cycling to elevated [CO2], to examine how changes in the P cycle affect the plant biomass response to elevated [CO2]. Our results show that elevated [CO2] significantly increased plant aboveground biomass (+13 %), stem biomass (+4 %), leaf biomass (+11 %), belowground biomass (+12 %), and the root: shoot ratio (+7 %). Effects of elevated [CO2] on aboveground biomass, belowground biomass, and root: shoot ratio were best explained by plant P uptake. In addition, elevated [CO2]-induced changes in the aboveground P pool, leaf P pool, and leaf P concentration were modulated by ecological drivers, such as ΔCO2, experimental duration, and aridity index. Our findings highlight the importance of plant P uptake for both above- and belowground plant biomass responses under elevated [CO2], which should be considered in future biosphere models to improve predictions of terrestrial carbon-climate feedbacks.

Temperature and Rainfall Patterns Constrain the Multidimensional Rewilding of Global Forests.

The long-term contribution of global forest restoration to support multiple dimensions of biodiversity and ecosystem function remains largely illusive across contrasting climates and forest types. This hampers the capacity to predict the future of forest rewilding under changing global climates. Here, 120 studies are synthesized across five continents, and it is found that forest restoration promotes multiple dimensions of biodiversity and ecosystem function such as soil fertility, plant biomass, microbial habitat, and carbon sequestration across contrasting climates and forest types. Based on global relationship between stand age and soil organic carbon stock, planting 350 million hectares of forest under the UN Bonn Challenge can sequester >30 Gt soil C in the surface 20 cm over the next century. However, these findings also indicate that predicted increases in temperature and reductions in precipitation can constrain the positive effects of forest rewilding on biodiversity and ecosystem function. Further, important tradeoffs are found in very old forests, with considerable disconnection between biodiversity and ecosystem function. Together, these findings provide evidence of the importance of the multidimensional rewilding of forests, suggesting that on-going climatic changes may dampen the expectations of the positive effects of forest restoration on biodiversity and ecosystem function.

The application of targeted nanopore sequencing for the identification of pathogens and resistance genes in lower respiratory tract infections.

Objectives: Lower respiratory tract infections (LRTIs) are one of the causes of mortality among infectious diseases. Microbial cultures commonly used in clinical practice are time-consuming, have poor sensitivity to unculturable and polymicrobial patterns, and are inadequate to guide timely and accurate antibiotic therapy. We investigated the feasibility of targeted nanopore sequencing (TNPseq) for the identification of pathogen and antimicrobial resistance (AMR) genes across suspected patients with LRTIs. TNPseq is a novel approach, which was improved based on nanopore sequencing for the identification of bacterial and fungal infections of clinical relevance. Methods: This prospective study recruited 146 patients suspected of having LRTIs and with a median age of 61 years. The potential pathogens in these patients were detected by both TNPseq and the traditional culture workups. We compared the performance between the two methods among 146 LRTIs-related specimens. AMR genes were also detected by TNPseq to prompt the proper utilization of antibiotics. Results: At least one pathogen was detected in 133 (91.1%) samples by TNPseq, but only 37 (25.3%) samples contained positive isolates among 146 cultured specimens. TNPseq possessed higher sensitivity than the conventional culture method (91.1 vs. 25.3%, P < 0.001) in identifying pathogens. It detected more samples with bacterial infections (P < 0.001) and mixed infections (P < 0.001) compared with the clinical culture tests. The most frequent AMR gene identified by TNPseq was bla TEM (n = 29), followed by bla SHV (n = 4), bla KPC (n = 2), bla CTX-M (n = 2), and mecA (n = 2). Furthermore, TNPseq discovered five possible multi-drug resistance specimens. Conclusion: TNPseq is efficient to identify pathogens early, thus assisting physicians to conduct timely and precise treatment for patients with suspected LRTIs.

Dextran-stabilized Fe-Mn bimetallic oxidase-like nanozyme for total antioxidant capacity assay of fruit and vegetable food.

The total antioxidant capacity (TAC) has become increasingly vital for evaluating antioxidant food quality in the field of healthcare. Herein, a convenient and sensitive method for TAC assay was proposed based on the absorbance difference of reaction systems between various antioxidants existed in food and Dex-FeMnzyme/oxTMB. Under the optimum condition, the limit of detection (LOD) of the colorimetric sensor was 1.17 µM with the linear concentration range from 1 µM to 30 µM. The analysis results demonstrated the excellent feasibility of practical application in fruit and vegetable food, which offered a new avenue for the establishment of colorimetric biosensors.

Photothermal-boosted effect of binary CuFe bimetallic magnetic MOF heterojunction for high-performance photo-Fenton degradation of organic pollutants.

Overcoming the relatively low catalytic activity and strict acid pH condition of common photo-Fenton reaction is the key to alleviate the serious global burden caused by common organic pollutants. Herein, a binary homologous bimetallic heterojunction of magnetic CuFe2O4@MIL-100(Fe, Cu) metal-organic frameworks (MCuFe MOF) with photothermal-boosted photo-Fenton activity is constructed as an ideal practical photo-Fenton catalyst for the degradation of organic pollutants. Through an in-situ derivation strategy, the formed homologous bimetallic heterojunction with binary redox couples can simultaneously improve the visible light harvesting capacity and expedite the separation and transfer of photogenerated electrons/holes pairs, leading to the continuous and rapid circulation of both FeIII/FeII and CuII/CuI redox couples. Notably, the heterojunction shows intrinsic photo-thermal conversion effect, which is found to be beneficial to boost the photo-Fenton activity. Impressively, MCuFe MOF shows remarkable catalytic performance towards the degradation of various organic pollutants by comprehensively increasing H2O2 decomposition efficiency and decreasing the required dosage of MCuFe MOF (0.05 g L-1) with a wide pH range (3.0-10.0). As such, a photo-Fenton catalyst consisting of binary homologous bimetallic heterojunction is first disclosed, as well as its photothermal-enhanced effect, which is expected to drive great advance in the degradation of organic pollutants for practical applications.

Acid-Induced Self-Catalyzing Platform Based on Dextran-Coated Copper Peroxide Nanoaggregates for Biofilm Treatment.

Nanoantibacterial agents based on catalytic activity were limited due to the low levels of endogenous H2O2 in the microenvironment of bacterial biofilms. However, the additional H2O2 will trigger more side effects to healthy surroundings, which is still a great challenge. Herein, we report an acid-induced self-catalyzing platform based on dextran-coated copper peroxide nanoaggregates (DCPNAs) for antibiofilm and local infection therapy applications. The dextran-functionalized DCPNAs were mediated and conveniently purified via a dextran and ethanol precipitation method, which can also cluster nanodots into nanoaggregates and show good penetrability as well as biocompatibility. Bacterial biofilms were inhibited and destroyed by the reactive oxygen species generated from the Fenton reaction between the Cu2+ and H2O2 released from DCPNAs in an acidic environment, which did not require additional H2O2. As expected, the DCPNAs exhibit low cytotoxicity and excellent acid-induced antibacterial and antibiofilm ability. Moreover, the DCPNAs realized great therapeutic outcomes in the application for in vivo wound healing. The overall excellent properties associated with the DCPNAs highlight that they could be considered as a kind of ideal antimicrobial agents for microbial biofilm infection treatment.

Whole-genome characterization of chronological age-associated changes in methylome and circular RNAs in moso bamboo (Phyllostachys edulis) from vegetative to floral growth.

In mammals, DNA methylation is associated with aging. However, age-related DNA methylation changes during phase transitions largely remain unstudied in plants. Moso bamboo (Phyllostachys edulis) requires a very long time to transition from the vegetative to the floral phase. To comprehensively investigate the association of DNA methylation with aging, we present here single-base-resolution DNA methylation profiles using both high-throughput bisulfite sequencing and single-molecule nanopore-based DNA sequencing, covering the long period of vegetative growth and transition to flowering in moso bamboo. We discovered that CHH methylation gradually accumulates from vegetative to reproductive growth in a time-dependent fashion. Differentially methylated regions, correlating with chronological aging, occurred preferentially at both transcription start sites and transcription termination sites. Genes with CG methylation changes showed an enrichment of Gene Ontology (GO) categories in 'vegetative to reproductive phase transition of meristem'. Combining methylation data with mRNA sequencing revealed that DNA methylation in promoters, introns and exons may have different roles in regulating gene expression. Finally, circular RNA (circRNA) sequencing revealed that the flanking introns of circRNAs are hypermethylated and enriched in long terminal repeat (LTR) retrotransposons. Together, the observations in this study provide insights into the dynamic DNA methylation and circRNA landscapes, correlating with chronological age, which paves the way to study further the impact of epigenetic factors on flowering in moso bamboo.

Profiling of circular RNA N6 -methyladenosine in moso bamboo (Phyllostachys edulis) using nanopore-based direct RNA sequencing.

N6 -methyladenosine (m6 A) is a prevalent modification in messenger RNAs and circular RNAs that play important roles in regulating various aspects of RNA metabolism. However, the occurrence of the m6 A modification in plant circular RNAs has not been reported. A widely used method to identify m6 A modifications relies on m6 A-specific antibodies followed by next-generation sequencing of precipitated RNAs (MeRIP-Seq). However, one limitation of MeRIP-Seq is that it does not provide the precise location of m6 A at single-nucleotide resolution. Although more recent sequencing techniques such as Nanopore-based direct RNA sequencing (DRS) can overcome such limitations, the technology does not allow sequencing of circular RNAs, as these molecules lack a poly(A) tail. Here, we developed a novel method to detect the precise location of m6 A modifications in circular RNAs using Nanopore DRS. We first enriched our samples for circular RNAs, which we then fragmented and sequenced on the Nanopore platform with a customized protocol. Using this method, we identified 470 unique circular RNAs from DRS reads based on the back-spliced junction region. Among exonic circular RNAs, about 10% contained m6 A sites, which mainly occurred around acceptor and donor splice sites. This study demonstrates the utility of our antibody-independent method in identifying total and methylated circular RNAs using Nanopore DRS. This method has the additional advantage of providing the exact location of m6 A sites at single-base resolution in circular RNAs or linear transcripts from non-coding RNA without poly(A) tails.

Ionic silver-infused peroxidase-like metal-organic frameworks as versatile "antibiotic" for enhanced bacterial elimination.

The fabrication of multiple antibacterial modalities for combating bacterial pathogens and treating infected wounds is of vital importance. Accordingly, nanozymes have emerged as a new generation of "antibiotics" with broad-spectrum antibacterial potency and high stability; however, the further application of nanozymes in clinical medicine is still limited by their single-modal antibacterial process, which cannot eradicate bacteria totally. Herein, we infused the NH2-MIL-88B(Fe) peroxidase-like nanomaterial with a small amount of Ag(i) to construct NH2-MIL-88B(Fe)-Ag, a potent and benign "antibiotic" with the ability to eliminate bacteria completely. This versatile system could efficiently convert H2O2 into the more toxic ˙OH and release Ag(i) simultaneously, making pathogenic bacteria more vulnerable to be eliminated, which decreased the requirement for the toxic H2O2 and high concentration of Ag(i). More importantly, the in vivo results indicated that the synergistic germicidal system could be used for wound disinfection successfully with excellent antibacterial efficacy and negligible biotoxicity. This strategy paves the way for the development of integrated antibacterial agents with enhanced antibacterial function and alternative antibiotics.

Effects of rizatriptan on the expression of calcitonin gene-related peptide and cholecystokinin in the periaqueductal gray of a rat migraine model.

Triptans are serotonin 5-hydroxytryptamine receptor 1B/D agonists that are highly effective in the treatment of migraine. We previously found that rizatriptan can reduce the expression of proenkephalin and P substance in the rat midbrain, suggesting that rizatriptan may exert its analgesic effects by influencing the endogenous pain modulatory system. Calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) are mainly responsible for antagonizing the analgesic effects of opioid peptides in the endogenous pain modulatory system. In this study, we investigated the effects of rizatriptan on the expression of CGRP and CCK in the periaqueductal gray (PAG), a key structure of the endogenous pain modulatory system, in a rat migraine model induced by nitroglycerin. We found that the mRNA and protein levels of CGRP and CCK in the PAG of migraine rats were significantly increased compared to those in control rats, and these levels were significantly reduced upon treatment with rizatriptan in migraine rats (P<0.05). Our results suggest that the expression of CGRP and CCK in the endogenous pain modulatory system may be increased during migraine attacks, which further antagonizes the analgesic effects of endogenous opioid peptides and induces sustained migraine. Rizatriptan, however, significantly reduces the levels of CGRP and CCK to enhance the inhibition of pain signals via the endogenous pain modulatory system, resulting in effective treatment of migraine.

Therapeutic effects and safety of olcegepant and telcagepant for migraine: A meta-analysis.

OBJECTIVE: To evaluate the therapeutic effects and adverse reactions of olcegepant and telcagepant for the treatment of migraine. DATA RETRIEVAL: We identified studies using Medline (1966-01/2012-06), PubMed (1966-01/2012-06), Scopus (1980-01/2012-06), Cochrane Central Register of Controlled Trials (1980-01/2012-06) and China National Knowledge Infrastructure (1980-01/2012-06). SELECTION CRITERIA: The included studies were double-blind, randomized and placebo-controlled trials of olcegepant or telcagepant for the treatment of single acute migraine in patients with or without aura. Adverse reaction data were also included. Two independent investigators performed quality evaluation and data extraction using Jadad scoring. Meta-analyses were undertaken using RevMan 5.0.25 software. MAIN OUTCOME MEASURES: Pain relief rate, pain-free rate, and incidence of adverse reactions were measured in patients 2 and 24 hours after injection of olcegepant and oral telcagepant. RESULTS: Six randomized, controlled trials were included. Meta-analysis demonstrated that compared with placebo, the pain relief rate (odds ratio, OR = 5.21, 95% confidence interval, CI: 1.91-14.2, P < 0.01) and pain-free rate (OR = 31.11, 95% CI: 3.80-254.98, P < 0.01) significantly increased 2 hours after 2.5 mg/d olcegepant treatment. Pain relief rate and pain-free rate 2 and 24 hours after treatment with telcagepant 150 mg/d and 300 mg/d were superior to placebo (P < 0.01). Moreover, the remission rate of unrelenting headache was higher after 24 hours of 300 mg/d telcagepant treatment compared with 150 mg/d (OR = 0.78, 95% CI: 0.62-0.97, P < 0.05). The incidence of adverse reactions with olcegepant was not significantly greater than placebo (P = 0.28), but within 48 hours of administration of telcagepant 300 mg/d, the incidence of adverse reactions was higher than placebo (OR = 1.21, 95% CI: 1.04-1.42, P < 0.01). Few studies have compared the therapeutic effects of olcegepant and telcagepant. CONCLUSION: The calcitonin-gene-related peptide receptor antagonists olcegepant and telcagepant have shown good therapeutic effects in the treatment of migraine. Moreover, the incidence of adverse reactions compares favorably with placebo, although liver transaminases may become elevated after long-term use.

Meta-analysis of efficacy of topiramate in migraine prophylaxis.

OBJECTIVE: To evaluate the treatment effects and safety of topiramate in migraine prophylaxis. DATA RETRIEVAL: We searched the Medline database, EMbase, Cochrane Library and China National Knowledge Infrastructure database for articles published between January 1995 and May 2011, using the key words "migraine", "topiramate", and "prophylaxis". SELECTION CRITERIA: We selected randomized controlled trials of migraine patients, in which the experimental group was orally administered topiramate, and the control group was given placebo. Odds ratios (ORs) and mean differences (MDs) were calculated using a fixed effects model/random effects model. Quality evaluation and data extraction were performed independently by two researchers utilizing RevMan 5.0 software. MAIN OUTCOME MEASURES: Efficacy was recorded as the responder rate (response defined as at least a 50% reduction in average monthly migraine frequency) and change in mean monthly number of migraine days. Adverse events were recorded as the number of subjects exhibiting at least one adverse event. RESULTS: Eight randomized controlled trials were found to be appropriate, and had available data. The meta-analysis results revealed that topiramate (100 or 200 mg/d) was more effective than placebo in responder rate (OR = 2.97, 95% confidence interval (CI): 2.17-4.08, P < 0.01; OR = 2.35, 95%CI: 1.77-3.12, P < 0.01). Topiramate (100 mg/d) was more effective than placebo in terms of the change in mean monthly migraine days (MD: -1.14, 95%CI: -1.69 to -0.59, P < 0.01). The total incidence rate of adverse events for topiramate was higher than in the placebo group (P < 0.01), but most adverse events were mild to moderate. CONCLUSION: Overall, topiramate obtained good outcomes and safety in migraine prophylaxis.