Enhancing photodynamic immunotherapy by reprograming the immunosuppressive tumor microenvironment with hypoxia relief.

Tumor hypoxia impairs the generation of reactive oxygen species and the induction of immunogenic cell death (ICD) for photodynamic therapy (PDT), thus impeding its efficacy and the subsequent immunotherapy. In addition, hypoxia plays a critical role in forming immunosuppressive tumor microenvironments (TME) by regulating the infiltration of immunosuppressive tumor-associated macrophages (TAMs) and the expression of programmed death ligand 1 (PD-L1). To simultaneously tackle these issues, a MnO2-containing albumin nanoplatform co-delivering IR780, NLG919, and a paclitaxel (PTX) dimer is designed to boost photodynamic immunotherapy. The MnO2-catalyzed oxygen supply bolsters the efficacy of PDT and PTX-mediated chemotherapy, collectively amplifying the induction of ICD and the expansion of tumor-specific cytotoxic T lymphocytes (CTLs). More importantly, hypoxia releif reshapes the immunosuppressive TME via down-regulating the intratumoral infiltration of M2-type TAMs and the PD-L1 expression of tumor cells to enhance the infiltration and efficacy of CTLs in combination with immune checkpoint blockade (ICB) by NLG919, consequently eradicating primary tumors and almost completely preventing tumor relapse and metastasis. This study sets an example of enhanced immunotherapy for breast cancers through dual ICD induction and simultaneous immunosuppression modulation via both hypoxia relief and ICB, providing a strategy for the treatment of other hypoxic and immunosuppressive cancers.

Cerebellar Purkinje cell firing promotes conscious recovery from anesthesia state through coordinating neuronal communications with motor cortex.

Background: The neurobiological basis of gaining consciousness from unconscious state induced by anesthetics remains unknown. This study was designed to investigate the involvement of the cerebello-thalamus-motor cortical loop mediating consciousness transitions from the loss of consciousness (LOC) induced by an inhalational anesthetic sevoflurane in mice. Methods: The neural tracing and fMRI together with opto-chemogenetic manipulation were used to investigate the potential link among cerebello-thalamus-motor cortical brain regions. The fiber photometry of calcium and neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA) and norepinephrine (NE), were monitored from the motor cortex (M1) and the 5th lobule of the cerebellar vermis (5Cb) during unconsciousness induced by sevoflurane and gaining consciousness after sevoflurane exposure. Cerebellar Purkinje cells were optogenetically manipulated to investigate their influence on consciousness transitions during and after sevoflurane exposure. Results: Activation of 5Cb Purkinje cells increased the Ca2+ flux in the M1 CaMKIIα+ neurons, but this increment was significantly reduced by inactivation of posterior and parafascicular thalamic nucleus. The 5Cb and M1 exhibited concerted calcium flux, and glutamate and GABA release during transitions from wakefulness, loss of consciousness, burst suppression to conscious recovery. Ca2+ flux and Glu release in the M1, but not in the 5Cb, showed a strong synchronization with the EEG burst suppression, particularly, in the gamma-band range. In contrast, the Glu, GABA and NE release and Ca2+ oscillations were coherent with the EEG gamma band activity only in the 5Cb during the pre-recovery of consciousness period. The optogenetic activation of Purkinje cells during burst suppression significantly facilitated emergence from anesthesia while the optogenetic inhibition prolonged the time to gaining consciousness. Conclusions: Our data indicate that cerebellar neuronal communication integrated with motor cortex through thalamus promotes consciousness recovery from anesthesia which may likely serve as arousal regulation.

Effects of 13C isotope-labeled allelochemicals on the growth of the invasive plant Alternanthera philoxeroides.

The secondary metabolites of indigenous plants have significant allelopathic inhibitory effects on the growth and development of invasive alien plants. Methyl palmitate (MP) and methyl linolenate (ML) were used as exogenous allelopathic substances. The research investigated the differences of inhibitory effects of MP and ML on the growth of seedlings of Alternanthera philoxeroides, and calculated their morphological characteristics, biomass, physiological indicators and the response index (RI). The synthetical allelopathic index (SE) of 1 mmol/L MP was the smallest (- 0.26) and the allelopathic inhibition was the strongest; therefore, it was selected as a 13C-labeled allelochemical. The distribution of 1 mmol/L MP in different parts of A. philoxeroides and the correlation between the biomass ratios of roots, stems and leaves and the 13C content were studied by 13C stable isotope tracing experiments. Atom percent excess (APE) between roots, stems and leaves of A. philoxeroides treated with 1 mmol/L MP were significantly different in terms of magnitude, with leaves (0.17%) > roots (0.12%) > stems (0.07%). The root, stem and leaf biomass ratios of invasive weeds had great significant positive correlation with 13C content (p < 0.01, R2 between 0.96 and 0.99). This current research provides a new idea and method for the control of A. philoxeroides, but large-scale popularization remains to be studied.

Effects of propofol and sevoflurane on social and anxiety-related behaviours in sleep-deprived rats.

BACKGROUND: Sleep disorders can profoundly affect neurological function. We investigated changes in social and anxiety-related brain functional connectivity induced by sleep deprivation, and the potential therapeutic effects of the general anaesthetics propofol and sevoflurane in rats. METHODS: Twelve-week-old male Sprague-Dawley rats were subjected to sleep deprivation for 20 h per day (from 14:00 to 10:00 the next day) for 4 consecutive weeks. They were free from sleep deprivation for the remaining 4 h during which they received propofol (40 mg kg-1 i.p.) or sevoflurane (2% for 2 h) per day or no treatment. These cohorts were instrumented for EEG/EMG recordings on days 2, 14, and 28. Different cohorts were used for open field and three-chambered social behavioural tests, functional MRI, nuclear magnetic resonance spectroscopy, and positron emission tomography imaging 48 h after 4 weeks of sleep deprivation. RESULTS: Propofol protected against sleep deprivation-induced anxiety behaviours with more time (44.7 [8.9] s vs 24.2 [4.1] s for the sleep-deprivation controls; P<0.001) spent in the central area of the open field test and improved social preference index by 30% (all P<0.01). Compared with the sleep-deprived rats, propofol treatment enhanced overall functional connectivity by 74% (P<0.05) and overall glucose metabolism by 30% (P<0.01), and improved glutamate kinetics by 20% (P<0.05). In contrast, these effects were not found after sevoflurane treatment. CONCLUSIONS: Unlike sevoflurane, propofol reduced sleep deprivation-induced social and anxiety-related behaviours. Propofol might be superior to sevoflurane for patients with sleep disorders who receive anaesthesia, which should be studied in clinical studies.

Controllable hypoxia-activated chemotherapy as a dual enhancer for synergistic cancer photodynamic immunotherapy.

The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates 1O2 for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors.

Nitrogen addition affects floral and vegetative traits, reproduction, and pollinator performance in Capsicum annuum L.

BACKGROUND AND AIMS: It has been demonstrated that nitrogen (N) addition alters flower morphology, floral rewards and pollinator performance. However, little is known about the effects of N addition on plant reproduction, including fruit set and seed set during selfing and outcrossing, floral and vegetative traits, and pollinator performance. We hypothesized that N addition would influence fruit set, seed set in selfed and outcrossed flowers, the relationship between vegetative and flower traits, and pollinator performance. METHODS: A 2-year pot experiment was conducted in which Capsicum annuum was exposed to three levels of relatively short-term N supply, i.e. 0 g m-2 (no N addition, as a control), 4 g m-2 (4N) and 16 g m-2 (16N), which are equivalent to about 0-, 1- and 4-fold of the peak local N deposition. We measured flower rewards, flower morphology, flowering phenology, as well as pollinator visitation rate, fruit set and seed set by self- and outcross-fertilization of C. annuum. RESULTS: The four levels of N addition increased plant biomass, biomass allocation to flowers, flower size, stigma-anther separation, nectar production and pollen production, resulting in an increase in pollinator visitation and fruit set. Nevertheless, the control and 16 levels of N addition reduced plant biomass, biomass allocation to flowers, flower size and stigma-anther separation, and nectar and pollen production, and consequently decreased pollinator visitation and fruit set. Exclusion of pollinators and hand-pollination experiments revealed that low levels of N addition were associated with high seed set in outcrossed flowers; however, this trend was reversed in flowers grown in the control and 16N treatments. CONCLUSION: Our results suggest that an optimal level of 4N can enhance the correlation between flower traits, pollinator performance and plant reproduction. Our findings cast new light on the underlying mechanisms of plant-pollinator interactions and plant adaptation to nitrogen deposition.

A Kaposi's sarcoma-associated herpes virus-encoded microRNA contributes to dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation. By microRNA (miRNA) array, a Kaposi's sarcoma-associated herpes virus (KSHV)-encoded miRNA, kshv-miR-K12-1-5p, was detected in patients with DCM. The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up. Increased KSHV seropositivity and quantitative titers were found in the patients with DCM compared with the non-DCM group (22.0% versus 9.1%, p < 0.05; 168 versus 14 copies/mL plasma, p < 0.05). The risk of the individual end point of death from cardiovascular causes or heart transplantation was increased among DCM patients with the KSHV DNA seropositivity during follow-up (adjusted hazard ratio 1.38, 95% confidence interval 1.01-1.90; p < 0.05). In heart tissues, the KSHV DNA load was also increased in the heart from patients with DCM in comparison with healthy donors (1016 versus 29 copies/105 cells, p < 0.05). The KSHV and kshv-miR-K12-1-5p in DCM hearts were detected using immunofluorescence and fluorescence staining in situ hybridization. KSHV itself was exclusively detectable in CD31-positive endothelium, while kshv-miR-K12-1-5p could be detected in both endothelium and cardiomyocytes. Moreover, kshv-miR-K12-1-5p released by KSHV-infected cardiac endothelium could disrupt the type I interferon signaling pathway in cardiomyocytes. Two models of kshv-miR-K12-1-5p overexpression (agomiR and recombinant adeno-associated virus) were used to explore the roles of KSHV-encoded miRNA in vivo. The kshv-miR-K12-1-5p aggravated known cardiotropic viruses-induced cardiac dysfunction and inflammatory infiltration. In conclusion, KSHV infection was a risk factor for DCM, providing developmental insights of DCM involving virus and its miRNA ( https://clinicaltrials.gov . Unique identifier: NCT03461107).

Overexpression of Sirt6 ameliorates sleep deprivation induced-cognitive impairment by modulating glutamatergic neuron function.

Sleep benefits the restoration of energy metabolism and thereby supports neuronal plasticity and cognitive behaviors. Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes. The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation (CSD). We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex (PrL). We then assessed cerebral functional connectivity (FC) using resting-state functional MRI, neuron/astrocyte metabolism using a metabolic kinetics analysis; dendritic spine densities using sparse-labeling; and miniature excitatory postsynaptic currents (mEPSCs) and action potential (AP) firing rates using whole-cell patch-clamp recordings. In addition, we evaluated cognition via a comprehensive set of behavioral tests. Compared with controls, Sirt6 was significantly decreased (P < 0.05) in the PrL after CSD, accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus, piriform cortex, motor cortex, somatosensory cortex, olfactory tubercle, insular cortex, and cerebellum. Sirt6 overexpression reversed CSD-induced cognitive impairment and reduced FC. Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4 and GABA2 synthesis, which could be fully restored via forced Sirt6 expression. Furthermore, Sirt6 overexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons. These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network, neuronal glucose metabolism, and glutamatergic neurotransmission. Thus, Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.

SAG treatment ameliorates memory impairment related to sleep loss by upregulating synaptic plasticity in adolescent mice.

Adequate sleep during the developmental stage can promote learning and memory functions because synaptic protein synthesis at primed synapses during sleep profoundly affects neurological function. The Sonic hedgehog (Shh) signaling pathway affects neuroplasticity in the hippocampus during the development of the central nervous system. In this study, the changes in synaptic morphology and function induced by sleep deprivation and the potential therapeutic effect of a Shh agonist (SAG) on these changes were investigated in adolescent mice. Adolescent mice were subjected to sleep deprivation for 20 hrs (2 pm to 10 am the next day) and were free to sleep for the remaining 4 hrs per day for 10 consecutive days. Sleep-deprived mice were injected with SAG (10 mg/kg body weight, i.p.) or saline (i.p.) every day 5 min before the onset of the 20 h sleep deprivation period. Chronic sleep deprivation impaired recognition and spatial memory, decreased the number of dendritic spines and mEPSCs of hippocampal CA1 pyramidal neurons, decreased the postsynaptic density, and reduced Shh and glioma-associated oncogene homolog 1 (Gli1) expression. SAG significantly protected against sleep deprivation-induced memory dysfunction, increased the CA1 pyramidal neuronal dendritic spine number and mEPSC frequency, and increased Gli1 expression. In conclusion, sleep deprivation induces memory impairment in adolescent mice, and SAG treatment prevents this impairment, probably by enhancing synaptic function in the hippocampal CA1 region.

Reactive oxygen species-powered cancer immunotherapy: Current status and challenges.

Reactive oxygen species (ROS) are crucial signaling molecules that can arouse immune system. In recent decades, ROS has emerged as a unique therapeutic strategy for malignant tumors as (i) it can not only directly reduce tumor burden but also trigger immune responses by inducing immunogenic cell death (ICD); and (ii) it can be facilely generated and modulated by radiotherapy, photodynamic therapy, sonodynamic therapy and chemodynamic therapy. The anti-tumor immune responses are, however, mostly downplayed by the immunosuppressive signals and dysfunction of effector immune cells within the tumor microenvironment (TME). The past years have seen fierce developments of various strategies to power ROS-based cancer immunotherapy by e.g. combining with immune checkpoints inhibitors, tumor vaccines, and/or immunoadjuvants, which have shown to potently inhibit primary tumors, metastatic tumors, and tumor relapse with limited immune-related adverse events (irAEs). In this review, we introduce the concept of ROS-powered cancer immunotherapy, highlight the innovative strategies to boost ROS-based cancer immunotherapy, and discuss the challenges in terms of clinical translation and future perspectives.

Myocarditis and myasthenia gravis induced by immune checkpoint inhibitor in a patient with relapsed thymoma: A case report.

Immune checkpoint inhibitors (ICIs)-targeting CTLA4 and PD1 constitute a promising class of cancer treatment but are associated with several immune-related adverse events (irAEs). A 55-year-old male patient with relapse thymoma was subjected to ICI therapy (PD-1 antibody), 2 weeks later, the patient started to manifest including droopy eyelids, weak neck, arms, and legs, and shortness of breath. Then the patient was admitted to the hospital because of the MG symptoms. Arterial blood gases (ABGs) revealed the presence of hypercapnia. Noninvasive ventilation was utilized for respiratory support. At admission, increased serum troponin levels, coupled with interventricular conduction abnormalities were observed. On the second day after admission, the patient developed transient loss of consciousness and twitching of the muscles, and electrocardiography monitoring showed intermittent third-degree atrioventricular block and ventricular pause necessitating temporary cardiac pacing. After excluding the possibility of acute coronary syndrome, intravenous steroids, intravenous immunoglobulin, pyridostigmine, and mycophenolate mofetil were sequentially initiated. 2 weeks later after treatment initiation, cardiac biomarkers and conduction abnormalities were recovered. 7 weeks later, MG symptoms were markedly improved. ICI-related MG and myocarditis can be life-threatening without appropriate management and clinicians should have a high index of suspicion for these irAEs in cancer patients receiving ICIs therapy. Steroids remain the cornerstone in the current management of irAEs due to the fast onset of action and high efficacy. However, in severe and refractory cases where no improvement is achieved despite high-dose steroids, alternative immunosuppressants should be considered.

[Effect of Uremic Clearance Granules on improvement of chronic kidney disease in rats based on microbiome-metabolomics and its mechanism].

This research aimed to study the effect of Uremic Clearance Granules on chronic kidney disease in SD rats by using the methods of microbial functional genomics combined with metabolomics, and to preliminarily explore its mechanism. The SD rat model of chronic kidney disease was established by the adenine-induced method. After the model was successfully induced, the animals were randomly divided into a negative control group, a Uremic Clearance Granule treatment group, and a normal control group, with 8 rats in each group. After 4 weeks of administration, animal feces and serum were collected, and 16S rDNA sequencing technology was used to analyze the abundance, diversity, and function prediction of intestinal microorganisms. Liquid chromatography-mass spectrometry(LC-MS) technology was used to perform high-throughput sequencing to detect animal serum metabolites. The MetPA database was used to screen out potential biomarkers of chronic kidney disease in rats and conduct the enrichment analysis of metabolic pathways. Spearman's method was used to analyze the correlation between the two omics. The results showed that Uremic Clearance Granules effectively improved the body weight loss and renal function-related biochemical and appearance indicators in rats with chronic kidney disease. The results of 16S rDNA sequencing showed that Uremic Clearance Granules regulated the diversity and composition of the intestinal flora in rats with chronic kidney disease. The changes in the intestinal flora affected functional metabolic pathways such as amino acid biosynthesis and metabolism, lipid metabolism, and carbohydrate metabolism. The results of LC-MS showed that as compared with the negative control group, 15 metabolites were reversed in the Uremic Clearance Granule treatment group, among which 11 potential marker metabolites were significantly up-regulated and 4 potential marker metabolites were significantly down-regulated. Five amino acid metabolic pathways were mainly involved, which were significantly correlated with changes in the intestinal flora. Therefore, Uremic Clearance Granules can improve the renal function of rats with chronic kidney disease, and the mechanism may be related to its effect on the amino acid metabolism pathway by regulating the intestinal flora.

Recent applications of phase-change materials in tumor therapy and theranostics.

Phase-change materials (PCMs) are a type of special material which can store and release a large amount of thermal energy without any significant temperature change. They are emerging in recent years as a promising functional material in tumor therapy and theranostics due to their accurate responses to the temperature variations, biocompatibility and low toxicity. In this review, we will introduce the main types of PCMs and their desirable physiochemical properties for biomedical applications, and highlight the recent progress of PCM's applications in the modulated release of antitumor drugs, with special attentions paid to various ways to initiate temperature-dependent phase change, the concomitant thermal therapy and its combination with or activation of other therapies, particularly unconventional therapies. We will also summarize PCM's recent applications in tumor theranostics, where both drugs and imaging probes are delivered by PCMs for controlled drug release and imaging-guided therapy. Finally, the future perspectives and potential limitations of harnessing PCMs in tumor therapy will be discussed.

P2X7 receptor-activated microglia in cortex is critical for sleep disorder under neuropathic pain.

Neuropathic pain (NP) is associated with sleep disturbances, which may substantially influence the quality of life. Clinical and animal studies demonstrated that neurotransmitter is one of the main contributors to cause sleep disturbances induced by NP. Recently, it was reported that P2X7 receptors (P2X7R) are widely expressed in microglia, which serves crucial role in neuronal activity in the pain and sleep-awake cycle. In this study, we adopted the chronic constriction injury (CCI) model to establish the progress of chronic pain and investigated whether P2X7R of microglia in cortex played a critical role in sleep disturbance induced by NP. At electroencephalogram (EEG) level, sleep disturbance was observed in mice treated with CCI as they exhibited mechanical and thermal hypersensitivity, and inhibition of P2X7R ameliorated these changes. We showed a dramatic high level of P2X7R and Iba-1 co-expression in the cortical region, and the inhibition of P2X7R also adversely affected it. Furthermore, the power of LFPs in ventral posterior nucleus (VP) and primary somatosensory cortex (S1) which changed in the CCI group was adverse after the inhibition of P2X7R. Furthermore, inhibition of P2X7R also decreased the VP-S1 coherence which increased in CCI group. Nuclear magnetic resonance demonstrated inhibition of P2X7R decreased glutamate (Glu) levels in thalamic and cortical regions which were significantly increased in the CCI mice. Our findings provide evidence that NP has a critical effect on neuronal activity linked to sleep and may built up a new target for the development of sleep disturbances under chronic pain conditions.

Are Hospice Google Ratings Correlated With Patient Experience Scores? Evidence from a National Hospice Study.

Background: Choosing hospice care for your loved ones is often challenging. Online ratings such as Google rating has become a go-to source for most consumers. The Consumer Assessment of Healthcare Providers and Systems (CAHPS) Survey for Hospice also provides quality information about hospice care to help patients and their families make decisions. Aim: To evaluate the perceived usefulness of publicly reported hospice quality indicators and compare hospice Google ratings with hospice CAHPS scores. Methods: A cross-sectional observational study was performed to test the relationship between Google ratings and CAHPS measures in 2020. We conducted descriptive statistics for all variables. Multivariate regressions were used to assess the relationship between Google ratings and the CAHPS scores of the sample. Results: Among our sample of 1,956 hospices, the average Google rating was 4.2 out of 5 stars. CAHPS score means ranged from 75 (Help for pain and symptoms) to 90 (Treating patients with respect) out of 100. Hospice Google ratings were highly correlated with hospice CAHPS scores. For-profit and chain-affiliated hospices reported lower CAHPS scores. Hospice operational time was positively associated with CAHPS scores. The percentage of minority residents in the community and residents' educational level was negatively associated with CAHPS scores. Conclusions: Hospice Google ratings were highly correlated with patients' and families' experience scores as measured by the CAHPS survey. Consumers can use information from both resources in making decisions about hospice care.

A cytotoxic triterpenoid from a Periplaneta americana-derived, Gordonia hongkongensis WA12-1-1.

The secondary metabolites produced by microorganisms are a source of novel compounds with antitumor activities. In this study, we isolated biologically active secondary metabolites produced by microorganisms in the intestinal tract of Periplaneta americana. Based on the 16S rRNA gene sequencing, Gordonia hongkongensis WA12-1-1 was identified as the main microorganisms in the intestinal tract of P. americana. The obtained sequence was deposited in the National Center for Biotechnology Information (NCBI) database under the accession number MZ348554. The isolated secondary metabolites were separated and purified by thin layer chromatography, silica gel column chromatography, Sephadex column chromatography, open octadecyl silane column chromatography, high-performance liquid chromatography (HPLC), and semipreparative HPLC. Next, the structure of individual compounds was determined by ultraviolet spectroscopy, nuclear magnetic resonance, and mass spectrometry. A total of 20 compounds were isolated from the secondary metabolites produced by G. hongkongensis WA12-1-1. A total of 12 compounds were obtained from the crude ethyl acetate extract of the culture supernatant and eight from the cellular fraction. Compound 1 was identified as a triterpenoid named gordonterpene and showed cytotoxicity against A549 and HepG2 cell lines. These findings form a basis for further studies on the bioactivity of gordonterpene to tumor cells.

Effects of simulated acid rain on rhizosphere microorganisms of invasive Alternanthera philoxeroides and native Alternanthera sessilis.

Acid rain not only has serious harm to the environment, but also has the same threat to plants, but the invasive plant Alternanthera philoxeroides still grows well compared to the native plant Alternanthera sessilis under acid rain stress. However, the underlying mechanism of resistance to the acid rain environment in invasive Alternanthera philoxeroides remains unclear. In the current study, we comparatively analyzed the plant physiological characteristics, soil physicochemical properties, and rhizosphere microbial communities of invasive A. philoxeroides and native A. sessilis under different pH condition. The simulated acid rain had a significant inhibitory effect on the morphological and physiological traits of A. philoxeroides and A. sessilis and reduced the soil nutrient content. However, A. philoxeroides was more tolerant of acid rain. Compared with CK, simulated acid rain treatment at pH 2.5 significantly increased the Chao1, ACE, and Shannon indexes of A. philoxeroides microorganisms. Under simulated acid rain treatment at pH 2.5, the fungal flora Chao1, ACE and Shannon index were significantly higher than those of CK by 14.5%, 12.4%, and 30.4%, respectively. The dominant bacterial phyla of soil bacteria were Proteobacteria, Actinobacteria, Bacteroidota, Actinobacteria, Firmicutes, Myxococcota, Chloroflexi, Patescibacteria, Gemmatimonadota, Verrucomicrobiota, and Armatimonadota. The dominant fungi were Ascomycota, Basidiomycota, Rozellomycota, and Olpidiomycota. The bacterial and fungal diversity and structure of A. philoxeroides and A. sessilis showed the greatest difference between the pH 2.5 treatment and CK. Redundancy analysis showed that electrical conductivity (EC) and total phosphorus (TP) were the main factors changing the bacterial communities, and available phosphorus (AP), organic matter (OM), EC, and pH were the main factors changing the fungal communities. This study contributes to the microbial community structure of the invasive plant A. philoxeroides and provides a theoretical basis for studying the invasion mechanism of invasive plants under acid rain.

Inactivation of a wheat protein kinase gene confers broad-spectrum resistance to rust fungi.

Wheat crops are frequently devastated by pandemic stripe rust caused by Puccinia striiformis f. sp. tritici (Pst). Here, we identify and characterize a wheat receptor-like cytoplasmic kinase gene, TaPsIPK1, that confers susceptibility to this pathogen. PsSpg1, a secreted fungal effector vital for Pst virulence, can bind TaPsIPK1, enhance its kinase activity, and promote its nuclear localization, where it phosphorylates the transcription factor TaCBF1d for gene regulation. The phosphorylation of TaCBF1d switches its transcriptional activity on the downstream genes. CRISPR-Cas9 inactivation of TaPsIPK1 in wheat confers broad-spectrum resistance against Pst without impacting important agronomic traits in two years of field tests. The disruption of TaPsIPK1 leads to immune priming without constitutive activation of defense responses. Taken together, TaPsIPK1 is a susceptibility gene known to be targeted by rust effectors, and it has great potential for developing durable resistance against rust by genetic modifications.

Isolation, Identification and Hyperparasitism of a Novel Cladosporium cladosporioides Isolate Hyperparasitic to Puccinia striiformis f. sp. tritici, the Wheat Stripe Rust Pathogen.

Wheat rust outbreaks have caused significantly economic losses all over the world. Puccinia striiformis f. sp. tritici (Pst) is an obligate biotrophic fungus causing stripe rust on wheat. Application of fungicides may cause environmental problems. The effects of hyperparasites on plant pathogens are the basis for biological control of plant pathogenic fungi and parasites of Pst have great value in biological agents development. Here, we report the isolation and characterization of isolate of Cladosporium cladosporioides from Pst based on morphological characterization and analysis of molecular markers. The hyperparasitic isolate was isolated from taupe-colored uredinia of Pst. Upon artificial inoculation, the hyperparasitic isolate was able to reduce the production and germination rate of Pst urediospores, and Pst uredinia changed color from yellow to taupe. Scanning electron microscopy demonstrated that the strain could efficiently colonize Pst urediospores. Therefore, the isolate has the potential to be developed into a biological control agent for managing wheat stripe rust.