J-Aggregate Promoting NIR-II Emission for Fluorescence/ Photoacoustic Imaging-Guided Phototherapy.

J-aggregate is a promising strategy to enhance second near-infrared window (NIR-II) emission, while the controlled synthesis of J-aggregated NIR-II dyes is a huge challenge because of the lack of molecular design principle. Herein, bulk spiro[fluorene-9,9'-xanthene] functionalized benzobisthiadiazole-based NIR-II dyes (named BSFX-BBT and OSFX-BBT) were synthesized with different alkyl chains. The weak repulsion interaction between the donor and acceptor units and the S…N secondary interactions make the dyes to adopt a co-planar molecular conformation and display a peak absorption > 880 nm in solution. Importantly, BSFX-BBT can form a desiring J-aggregate in the condensed state, and femtosecond transient absorption spectra reveal that the excited states of J-aggregate are the radiative states, and J-aggregate can facilitate stimulated emission. Consequently, the J-aggregated nanoparticles (NPs) display a peak emission at 1124 nm with a high relative quantum yield of 0.81%. The efficient NIR-II emission, good photothermal effect and biocompatibility make the J-aggregated NPs demonstrate efficient antitumor efficacy via fluorescence/photoacoustic imaging-guided phototherapy. The paradigm illustrates that tuning the aggregate states of NIR-II dye via spiro-functionalized strategy is an effective approach to enhance photo-theranostic performance. This article is protected by copyright. All rights reserved.

Single-embryo transcriptomic atlas of oxygen response reveals the critical role of HIF-1α in prompting embryonic zygotic genome activation.

Adaptive response to physiological oxygen levels (physO2; 5% O2) enables embryonic survival in a low-oxygen developmental environment. However, the mechanism underlying the role of physO2 in supporting preimplantation development, remains elusive. Here, we systematically studied oxygen responses of hallmark events in preimplantation development. Focusing on impeded transcriptional upregulation under atmospheric oxygen levels (atmosO2; 20% O2) during the 2-cell stage, we functionally identified a novel role of HIF-1α in promoting major zygotic genome activation by serving as an oxygen-sensitive transcription factor. Moreover, during blastocyst formation, atmosO2 impeded H3K4me3 and H3K27me3 deposition by deregulating histone-lysine methyltransferases, thus impairing X-chromosome inactivation in blastocysts. In addition, we found atmosO2 impedes metabolic shift to glycolysis before blastocyst formation, thus resulting a low-level histone lactylation deposition. Notably, we also reported an increased sex-dimorphic oxygen response of embryos upon preimplantation development. Together, focusing on genetic and epigenetic events that are essential for embryonic survival and development, the present study advances current knowledge of embryonic adaptive responses to physO2, and provides novel insight into mechanism underlying irreversibly impaired developmental potential due to a short-term atmosO2 exposure.

Planar-structured thiadiazoloquinoxaline-based NIR-II dye for tumor phototheranostics.

Second near-infrared (NIR-II) fluorescence imaging shows huge application prospects in clinical disease diagnosis and surgical navigation, while it is still a big challenge to exploit high performance NIR-II dyes with long-wavelength absorption and high fluorescence quantum yield. Herein, based on planar π-conjugated donor-acceptor-donor systems, three NIR-II dyes (TP-DBBT, TP-TQ1, and TP-TQ2) were synthesized with bulk steric hindrance, and the influence of acceptor engineering on absorption/emission wavelengths, fluorescence efficiency and photothermal properties was systematically investigated. Compared with TP-DBBT and TP-TQ2, the TP-TQ1 based on 6,7-diphenyl-[1,2,5]thiadiazoloquinoxaline can well balance absorption/emission wavelengths, NIR-II fluorescence brightness and photothermal effects. And the TP-TQ1 nanoparticles (NPs) possess high absorption ability at a peak absorption of 877 nm, with a high relative quantum yield of 0.69% for large steric hindrance hampering the close π-π stacking interactions. Furthermore, the TP-TQ1 NPs show a desirable photothermal conversion efficiency of 48% and good compatibility. In vivo experiments demonstrate that the TP-TQ1 NPs can serve as a versatile theranostic agent for NIR-II fluorescence/photoacoustic imaging-guided tumor phototherapy. The molecular planarization strategy provides an approach for designing efficient NIR-II fluorophores with extending absorption/emission wavelength, high fluorescence brightness, and outstanding phototheranostic performance.

A novel biochar-augmented enzymatic process for conversion of food waste to biofertilizers: Planting trial with leafy vegetable.

The present study developed a novel biochar-augmented enzymatic approach for fast conversion of food waste to solid and liquid biofertilizers. By augmented with 10 % of biochar and mediated with 5 % of food waste-derived hydrolytic enzymes mixture (i.e. fungal mash), 100 kg of food waste could be converted into 22.3 kg of solid biofertilizer with a water content of 30 % and 55.0 kg of liquid biofertilizer, which fulfilled Chinese national standards for solid and liquid organic biofertilizers, respectively. Field plantation results showed that the Pak Choi grown on food waste-derived biofertilizers was comparable with that on commercial ones, in terms of the vegetable productivity and nutrient contents. It was further revealed that the application of food waste-derived biofertilizers did not change soil chemical properties but enriched microbial diversity. This study clearly indicated that the biochar-augmented enzymatic approach for food waste conversion to biofertilizers was technically feasible and economically viable towards circular agriculture economy.

Glutathione safeguards TET-dependent DNA demethylation and is critical for the acquisition of totipotency and pluripotency during preimplantation development.

During early development, both genome-wide epigenetic reprogramming and metabolic remodeling are hallmark changes of normal embryogenesis. However, little is known about their relationship and developmental functions during the preimplantation window, which is essential for the acquisition of totipotency and pluripotency. Herein, we reported that glutathione (GSH), a ubiquitous intracellular protective antioxidant that maintains mitochondrial function and redox homeostasis, plays a critical role in safeguarding postfertilization DNA demethylation and is essential for establishing developmental potential in preimplantation embryos. By profiling mitochondria-related transcriptome that coupled with different pluripotency, we found GSH is a potential marker that is tightly correlated with full pluripotency, and its beneficial effect on prompting developmental potential was functionally conformed using in vitro fertilized mouse and bovine embryos as the model. Mechanistic study based on preimplantation embryos and embryonic stem cells further revealed that GSH prompts the acquisition of totipotency and pluripotency by facilitating ten-eleven-translocation (TET)-dependent DNA demethylation, and ascorbic acid (AsA)-GSH cycle is implicated in the process. In addition, we also reported that GSH serves as an oviductal paracrine factor that supports development potential of preimplantation embryos. Thus, our results not only advance the current knowledge of functional links between epigenetic reprogramming and metabolic remodeling during preimplantation development but also provided a promising approach for improving current in vitro culture system for assisted reproductive technology.

Field outcomes of laparoscopic ovum pick-up combined with in vitro embryo production in sheep: Effects of long-acting recombinant ovine FSH pre-stimulation, collection frequency, and donor breed.

Laparoscopic ovum pick-up (LOPU) combined with in vitro embryo production (IVEP) is a technology platform that improves the utilization rate of the elite ewe's ovarian oocytes and increases the number of obtained offspring. This study aimed to evaluate the effects of FSH pre-stimulation, serial oocyte collection, and breed on LOPU-IVEP under field conditions. Donors were randomly assigned to five groups (group A: decreasing doses of pituitary FSH (p-FSH); group B: constant doses of p-FSH; group C: two doses of long-acting recombinant ovine FSH (ro-FSH); group D: single administration of a long-acting ro-FSH in; group E: no FSH stimulation). Oocyte yield following LOPU (average recovered oocytes: 20.9 ± 0.5; average viable oocytes: 17.2 ± 0.4) and oocyte developmental competence (average blastocysts: 7.0 ± 0.2) in group C were significantly better than these of group D and group E, and similar to these of groups A and B. Meanwhile, there were no differences in oocyte yield and developmental capacity using repeated LOPU session at 1-, 2-, and 3-month intervals (p > 0.05). Finally, we compared LOPU-IVEP outcomes among five sheep breeds. The results indicated that East Friesian × Chinese Mongolian crossbred sheep and purebred East Friesian sheep had the more recovered oocytes and viable oocytes compared with the Suffolk, Dorper, and Texel breeds, and average number of blastocysts in East Friesian × Chinese Mongolian sheep group was also highest among the groups (8.1 ±0.3, p < 0.05). In summary, the results of this study indicate long-acting ro-FSH pre-stimulation combined with 12 times LOPU sessions over one year maximizes embryo production of elite donor ewes under field conditions.

"Meiosis arrester" C-natriuretic peptide directly stimulates oocyte mtDNA accumulation and is implicated in aging-associated oocyte mtDNA loss.

C-natriuretic peptide (CNP) is the central regulator of oocyte meiosis progression, thus coordinating synchronization of oocyte nuclear-cytoplasmic maturation. However, whether CNP can independently regulate cytoplasmic maturation has been long overlooked. Mitochondrial DNA (mtDNA) accumulation is the hallmark event of cytoplasmic maturation, but the mechanism underlying oocyte mtDNA replication remains largely elusive. Herein, we report that CNP can directly stimulate oocyte mtDNA replication at GV stage, and deficiency of follicular CNP may contribute largely to lower mtDNA copy number in in vitro matured oocytes. The mechanistic study showed that cAMP-PKA-CREB1 signaling cascade underlies the regulatory role of CNP in stimulating mtDNA replication and upregulating related genes. Of interest, we also report that CNP-NPR2 signaling is inhibited in aging follicles, and this inhibition is implicated in lower mtDNA copy number in oocytes from aging females. Together, our study provides the first direct functional link between follicular CNP and oocyte mtDNA replication, and identifies its involvement in aging-associated mtDNA loss in oocytes. These findings, not only update the current knowledge of the functions of CNP in coordinating oocyte maturation but also present a promising strategy for improving in vitro fertilization outcomes of aging females.

Progesterone Activates the Histone Lactylation-Hif1α-glycolysis Feedback Loop to Promote Decidualization.

Decidualization is a progesterone-dependent cellular differentiation process that is essential for establishing pregnancy. Robust activation of glycolysis and lactate synthesis during decidualization is remarkable, but their developmental functions remain largely unknown. Herein, we identify that endometrial lactate production plays a critical role in establishing local histone lactylation, a newly identified histone modification, and is important for ensuring normal decidualization. Enhanced endometrial glycolysis is the hallmark metabolic change and is tightly coupled with H4K12la during decidualization. Inhibition of histone lactylation impaired decidualization, in either physiological conception or in vivo and in vitro induced decidualization models. Mechanistic study based on CUT&Tag and ATAC-seq revealed that a transcriptional factor hypoxia-inducible factor 1 α (Hif1α) is the critical regulatory target of H4K12la, and in turn forms an H4K12la-Hif1α-glycolysis feedback loop to drive decidualization. Moreover, we demonstrate that the loop is directly activated by progesterone during decidualization. Our study not only advances the current knowledge of the role of lactate in regulating uterine function, but also establishes a novel functional link among the major endocrine factors, endometrial metabolic change, and epigenetic modification during endometrial remodeling. These findings present valuable clues to develop clinical intervention strategies to improve pregnancy outcomes following both natural conception and assisted reproduction.

A Redesigned Method for CNP-Synchronized In Vitro Maturation Inhibits Oxidative Stress and Apoptosis in Cumulus-Oocyte Complexes and Improves the Developmental Potential of Porcine Oocytes.

In vitro embryo production depends on high-quality oocytes. Compared with in vivo matured oocytes, in vitro oocytes undergo precocious meiotic resumption, thus compromising oocyte quality. C-type natriuretic peptide (CNP) is a follicular factor maintaining meiotic arrest. Thus, CNP-pretreatment has been widely used to improve the in vitro maturation (IVM) of oocytes in many species. However, the efficacy of this strategy has remained unsatisfactory in porcine oocytes. Here, by determining the functional concentration and dynamics of CNP in inhibiting spontaneous meiotic resumption, we improved the current IVM system of porcine oocytes. Our results indicate that although the beneficial effect of the CNP pre-IVM strategy is common among species, the detailed method may be largely divergent among them and needs to be redesigned specifically for each one. Focusing on the overlooked role of cumulus cells surrounding the oocytes, we also explore the mechanisms relevant to their beneficial effect. In addition to oocytes per se, the enhanced anti-apoptotic and anti-oxidative gene expression in cumulus cells may contribute considerably to improved oocyte quality. These findings not only emphasize the importance of screening the technical parameters of the CNP pre-IVM strategy for specific species, but also highlight the critical supporting role of cumulus cells in this promising strategy.

Computational protocol for the identification of X-linked genes contributing to X chromosome upregulation from RNA-sequencing datasets.

The X chromosome/autosome ratio has been widely used to profile XCU at the chromosomal level. However, this approach overlooks features of inside genes. Here, we present a computational protocol for the identification of X-linked genes contributing to X chromosome upregulation from RNA-sequencing datasets. We describe steps for selecting data, preparing software, processing data, and data analysis. This protocol quantifies the contribution value and contribution increment of each X-linked gene to XCU. For complete details on the use and execution of this protocol, please refer to Lyu et al. (2022).1.

Microalgal capture of carbon dioxide: A carbon sink or source?

The rapidly evolving global warming is triggering all levels of actions to reduce industrial carbon emissions, while capturing carbon dioxide of industrial origin via microalgae has attracted increasing attention. This article attempted to offer preliminary analysis on the carbon capture potential of microalgal cultivation. It was shown that the energy consumption-associated with operation and nutrient input could significantly contribute to indirect carbon emissions, making the microalgal capture of carbon dioxide much less effective. In fact, the current microalgae processes may not be environmentally sustainable and economically viable in the scenario where the carbon footprints of both upstream and downstream processing are considered. To address these challenging issues, renewable energy (e.g., solar energy) and cheap nutrient source (e.g., municipal wastewater) should be explored to cut off the indirect carbon emissions of microalgae cultivation, meanwhile produced microalgae, without further processing, should be ideally used as biofertilizer or aquafeeds for realizing complete nutrients recycling.

CUDC­101 is a potential target inhibitor for the EGFR­overexpression bladder cancer cells.

Bladder cancer is one of the most common urological malignancies worldwide. The molecular mechanism underlying its development is complex, but its carcinogenesis has been proposed to occur with cell proliferation and resistance to apoptosis, driven by the signaling activity of abundant EGFR and receptor tyrosine­protein kinase erbB­2. In the present study, T24 bladder cancer cell lines with EGFR­overexpression were constructed, before the multi­target inhibitor CUDC­101 was used to investigate its potential as a targeted therapeutic agent for bladder cancer using chemosensitivity methods. The results showed that CUDC­101 induced cytotoxic effects, inhibited growth vitality and proliferation in a dose­dependent manner. CUDC­101 also altered the skeletal morphology and microfilament structure, while blocking cell cycle progression and causing apoptosis. These results supported the proposed cytotoxic effects of CUDC­101, in addition to its inhibitory effects on cell division and proliferation in EGFR­overexpressing bladder cancer cells. Therefore CUDC­101 may to be a potential therapeutic option for the treatment of bladder cancer.

Sulfone/Carbonyl-Based Donor-Acceptor Fluorescent Dyes: Synthesis, Structures, Photophysical Properties and Cell Imaging.

Electron-accepting units play vital roles in constructing donor-acceptor (D-A) conjugated organic optoelectronic materials; the electronic structures and functions of the acceptors need to be carefully unveiled to controllably tailor the optoelectronic properties. We have synthesized two D-A conjugated organic fluorophores, TPA-SO and TPA-CO, with similar molecular skeletons based on sulfone- or carbonyl-containing polycyclic aromatic acceptors. Both TPA-SO and TPA-CO display obvious solvent polarity-dependent photophysical properties and large Stokes shift of over 100 nm for strong intramolecular charge transfer processes. Experimental evidence indicates that the sulfone group in TPA-SO merely serves as a strong electron-withdrawing unit. TPA-SO shows yellowish-green emission with a peak at 542 nm and an absolute photoluminescence quantum yield (PLQY) of 98 % in solution, whereas the carbonyl group in TPA-CO can act as both an electron-withdrawing unit and spin transition convertor, so TPA-CO displays red emission with a low absolute PLQY of 0.32 % in solution. Impressively, upon going from solution to aggregate state, TPA-SO nanoparticles keep a high PLQY of 9.5 % and moderate biocompatibility, thus they are good nano-agents for cellular fluorescence imaging. The results reveal that the inherent acceptor characteristic acts as a crucial effect in the photophysical properties and applications of the organic fluorophores.

Urolithins: A Prospective Alternative against Brain Aging.

The impact of host-microbiome interactions on cognitive health and disease has received increasing attention. Microbial-derived metabolites produced in the gut are one of crucial mechanisms of the gut-brain axis interaction, showing attractive perspectives. Urolithins (Uros) are gut microbial-derived metabolites of ellagitannins and ellagic acid, whose biotransformation varies considerably between individuals and decreases greatly with age. Recently, accumulating evidence has suggested that Uros may have specific advantages in preventing brain aging including favorable blood-brain barrier permeability, selective brain distribution, and increasingly supporting data from preclinical and clinical studies. However, the usability of Uros in diagnosis, prevention, and treatment of neurodegenerative diseases remains elusive. In this review, we aim to present the comprehensive achievements of Uros in age-related brain dysfunctions and neurodegenerative diseases and discuss their prospects and knowledge gaps as functional food, drugs, or biomarkers against brain aging.

Effect of pretreatment with a P2Y12 inhibitor in patients with non-ST-elevation acute coronary syndrome: a systematic review and network meta-analysis.

Background: This study aimed to systematically evaluate the effects of different types and doses of pretreatment with P2Y12 inhibitors in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). Methods: Electronic databases were searched for studies comparing pretreatment with different types and doses of P2Y12 inhibitors or comparison between P2Y12 inhibitor pretreatment and nonpretreatment. Electronic databases included the Cochrane Library, PubMed, EMBASE, and Web of Science. Literature was obtained from the establishment of each database until June 2022. The patients included in the study had pretreatment with P2Y12 inhibitors with long-term oral or loading doses, or conventional aspirin treatment (non-pretreatment). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) during follow-up within 30 days after PCI, which included determining the composite endpoints of cardiac death, myocardial infarction, ischemia-driven revascularization, and stroke. The safety endpoint was a major bleeding event. Results: A total of 119,014 patients from 21 studies were enrolled, including 13 RCTs and eight observational studies. A total of six types of interventions were included-nonpretreatment (placebo), clopidogrel pretreatment, ticagrelor pretreatment, prasugrel pretreatment, double loading pretreatment (double loading dose of clopidogrel, ticagrelor, prasugrel) and P2Y12 inhibitors pretreatment (the included studies did not distinguish the types of P2Y12 inhibitors, including clopidogrel, ticagrelor, and prasugrel). The network meta-analysis results showed that compared to patients without pretreatment, patients receiving clopidogrel pretreatment (RR = 0.78, 95% CI:0.66, 0.91, P < 0.05) and double-loading pretreatment (RR = 0.62, 95% CI:0.41, 0.95, P < 0.05) had a lower incidence of MACCEs. There was no statistically significant difference in the incidence of major bleeding events among the six pretreatments (P > 0.05). Conclusions: In patients with NSTE-ACS, pretreatment with P2Y12 inhibitors before percutaneous intervention reduced the incidence of recurrent ischemic events without increasing the risk of major bleeding after PCI compared with nonpretreatment. Clopidogrel or double loading dose P2Y12 inhibitors can be considered for the selection of pretreatment drugs.

Revisiting molecularly conformation-planarized organic dyes for NIR-II fluorescence imaging.

Fluorescence imaging in the second window (NIR-II, 1000-1700 nm) provides deeper penetration depth and higher resolution, but there is still a dilemma for designing NIR-II dyes for simultaneously enhancing fluorescence efficiency and prolonging excitation wavelength. Herein, a molecular conformation planarization strategy has been revisited to guide the synthesis of two donor-acceptor-donor dyes (named T-BBT and BT-BBT). On the one hand, conformational planarization can extend the absorption peaks of T-BBT and BT-BBT to the NIR region with high molar extinction coefficients of 30.5 × 103 and 16.4 × 103 L (mol-1 cm-1) at 1064 nm, respectively. On the other hand, structural rigidity can weaken electronic vibration coupling-related non-radiative decay pathways, whereby both T-BBT and BT-BBT display rather high fluorescence efficiencies of 3.6% and 13.5% in solution. Furthermore, a molecular doping strategy is adopted to alleviate fluorescence quenching in the aggregated state by suppressing long-distance energy migration, and 2.5 wt% doped BT-BBT nanoparticles show a high fluorescence efficiency of 2.0%, which enables the application of in vivo deep NIR-II fluorescence imaging for vessels and tumors with high resolution under 980 nm excitation. This work demonstrates that organic dyes with structural planarization can bridge the gap between NIR-II absorption and fluorescence efficiency.

A novel de-escalation antiplatelet therapy for patients with acute coronary syndrome undergoing percutaneous coronary intervention.

To investigate the effect of different DAPTs in patients with ACS undergoing PCI, and to identify the most efficient DAPT to reduce the risk of ischemia and bleeding after PCI. Between March 2017 and December 2021, 1598 patients with ACS who underwent PCI were included in the study. The DAPT protocol included the clopidogrel group (aspirin 100 mg + clopidogrel 75 mg), ticagrelor group (aspirin 100 mg + ticagrelor 90 mg), de-escalation Group 1 (reduced dose of ticagrelor [from 90 mg to 60 mg]) after 3 months of oral DAPT [aspirin 100 mg + ticagrelor 90 mg]), and de-escalation Group 2 (switched from ticagrelor to clopidogrel after 3 months of oral DAPT [aspirin 100 mg + ticagrelor 90 mg]). All patients received a 12-month follow-up. The primary endpoint was net adverse clinical events (NACEs) that included the composite endpoints of cardiac death, myocardial infarction, ischemia-driven revascularization, stroke, and bleeding events. There were 2 secondary endpoints, major adverse cardiovascular and cerebrovascular events (MACCEs) and bleeding. No statistically significant difference was found in the incidence of NACEs between the 4 groups at the average 12-month follow-up (15.7% vs 19.2% vs 16.7% vs 20.4%). Cox regression analysis revealed that DAPT ticagrelor group regimen (hazard ratio [HR] 0.547; 95% confidence interval [CI]: 0.334-0.896; P  = .017) were associated with a lower risk of MACCEs. Age (HR 1.024; 95% CI: 1.003-1.046; P  = .022). DAPT de-escalation Group 2 regimen (HR 1.665; 95% CI: 1.001-2.767; P  = .049) were marginally associated with a higher risk of MACCEs. Ticagrelor group regimen (HR 1.856; 95% CI: 1.376-2.504; P  < .001) was associated with higher risk of bleeding events. Ticagrelor group regimen (HR 1.606; 95% CI: 1.179-2.187; P  = .003) were associated with a higher risk of minor bleeding events. For patients with ACS underwent PCI, there were no significant difference in the incidence of NACEs between 3 and 12 months after PCI between de-escalation and non-de-escalation therapies. Compared with ticagrelor-based 12-month DAPT, there was no significant difference in MACCEs and bleeding events in patients receiving de-escalation treatment (ticagrelor reduction from 90 to 60 mg, 3 months after PCI).