Angiogenesis is limited by LIC1-mediated lysosomal trafficking.

Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, DYNC1LI1) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to regulate Rab-mediated endosomal recycling and lysosomal degradation. Defects in this gene are predicted to alter dynein motor function, Rab binding capabilities, and cytoplasmic cargo trafficking. Here, we have identified a dync1li1 zebrafish mutant, harboring a premature stop codon at the exon 12/13 splice acceptor site, that displays increased angiogenesis. In vitro, LIC1-deficient human endothelial cells display increases in cell surface levels of the pro-angiogenic receptor VEGFR2, SRC phosphorylation, and Rab11-mediated endosomal recycling. In vivo, endothelial-specific expression of constitutively active Rab11a leads to excessive angiogenesis, similar to the dync1li1 mutants. Increased angiogenesis is also evident in zebrafish harboring mutations in rilpl1/2, the adaptor proteins that promote Rab docking to Lic1 to mediate lysosomal targeting. These findings suggest that LIC1 and the Rab-adaptor proteins RILPL1 and 2 restrict angiogenesis by promoting degradation of VEGFR2-containing recycling endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting increases Rab11-mediated recycling endosome activity, promoting excessive SRC signaling and angiogenesis.

Synergistic effects of tree-herb intercropping on the phytoremediation efficiency of cadmium and lead contaminated soil.

Tree-herb intercropping has emerged as an effective strategy for the remediation of soil contamination. In this study, the effects of intercropping willow with herbaceous plants Lolium perenne L., Iris lactea Pall. and Bidens pilosa L. were investigated on the phytoremediation of Cd- and Pb-contaminated soil. After a 90-day of cultivation, the results showed that intercropping stimulated the phytoremediation efficiency through increased metal accumulation in plants. Intercropping caused a significant (p < 0.05) increase in willow biomass ranging from 48.07 % to 95.58 % by promoting photosynthesis activities and antioxidant responses. Metal contents in willow leaves and roots were also observably (p < 0.05) enhanced, indicating a beneficial effect in tree-herb intercropping systems. The biomass and metal accumulation of I. lactea Pall. and B. pilosa L. decreased due to competitive interactions with willow in the intercropping treatments. However, intercropping with willow (p < 0.05) significantly increased the Pb contents of L. perenne L. Intercropping improved the absorption of bioavailable fractions of Cd and Pb by willow and herbs in comparison to the monoculture. The decrease in soil Cd contents was partly due to the chemical changes induced by root exudates, which enhanced the transfer of Cd from the soil to the plants. Willow showed a tendency for Cd accumulation, whereas herbs exhibited Pb accumulation, reflecting the complementarity of metal accumulation in tree-herb intercropping patterns. Intercropping willow with B. pilosa L. was found to be an effective method for the remediation of Cd-contaminated soil, whereas the combination of willow with L. perenne L. proved suitable for the Pb-contaminated soil. These findings might support the potential of tree-herb intercropping as an effective strategy for enhancing the phytoremediation of contaminated soils.

Hydrogen-Bond-Assisted Electrocatalytic Semi-Oxidation of 5-Hydroxymethylfurfural into 2,5-Diformylfuran by Operando Dissociated N-Oxyl Mediator.

The conversion of 5-hydroxymethylfurfural (HMF) to 2,5-diformylfuran (DFF) is a promising approach for enhancing biomass utilization. Nevertheless, traditional methods using noble metal catalysts face challenges due to high costs and poor selectivity towards DFF. Herein, we developed a novel catalytic electrode integrating N-hydroxyphthalimide (NHPI) into a metal-organic framework on a hydrophilic carbon cloth. This design significantly enhances the selective adsorption of HMF due to stronger hydrogen-bond interaction between the electrode's hydrophilic surface and the C(sp3)-OH group in HMF compared to the C(sp2)=O in DFF. Additionally, the electro-driven dissociation of the NHPI-linker generates stabilized N-Oxyl radicals that promote selective semi-oxidation of HMF under neutral conditions. As a result, this approach achieves a high yield rate of 138.2 mol molcat-1 h-1 with a selectivity of 96.7% for the HMF-to-DFF conversion. This work introduces a novel strategy for designing catalytic electrodes with stabilized N-Oxyl radicals, and offers a promising method for electrocatalytic DFF synthesis, leveraging hydrogen-bond interaction between electrode surface and HMF.

CXCR3-CXCL11 Signaling Restricts Angiogenesis and Promotes Pericyte Recruitment.

BACKGROUND: Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development. METHODS: We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral responses to blood flow. Additionally, genetic mutants and pharmacological modulators were used in zebra fish in vivo to study the impacts of CXCR3 loss and gain of function on vascular development. RESULTS: In vitro modeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes. In vivo, phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with ECs and expansion of the vasculature in zebra fish treated with the Cxcr3 inhibitor AMG487 or in homozygous cxcr3.1/3.2/3.3 triple mutants. We also demonstrate that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared with their control counterparts. CONCLUSIONS: Our results suggest that CXCR3 signaling in ECs helps promote vascular stabilization events during development by preventing EC overgrowth and promoting pericyte recruitment.

Investigation of the effects of polyethylene microplastics at environmentally relevant concentrations on the plant-soil-microbiota system: A two-year field trial.

Microplastics are a potential threat to agricultural sustainability. However, the effects of microplastics at environmentally relevant concentrations on the plant-soil-microbiota system in realistic field conditions are largely unknown. Herein, we conducted a two-year field trial to study the effects of polyethylene (PE) microplastics at 0, 100, and 600 mg/kg on crop growth, soil properties, and the composition and function of microbial communities in a farmland with rice-wheat rotation. PE did not affect wheat growth but it increased the rice grain weight by 42.5 % at 600 mg/kg, and enhanced rice height by 35.4 % and 30.2 % at 100 and 600 mg/kg, respectively. The presence of PE significantly decreased soil available phosphorus during the wheat season, while it reduced soil total nitrogen, NH4+-N and available phosphorus during the rice season. There were five and sixteen bacterial orders identified changed by PE in wheat and rice soils, respectively. Specifically, PE at different concentrations differentially altered the abundances of sulfate-reducing bacteria Thermodesulfovibrionia, Thermoactinomycetales and Syntrophobacterales, and further modified soil sulfate respiration in wheat soils. During the rice season, PE (100 mg/kg) increased the abundance of Xanthomonadales by 98.0 % and enriched the functional groups of intracellular parasites, while PE (600 mg/kg) inhibited twelve cluster of orthologous group function classes and disturbed bacterial metabolism. This study suggests that PE exhibits a greater impact on the plant-soil-microbiota system during the rice season compared to the previous year's wheat season, highlighting the importance of crop type and cultivation practices in determining the environmental risks of microplastics in agroecosystems.

Investigating the prevalence burden of peptic ulcer disease in older adults aged 70+ from 1990 to 2019: an analysis of Global Disease Burden Studies.

BACKGROUND: Peptic ulcer disease (PUD) affects individuals aged ≥70 years globally, exerting a significant impact on their health and well-being. Understanding its epidemiological evolution and associated factors is crucial for guiding interventions and improving management. METHODS: This study utilized Global Burden of Disease Study data to examine the prevalence and temporal changes of PUD in individuals aged 70 years and older between 1990 and 2019. The analysis included assessing estimated annual percentage changes (EAPCs) to investigate temporal trends and regional variations. RESULTS: Over the past 30 years, the number of individuals aged 70 years and above suffering from PUD globally has increased from 1 065 730 cases in 1990 to 1 608 463 cases in 2019. Despite an increasing number of cases, the prevalence of PUD among the elderly has exhibited a steady decline, with an EAPC of -1.47 (95% confidence interval: -1.57 to -1.37) over this timeframe. In 2019, the prevalence rates of PUD among individuals aged 70-74, 75-79, 80-84, and 85 years and older were 313.36, 365.77, 388.45, and 352.51 per 100 000 population, respectively. South Asia, high-income North America, and Central Sub-Saharan Africa were the regions with the highest prevalence rates of PUD in 2019, with rates of 624.90, 575.48, and 474.80 per 100 000 population, respectively. At the national level, Ireland, Australia, Brazil, Brunei Darussalam, and Bangladesh have effectively managed the burden of PUD among the elderly, achieving the greatest reduction. Additionally, regions with higher levels of socioeconomic development tended to have relatively lower burdens of PUD among the elderly, and prevalence rates varied across different regions and age groups. CONCLUSION: Our study highlights the enduring burden of PUD among the global elderly population, emphasizing the significance of tailored interventions to address this pressing issue. This research underscores the critical need for targeted public health strategies aimed at improving outcomes specifically for older adults affected by PUD.

Astilbin exerts a neuroprotective effect by upregulating the signaling of nuclear NF-E2-related factor 2 in vitro.

Objective: The present study aims to evaluate the impact of Astilbin (AST) on cortical neuron survival in vitro under conditions of oxygen-glucose deprivation and reoxygenation (OGD/R) and determine the role of NF-E2-related factor 2 (Nrf2) in this process. Methods: Primary neurons were pre-treated with various concentrations of AST for 8 h before OGD induction. Cell viability and lactate dehydrogenase (LDH) leakage were assessed to determine the optimal concentration. Biomarkers related to oxidative stress, antioxidant enzyme activities, and apoptosis were evaluated at 24 h post-OGD/R. To investigate the involvement of Nrf2 in AST-mediated neuroprotection, we conducted molecular docking and microscale thermophoresis analyses, as well as examined the expression levels of Nrf2 and its regulatory genes including heme oxygenase-1(HO-1), (NAD(P)H: quinone oxidoreductase 1 (NQO-1), and peroxiredoxin 1 (Prdx1). Additionally, lentivirus-mediated knockdown of Nrf2 and overexpression of Nrf2 with L-sulforaphane (SFN) were performed, followed by an assessment of cell viability, oxidative stress, antioxidant enzyme activities and apoptosis. Results: Pre-treatment with AST reduced oxidative stress levels while increasing antioxidant enzyme activities and mitigating neuronal apoptosis. After OGD/R exposure, AST upregulated nuclear Nrf2 expression and increased the expression of HO-1, NQO-1 and Prdx1 in the cytoplasm. However, the knockdown of Nrf2 abolished the antioxidative and protective effects exerted by AST treatment. Conversely, combining AST with the Nrf2 agonist SFN demonstrated an enhancement in the protective effects provided by AST. These results demonstrate that Nrf2-dependent antioxidant responses contribute to AST-induced tolerance against neuronal injury caused by OGD/R injury. Conclusions: Overall findings support the ability of AST to protect primary neurons from OGD/R-induced damage through activation of Nrf2-dependent antioxidant responses.

High Carriage of tetA, sul1, sul2 and bla TEM Resistance Genes among the Multidrug-resistant Uropathogenic Escherichia coli (UPEC) Strains from Malaysian Patients.

The rapid emergence of multidrug-resistant (MDR) uropathogenic Escherichia coli (UPEC) strains pose a critical challenge in urinary tract infection (UTI) treatments. However, little work elucidated the resistance mechanisms of the MDR UPEC clinical strains in Malaysia. Therefore, this study aimed to determine the antimicrobial susceptibility profiles and the prevalence of antimicrobial resistance genes among the UPEC strains. Polymerase chain reactions were conducted to detect the presence of 6 antimicrobial resistance genes among 60 UPEC strains. Meanwhile, the antimicrobial resistance profiles against 9 antimicrobials were examined through the Kirby-Bauer disk diffusion method. In this study, the MDR isolates accounted for 40.0% (24/60), with the highest prevalence of resistance towards ampicillin (43/60; 71.7%), followed by tetracycline (31/60; 51.7%), nalidixic acid (30/60; 50.0%), co-trimoxazole (20/60, 33.3%), ciprofloxacin (19/60, 31.7%), levofloxacin (16/60, 21.6%) and chloramphenicol (10/60, 16.7%). In contrast, low resistance rates were observed among minocycline (1/60; 1.7%) and imipenem (0/60; 0.0%). bla TEM was the most prevalent gene (36/60; 60.0%), followed by tetA (27/60; 45.0%), sul2 (25/60; 41.7%), sul1 (13/60; 21.7%) and tetB (8/60; 13.3%). Surprisingly, bla SHV was not detected among the UPEC isolates. The MDR, ampicillin and tetracycline-resistant isolates were significantly associated with a higher prevalence of tetA, sul1, sul2 and bla TEM. In contrast, tetB displayed no significant relationship with any of the antimicrobials tested. The patient's age and gender were not the risk factors for the carriage of the resistance genes. Our findings identified the common resistance genes carried by the antimicrobial resistant UPEC isolates and provide valuable insights into developing the best antibiotic prescription regime to treat UTIs in our local scene.

Discovery and genomic characterization of three double-stranded RNA viruses coinfecting Conidiobolus taihushanensis.

Conidiobolus sensu lato, a genus within the family Ancylistaceae, encompasses a diverse range of fungal species that are widely distributed in plant debris and soil. In this study, we identified three double-stranded RNA (dsRNA) viruses coinfecting a strain of Conidiobolus taihushanensis. These viruses were identified as Conidiobolus taihushanensis totivirus 1 (CtTV1), Conidiobolus nonsegmented RNA virus 1-2 (CNRV1-2), and Conidiobolus taihushanensis virus 1 (CtV1). Through high-throughput sequencing and RNA-ligase-mediated rapid amplification of cDNA ends (RLM-RACE), we determined their complete genome sequences. The genome of CtTV1 is 6,921 nucleotides in length, containing two open reading frames (ORFs). ORF1 encodes a 1,124-amino-acid capsid protein (CP) with a molecular weight of 125.07 kDa, and ORF2 encodes a 780-amino-acid RNA-dependent RNA polymerase (RdRp) with a molecular weight of 88.05 kDa. CNRV1-2, approximately 3.0 kb in length, also contains two ORFs, which are predicted to encode a 186-amino-acid hypothetical protein (HP) and a 758-amino-acid RdRp. CtV1 has a smaller genome consisting of 3,081 base pairs (bp) with two ORFs: one encoding a 244-amino-acid HP (26.85 kDa) and the other encoding a 707-amino-acid RdRp (80.64 kDa). Phylogenetic analysis based on RdRp sequences revealed that CtTV1 shows the highest similarity to Phytophthora pluvialis RNA virus 1, with 38.79% sequence identity, and clusters with members of the family Orthototiviridae, and it is most closely related to Utsjoki toti-like virus. In contrast, CtV1 formed a unique branch and might represent a new genus. The genome sequence of CNRV1-2 is 99.74% identical to that of the previously described Conidiobolus non-segmented RNA virus 1 (CNRV1). Our findings indicate that CtTV1 and CtV1 are distinct novel viruses, while CNRV1-2 appears to be a variant of CNRV1. This study enhances our understanding of the genetic diversity and evolutionary relationships among mycoviruses associated with C. taihushanensis.

Heart Failure Among Asian American Subpopulations.

Importance: Heart failure (HF) is a leading cause of death in the US. The current evidence on the burdens of HF in Asian American populations, especially Asian American subgroups, is limited and inconsistent. Objective: To assess and compare the incidence and prevalence of HF in Asian American subgroups. Design, Setting, and Participants: This retrospective cohort study used electronic health record data from patients 40 years or older with health care encounters from January 1, 2015, to December 31, 2019, recorded in the Oracle Electronic Health Record Real-World Data database, which has more than 100 health care systems across the US contributing to the database as of February 2024. For prevalence analysis, the study samples were those who had at least 1 encounter in the study calendar year. For incidence analysis, participants were additionally limited to those without HF before the study year who also had encounter(s) the year before the study year. Data analysis was performed from August 1, 2023, to July 31, 2024. Exposure: Race and ethnicity were determined using patient self-reported data, which were categorized as Black, East Asian, South Asian, Southeast Asian, other Asian (without specified ethnicity), and White. Main Outcomes and Measures: Outcomes were incidence and prevalence of HF, identified using recorded International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes. Age- and sex-standardized incidence and prevalence were used to calculate the risk ratio of each racial and ethnic group compared with White patients. Results: Incidence and prevalence analyses were performed for 6 845 791 patients (mean [SD] age, 62.1 [12.5] years; 59.9% female; 2.8% Asian, 6.7% Black, and 90.5% White) and for 13 440 234 patients (mean [SD] age, 61.7 [12.7] years; 57.0% female; 2.9% Asian, 7.1% Black, and 90.0% White), respectively. Using the 2015 population as the standard, age- and sex-standardized HF incidence was 2.26% (95% CI, 2.07%-2.45%) for Southeast Asian patients, 1.56% (95% CI, 1.31%-1.82%) for South Asian patients, and 1.22% (95% CI, 1.06%-1.38%) for East Asian patients compared with 1.58% (95% CI, 1.57%-1.59%) for White patients and 2.39% (95% CI, 2.36%-2.42%) for Black patients. Similarly, heterogeneous rates in Asian American subgroups were also observed in the prevalence analysis. Conclusions and Relevance: In this study of HF outcomes, the disparities between Southeast and East Asian patients were larger than those between Black and White patients, with the estimates in Southeast Asian patients being similar to those of Black patients. These findings reinforce that individual Asian ethnicities and cardiovascular risk factors should be considered in the assessment of HF risks.

BMAL1 deficiency provokes dry mouth and eyes by down-regulating ITPR2/3.

Secretory glands, responsible for tears and saliva production, play essential roles in maintaining ocular and oral well-being. Disruptions in gland secretion can arise from various factors, including rhythm disturbances associated with sleep disorders. However, the underlying mechanisms governing these disruptions remain largely unexplored. We demonstrate that BMAL1, a core component of the circadian system, plays a critical role in regulating secretory gland secretion. Loss of BMAL1 induces vacuolation and atrophy phenotypes in acinar cells, subsequently leading to cell apoptosis and gland hypofunction, but does not cause Sjogren's syndrome, which is characterized by localized inflammatory cell infiltration. Mechanically, BMAL1 directly modulates the transcription of ITPR2 and ITPR3, thereby altering the secretion of Lactoferrin and Lysozyme. Restoration of ITPR2 and ITPR3 expression in Bmal1-deficient rats effectively alleviated the symptoms of lacrimal and parotid glands secretory dysfunction and significantly reduced dry mouth and dry eye conditions in rhythm-disordered rats. These findings highlight the essential role of BMAL1 in regulating salivary and lacrimal gland secretion and suggest a novel therapeutic approach for treating dry mouth and dry eyes associated with rhythm disorders.

Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8.

Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development.

Exploring phytoremediation potential of willow NJU513 for cadmium-contaminated soil with and without epibrassinolide treatment.

There has been a growing concern over soil cadmium (Cd) pollution, underscoring the importance of finding effective remediation strategies. Willow trees have emerged as promising candidates for phytoremediation of Cd-contaminated soils. Nevertheless, the specific potential of a novel willow genotype, NJU513, in remediating Cd-polluted soil remains unexplored. Hence, the primary objectives of this study were twofold: firstly, to ascertain the suitability of the willow genotype NJU513 for remediating Cd-contaminated soil; and secondly, to elevate its remediation efficciency with the application of epibrassinolide (Brs). In the pot-culture experiment without Brs, its leaf and stem Cd concentrations were 203 mg kg-1 and 65.1 mg kg-1, with a bioaccumulation factor (BCF) of 20.8 and 6.68, respectively. In the pot-culture experiment with Brs, the corresponding Cd concentrations were 226 mg kg-1 and 59.2 mg kg-1, with a BCF of 23.1 and 6.06, respectively. In addition, the extracted Cd contents were higher in the Brs treatments (1.11-1.37 mg plant-1) than in the no-Brs treatments (0.78-0.96 mg plant-1) because Brs increased the plant biomass and leaf BCF. The mechanism underlying the Cd accumulation of NJU513 leaves with and without Brs was revealed by a transcriptome analysis. The expression levels of genes related to metal ion binding, channel activity, and transporters in leaves were up-regulated, which contributed to the high Cd accumulation and stress tolerance. Analyses of soil metabolites and bacteria in the presence and absence of Brs spraying on willow leaves indicated that soil organic compounds with carboxyl and amino groups may induce Cd activation and passivation, respectively. This study provides valuable insights for developing woody plant varieties that can be used for remediating Cd-contaminated soil.

Palladium-Catalyzed Denitrative α-Arylation of Heteroarenes with Nitroarenes via C-H and C-NO2 Bond Activations.

A general approach for the α-arylation of heteroarenes with nitroarenes via denitrative coupling is reported for the first time. Various heteroarenes, including derivatives of furan, benzofuran, pyrrole, indole, thiophene, and benzothiophene, can be arylated at the α-position in moderate to good yields. Mechanistic studies demonstrate that the reaction proceeds via a CMD pathway, with C-H bond activation as the rate-determining step. Furthermore, the scalability and applicability in the synthesis of a drug molecule exemplify the utility of this protocol.

Bioinspired deformation computational design method for muscle-driven soft robots using MPM.

In order to adapt to complex and changing environments, animals have a wide variety of locomotor forms, which has inspired the investigation of their deformation and driving mechanisms. In this paper, we propose a computational design method for muscle-driven soft robots to satisfy desired deformations, aiming to mimic the deformation behavior of muscle-driven animals in nature. In this paper, we generate the ideal muscle-driven layout for the soft robot by inputting an initial shape and a desired shape, so that it can closely achieve the desired deformation. The material point method is utilized to simulate the soft medium so as to achieve the effect of coupling and coordinated deformation of arbitrary shapes. Our method efficiently searches for muscle layouts corresponding to various deformations and realizes the deformation behaviors of a variety of bio-inspired robots, including soft robots such as bionic snakes, frogs, and human faces. Experimental results show that for both the bionic snake and frog soft robots, the overlap of the geometric contour regions between the actual and simulated deformations is more than 90%, which validates the effectiveness of the method. In addition, the global muscle distributions of the bionic snake and human face soft robots during motion are generated and validated by effective simulation.

Differential impacts of organic and inorganic phosphorus on the growth and phosphorus utilization of Microcystis aeruginosa.

Phytoplankton growth in freshwater is often limited by the availability of phosphorus (P), and thorough understandings of P availability are essential to prevent algal blooms. However, the differences in bioavailability and utilization mechanisms of different P forms remain unclear, especially whether organophosphorus could be used as P sources. This study investigated the effects of 0.5, 1.0, and 2.0 mg/L P on Microcystis aeruginosa, including dissolved organic P (DOP) (1-hydroxyethane 1,1-diphosphonic acid) and dissolved inorganic P (DIP) (dipotassium phosphate). Compared with DIP, intracellular P content absorbed in DOP treatment was significantly lower. DOP was more conducive to the synthesis of soluble protein and the release of extracellular polymeric substances. Alkaline phosphatase activity was generally enhanced in response to DIP deficiency. Both DIP and DOP promoted carbon uptake to the same extent. DOP groups absorbed carbon to synthesize energy and proteins in response to stress, while DIP groups were mainly used carbon for growth. They all reduced the content of microcystin releasing into the aquatic environment and therefore reduced ecological risk caused by microcystin. Compared with DIP, the expressions of photosynthesis-related genes were significantly down-regulated in DOP group, while the expressions of nucleoside phosphate catabolism, P transporter, and amino acid biosynthesis and metabolism were significantly up-regulated in response to P deficiency environment and the stress of 1.0 mg/L DOP concentration. In summary, the bioavailability of different P forms on cyanobacteria is different, so it is not sufficient to only use total P for assessing environmental risk. P forms should also be considered for risk management of freshwater ecosystems.

A refined formula derived from Jiawei-Xiaoyao pill exerts rapid antidepressant-like effects in LPS-induced depression by reducing neuroinflammation and restoring neuroplasticity signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei-Xiaoyao Pill (JWX), a classic formula in traditional Chinese medicine, is derived from Xiaoyao Pill by adding significant amounts of Gardeniae Fructus (GF) and Moutan Cortex (MC). It is frequently used for the treatment of depression. JWX has been demonstrated to uniquely elicit rapid antidepressant-like effects within the prescribed dosage range. To date, GF has been shown to have rapid antidepressant-like effects, but a much higher dose is required than its proportion in JWX. It is assumed that the synergism of GF with a minimum number of other herbs in JWX serves as a refined formula that exerts these rapid antidepressant-like effects. Identification of a refined formula is important for prioritizing the herbs and ingredients to optimize the quality control of JWX. However, such a refined formula for JWX has not been identified yet. AIM OF THE STUDY: Here we aimed to identify a refined formula derived from JWX for optimized rapid antidepressant-like effects. Since the neuroinflammation mechanism involving in depression treatment has not been previously investigated for JWX, we tested the mechanism for both JWX and the refined formula. MATERIALS AND METHODS: Individual herbs (MC; ASR, Angelica Sinensis Radix; Bupleuri Radix; Paeonia Radix Alba) that show antidepressant-like responses were mixed with GF at the proportional dosage in JWX to identify the refined formula. Rapid antidepressant-like effects were assessed by using NSF (Novelty Suppressed Feeding Test) and other behavioral tests following a single administration. The identified formula was further tested in a lipopolysaccharide (LPS)-induced depressive model, and the molecular signaling mechanisms were investigated using Western blot analysis, immunofluorescence, and pharmacological inhibition of mTOR signaling. Scopolamine (Scop) was used as a positive control for induction of rapid antidepressant effects. RESULTS: A combination of GF, MC and ASR (GMA) at their dosages proportional to JWX induced behavioral signs of rapid antidepressant-like responses in both normal and LPS-treated mice, with the antidepressant-like effects sustained for 5 d. Similar to JWX or Scop, GMA rapidly reduced the neuroinflammation signaling of Iba-1-NF-кB, enhanced neuroplasticity signaling of CaMKII-mTOR-BDNF, and attenuated the upregulated expressions of the NMDAR sub-units GluN1 and GluN2B in the hippocampus of LPS-treated mice. GMA, JWX and Scop rapidly restored the number of BDNF-positive cells reduced by LPS treatment in the CA3 region of the hippocampus. Furthermore, rapamycin, a selective inhibitor of mTOR, blunted the rapid antidepressant-like effects and hippocampal BDNF signaling upregulation by GMA. CONCLUSION: GMA may serve as a refined formula from JWX, capable of inducing rapid antidepressant-like effects. In the LPS-induced depression model, the effects of GMA were mediated via rapidly alleviating neuroinflammation and enhancing neuroplasticity.

Possible role of a malfunctioning immune system in discordant lymphoma with peripheral T­cell lymphoma secondary to classical Hodgkin lymphoma: A case report.

The present case report investigated the clinicopathological features and potential mechanisms underlying the transformation to peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), following treatment for classical Hodgkin lymphoma (CHL) in a 73-year-old man. The patient was admitted to hospital in 2012 and underwent a left cervical lymph node biopsy, which confirmed CHL of the nodular sclerosing type, with evident bone marrow involvement. The patient received four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy, after which they achieved complete remission. However, after 3 years, the patient presented with enlarged left inguinal lymph nodes and a biopsy revealed PTCL-NOS. Molecular studies indicated a T-cell receptor-γ gene rearrangement. A literature review, together with the current case, identified 11 patients with CHL that transformed into PTCL-NOS. Among these, nine patients (81.82%) were middle-aged or elderly (>45 years old), and eight (72.73%) experienced transformation within 3 years post-treatment of CHL. Among these eight patients, seven (87.50%) predominantly exhibited the nodular sclerosis subtype, with a median recurrence time of 26 months. Five (45.45%) patients died of the disease. The rare transformation of CHL to PTCL-NOS, primarily among men, underscores its clinical significance. Notably, nodular sclerosing-type CHL appears to be particularly prone to transformation into PTCL-NOS. The poor prognosis in such cases may be attributed to the complex tumor microenvironment of CHL.

[Modular pharmacology: research progress and development of analysis platform].

Based on the systematic deconstruction of multi-dimensional and multi-target biological networks, modular pharmacology explains the complex mechanism of diseases and the interactions of multi-target drugs. It has made progress in the fields of pathogenesis of disease, biological basis of disease and traditional Chinese medicine(TCM) syndrome, pharmacological mechanism of multi-target herbs, compatibility of formulas, and discovery of new drug of TCM compound. However, the complexity of multi-omics data and biological networks brings challenges to the modular deconstruction and analysis of the drug networks. Here, we constructed the "Computing Platform for Modular Pharmacology" online analysis system, which can implement the function of network construction, module identification, module discriminant analysis, hub-module analysis, intra-module and inter-module relationship analysis, and topological visualization of network based on quantitative expression profiles and protein-protein interaction(PPI) data. This tool provides a powerful tool for the research on complex diseases and multi-target drug mechanisms by means of modular pharmacology. The platform may have broad range of application in disease modular identification and correlation mechanism, interpretation of scientific principles of TCM, analysis of complex mechanisms of TCM and formulas, and discovery of multi-target drugs.

Hippocampal PACAP signaling activation triggers a rapid antidepressant response.

BACKGROUND: The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response. METHODS: The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus. RESULTS: Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optogenetic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor (BDNF) signaling. Finally, acute ketamine treatment upregulated hippocampal PACAP expression, whereas intra-DG blockade of PACAP signaling attenuated ketamine's rapid antidepressant response. CONCLUSIONS: Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKII inhibition-governed eEF2-mTOR-BDNF signaling.