Retrotransposon-mediated disruption of a chitin synthase gene confers insect resistance to Bacillus thuringiensis Vip3Aa toxin.

The vegetative insecticidal protein Vip3Aa from Bacillus thuringiensis (Bt) has been produced by transgenic crops to counter pest resistance to the widely used crystalline (Cry) insecticidal proteins from Bt. To proactively manage pest resistance, there is an urgent need to better understand the genetic basis of resistance to Vip3Aa, which has been largely unknown. We discovered that retrotransposon-mediated alternative splicing of a midgut-specific chitin synthase gene was associated with 5,560-fold resistance to Vip3Aa in a laboratory-selected strain of the fall armyworm, a globally important crop pest. The same mutation in this gene was also detected in a field population. Knockout of this gene via CRISPR/Cas9 caused high levels of resistance to Vip3Aa in fall armyworm and 2 other lepidopteran pests. The insights provided by these results could help to advance monitoring and management of pest resistance to Vip3Aa.

B. subtilis CNBG-PGPR-1 induces methionine to regulate ethylene pathway and ROS scavenging for improving salt tolerance of tomato.

Soil salinity severely threatens plant growth and crop yields. The utilization of PGPR is an effective strategy for enhancing plant salt tolerance, but the mechanisms involved in this process have rarely been reported. In this study, we investigated the effects of Bacillus subtilis CNBG-PGPR-1 on improving plant salt tolerance and elucidated the molecular pathways involved. The results showed that CNBG-PGPR-1 significantly improved the cellular homeostasis and photosynthetic efficiency of leaves and reduced ion toxicity and osmotic stress caused by salt in tomato. Transcriptome analysis uncovered that CNBG-PGPR-1 enhanced plant salt tolerance through the activation of complex molecular pathways, with plant hormone signal transduction playing an important role. Comparative analysis and pharmacological experiments confirmed that the ethylene pathway was closely related to the beneficial effect of CNBG-PGPR-1 on improving plant salt tolerance. Furthermore, we found that methionine, a precursor of ethylene synthesis, significantly accumulated in response to CNBG-PGPR-1 in tomato. Exogenous L-methionine largely mimicked the beneficial effects of CNBG-PGPR-1 and activated the expression of ethylene pathway-related genes, indicating CNBG-PGPR-1 induces methionine accumulation to regulate the ethylene pathway in tomato. Finally, CNBG-PGPR-1 reduced salt-induced ROS by activating ROS scavenger-encoding genes, mainly involved in GSH metabolism and POD-related genes, which were also closely linked to methionine metabolism. Overall, our studies demonstrate that CNBG-PGPR-1-induced methionine is a key regulator in enhancing plant salt tolerance through the ethylene pathway and ROS scavenging, providing a novel understanding of the mechanism by which beneficial microbes improve plant salt tolerance.

ppGpp is a dual-role regulator involved in balancing iron absorption and prodiginine biosynthesis in Pseudoalteromonas.

Iron is an essential element for microbial survival and secondary metabolism. However, excess iron availability and overloaded secondary metabolites can hinder microbial growth and survival. Microorganisms must tightly control iron homeostasis and secondary metabolism. Our previous studies have found that the stringent starvation protein A (SspA) positively regulates prodiginine biosynthesis by activating iron uptake in Pseudoalteromonas sp. strain R3. It is believed that the interaction between SspA and the small nucleotide ppGpp is important for iron to exert regulation functions. However, the roles of ppGpp in iron absorption and prodiginine biosynthesis, and the underlying relationship between ppGpp and SspA in strain R3 remain unclear. In this study, we found that ppGpp accumulation in strain R3 could be induced by limiting iron. In addition, ppGpp not only positively regulated iron uptake and prodiginine biosynthesis via increasing the SspA level but also directly repressed iron uptake and prodiginine biosynthesis independent of SspA, highlighting the finding that ppGpp can stabilize both iron levels and prodiginine production. Notably, the abolishment of ppGpp significantly increased prodiginine production, thus providing a theoretical basis for manipulating prodiginine production in the future. This dynamic ppGpp-mediated interaction between iron uptake and prodiginine biosynthesis has significant implications for understanding the roles of nutrient uptake and secondary metabolism for the survival of bacteria in unfavorable environments.

Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression.

BACKGROUND: Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ. METHODS: Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors. RESULTS: TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma. CONCLUSION: Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.

Excessive immunosuppression by regulatory T cells antagonizes T cell response to schistosome infection in PD-1-deficient mice.

Schistosomiasis is caused by parasitic flatworms known as schistosomes and affects over 200 million people worldwide. Prevention of T cell exhaustion by blockade of PD-1 results in clinical benefits to cancer patients and clearance of viral infections, however it remains largely unknown whether loss of PD-1 could prevent or cure schistosomiasis in susceptible mice. In this study, we found that S. japonicum infection dramatically induced PD-1 expression in T cells of the liver where the parasites chronically inhabit and elicit deadly inflammation. Even in mice infected by non-egg-producing unisex parasites, we still observed potent induction of PD-1 in liver T cells of C57BL/6 mice following S. japonicum infection. To determine the function of PD-1 in schistosomiasis, we generated PD-1-deficient mice by CRISPR/Cas9 and found that loss of PD-1 markedly increased T cell count in the liver and spleen of infected mice. IL-4 secreting Th2 cells were significantly decreased in the infected PD-1-deficient mice whereas IFN-γ secreting CD4+ and CD8+ T cells were markedly increased. Surprisingly, such beneficial changes of T cell response did not result in eradication of parasites or in lowering the pathogen burden. In further experiments, we found that loss of PD-1 resulted in both beneficial T cell responses and amplification of regulatory T cells that prevented PD-1-deficient T cells from unleashing anti-parasite activity. Moreover, such PD-1-deficient Tregs exert excessive immunosuppression and express larger amounts of adenosine receptors CD39 and CD73 that are crucial for Treg-mediated immunosuppression. Our experimental results have elucidated the function of PD-1 in schistosomiasis and provide novel insights into prevention and treatment of schistosomiasis on the basis of modulating host adaptive immunity.

The natural sesquiterpene lactone inulicin suppresses the production of pro-inflammatory mediators via inhibiting NF-κB and AP-1 pathways in LPS-activated macrophages.

OBJECTIVE: Inulicin is a sesquiterpene lactone in Inulae Flos which is clinically used for the treatment of inflammatory diseases, such as cough, sputum production, and vomiting. This study aimed to demonstrate the anti-inflammatory activity and the underlying mechanism of inulicin by using lipopolysaccharide (LPS)-induced in vitro and in vivo models. METHODS: LPS-stimulated RAW264.7 macrophages and mouse peritoneal macrophages (MPMs) were used for evaluating the in vitro anti-inflammatory activity of inulicin, while endotoxemia mice were used for evaluating its in vivo action. Cytokines' levels were determined by ELISA. RT-qPCR and western blot were used for assaying the mRNA and protein levels of target genes. RAW264.7 macrophages transfected with reporter plasmid pNFκB-TA-luc or pAP1-TA-luc were used for assaying the activation of NF-κB or AP-1 signaling. RESULTS: Inulicin significantly inhibited LPS-induced production of NO, IL-6, c-c motif chemokine ligand 2 (CCL2), and IL-1ß in both RAW264.7 cells and MPMs. Mechanism study indicated that it could suppress inducible nitric oxide synthase, IL-6, CCL2, and IL-1ß mRNA levels in LPS-stimulated RAW264.7 cells. Moreover, inulicin inhibited IκBα phosphorylation and prevented the nuclear translocation of p65, thereby inactivating NF-κB signaling. Concurrently, it also inhibited AP-1 signaling by reducing the phosphorylation of C-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). In endotoxemia mice, a single intraperitoneal administration of inulicin could decrease the production of pro-inflammatory cytokines in serum and peritoneal lavage fluid. CONCLUSIONS: The present study demonstrates that inulicin possesses anti-inflammatory effects in vitro and in vivo, which suggests that inulicin might be a promising candidate for the treatment of inflammatory diseases.

A20 is a master switch of IL-33 signaling in macrophages and determines IL-33-induced lung immunity.

BACKGROUND: IL-33 plays a major role in the pathogenesis of allergic diseases such as asthma and atopic dermatitis. On its release from lung epithelial cells, IL-33 primarily drives type 2 immune responses, accompanied by eosinophilia and robust production of IL-4, IL-5, and IL-13. However, several studies show that IL-33 can also drive a type 1 immune response. OBJECTIVE: We sought to determine the role of A20 in the regulation of IL-33 signaling in macrophages and IL-33-induced lung immunity. METHODS: We studied the immunologic response in lungs of IL-33-treated mice that specifically lack A20 in myeloid cells. We also analyzed IL-33 signaling in A20-deficient bone marrow-derived macrophages. RESULTS: IL-33-induced lung innate lymphoid cell type 2 expansion, type 2 cytokine production, and eosinophilia were drastically reduced in the absence of macrophage A20 expression, whereas neutrophils and interstitial macrophages in lungs were increased. In vitro, IL-33-mediated nuclear factor kappa B activation was only weakly affected in A20-deficient macrophages. However, in the absence of A20, IL-33 gained the ability to activate signal transducer and activator of transcription 1 (STAT1) signaling and STAT1-dependent gene expression. Surprisingly, A20-deficient macrophages produced IFN-γ in response to IL-33, which was fully STAT1-dependent. Furthermore, STAT1 deficiency partially restored the ability of IL-33 to induce ILC2 expansion and eosinophilia in myeloid cell-specific A20 knockout mice. CONCLUSIONS: We reveal a novel role for A20 as a negative regulator of IL-33-induced STAT1 signaling and IFN-γ production in macrophages, which determines lung immune responses.

Influence and mechanism of solids on the air pressure fluctuations on the building drainage system.

The conventional building drainage system was constructed based on the theory of two-phase flow involving water and air. However, the drainage system contained a more intricate three-phase flow, encompassing water, air, and solids, which was relatively overlooked in research. This study addressed the impact of solids on pressure fluctuations, air flow rates, and hydraulic jump fullness within the drainage system, considering three factors: the mass factor, cross-section factor, and viscosity. The investigation was conducted within a single-stack system using both experimental methods and CFD simulations. The findings revealed a positive correlation between both positive and negative pressures and above three factors. The mass factor and the cross-section factor had a more significant impact on the negative pressure of the system. The maximum growth rates of negative pressure extremes under different mass and cross-section factors reached 7.72 and 16.52%, respectively. In contrast, the viscosity of fecal sludge had a slightly higher effect on the positive pressure fluctuation of the drainage system, with the maximum growth rate of positive pressure extremes at 3.41%.

Hesperetin attenuates cognitive dysfunction via SIRT6/NLRP3 pathway in scopolamine-induced mice.

Neuroinflammation is a critical feature in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). Hesperetin can exert anti-inflammatory, antioxidant and other neuroprotective effects. In this study, the scopolamine (SCOP)-induced cognitive dysfunction in mice model was used to evaluate the neuroprotective effects of hesperetin. Behavioral tests (Morris water maze, open field, and novel object recognition tests) were conducted to evaluate the effect of hesperetin on cognitive dysfunction behaviors. Nissl staining and Immunofluorescence were used to evaluate hippocampal neuronal damage and microglial activation in mice. The levels of proinflammatory factors, oxidant stress, and the cholinergic neurotransmitter were detected by real-time quantitative fluorescence PCR (RT-qPCR) or biochemical reagent kits. Western blotting was used to detect the relative protein expression of the sirtuin 6 (SIRT6) / NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway. Results showed that hesperetin could ameliorate SCOP-induced cognitive impairment and neuronal damage, and regulate the levels of cholinergic neurotransmitters in the hippocampal of AD mice. Hesperetin could also enhance antioxidant defense by regulating the levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT). Hesperetin exerted anti-neuroinflammation effects through inhibiting of microglia activation and down-regulating the mRNA transcript levels of inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Meanwhile, hesperetin could attenuate the expression of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), thioredoxin-interacting protein (TXNIP), and caspase-1 p20 and upregulate the expression of SIRT6 in SCOP-induced mice. Overall, our study suggested that hesperetin might ameliorate SCOP-induced cognitive dysfunction by improving cholinergic system dysfunction and suppressing oxidative stress and attenuating neuroinflammation via SIRT6/NLRP3 pathway in mice.

A novel ZsGreen knock-in melanoma cell line reveals the function of CD11b in tumor phagocytosis.

Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) is an efficient tool for establishing genetic models including cellular models, and has facilitated unprecedented advancements in biomedical research. In both patients and cancer animal models, immune cells infiltrate the tumor microenvironment and some of them migrate to draining lymph nodes to exert antitumor effects. Among these immune cells, phagocytes such as macrophages and dendritic cells engulf tumor antigens prior to their crosstalk with T cells and elicit adaptive immune response against tumors. Melanoma cells are frequently used as a tumor model because of their relatively high level of somatic mutations and antigenicity. However, few genetic models have been developed using melanoma cell lines to track tumor cell phagocytosis, which is essential for understanding protective immune response in vivo. In this study, we used CRISPR/Cas9-mediated DNA cleavage and homologous recombination to develop a novel knock-in tool which expresses the ultra-bright fluorescent probe ZsGreen in YUMM1.7 melanoma cells. Using this novel tool, we measured the macrophagic engulfment of melanoma cells inside the tumor microenvironment. We also found that in tumor-grafted mice, a subset of dendritic cells efficiently engulfed YUMM1.7 cells and was preferentially trafficking tumor antigens to draining lymph nodes. In addition, we used this knock-in tool to assess the impact of a point mutation of CD11b on phagocytosis in the tumor microenvironment. Our results demonstrate that the ZsGreen-expressing YUMM1.7 melanoma model provides a valuable tool for the study of phagocytosis in vivo.

Stringent Starvation Protein SspA and Iron Starvation Sigma Factor PvdS Coordinately Regulate Iron Uptake and Prodiginine Biosynthesis in Pseudoalteromonas sp. R3.

Organisms need sufficient intracellular iron to maintain biological processes. However, cells can be damaged by excessive iron-induced oxidation stress. Therefore, iron homeostasis must be strictly regulated. In general, bacteria have evolved complex mechanisms to maintain iron homeostasis. In this study, we showed that Pseudoalteromonas sp. R3 has four sets of iron uptake systems. Among these, the siderophore pyoverdine-dependent iron uptake system and the ferrous iron transporter Feo system are more important for iron uptake and prodiginine biosynthesis. Stringent starvation protein SspA positively controls iron uptake and iron-dependent prodiginine biosynthesis by regulating the expression of all iron uptake systems. In turn, the expression of SspA can be induced and repressed by extracellular iron deficiency and excess, respectively. Interestingly, extracytoplasmic function sigma factor PvdS also regulates iron uptake and prodiginine production and responds to extracellular iron levels, exhibiting a similar phenomenon as SspA. Notably, not only do SspA and PvdS function independently, but they can also compensate for each other, and their expression can be affected by the other. All of these findings demonstrate that SspA and PvdS coordinate iron homeostasis and prodiginine biosynthesis in strain R3. More importantly, our results also showed that SspA and PvdS homologs in Pseudomonas aeruginosa PAO1 have similar functions in iron uptake to their counterparts in Pseudoalteromonas, suggesting that coordination between SspA and PvdS on iron homeostasis could be conserved in typical Gram-negative bacteria. Since master regulation of iron homeostasis is extremely important for cell survival, this cross talk between SspA and PvdS may be environmentally significant. IMPORTANCE Both deficiency and excess of intracellular iron can be harmful, and thus, the iron homeostasis needs to be tightly regulated in organisms. At present, the ferric uptake regulator (Fur) is the best-characterized regulator involved in bacterial iron homeostasis, while other regulators of iron homeostasis remain to be further explored. Here, we demonstrated that the stringent starvation protein SspA and the extracytoplasmic function sigma factor PvdS coordinate iron uptake and iron-dependent prodiginine biosynthesis in Pseudoalteromonas sp. R3. These two regulators work independently, but their functions can compensate for the other and their expression can be affected by the other. Moreover, their expression can be activated and repressed by extracellular iron deficiency and excess, respectively. Notably, SspA and PvdS homologs in Pseudomonas aeruginosa PAO1 exhibit similar functions in iron uptake to their counterparts in Pseudoalteromonas, suggesting that this novel fine-tuned mode of iron homeostasis could be conserved in typical Gram-negative bacteria.

Effects of linaclotide in the treatment of chronic constipation and irritable bowel syndrome with constipation: a meta-analysis.

OBJECTIVE: Linaclotide is a guanylate cyclase-C (GCC) agonist that is found in intestinal epithelial cells and is used when treating chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C). Several randomized controlled trials (RCTs) were conducted for evaluating its efficacy and safety. METHODS: The PubMed, EMBASE, and Cochrane databases and the Web of Science were searched to find multiple RCTs of patients with CC or IBS-C. The Jadad scoring system was used for evaluating each study's methodological quality, and RevMan5.3 was used for meta-analysis. The composite endpoint reaction approved by the FDA, abdominal pain and discomfort relief, symptom improvement, and diarrhea-related adverse reactions were chosen as observation indicators, and relative risk (RR) and 95% confidence interval (CI) were obtained for quantitative and comprehensive evaluation. RESULTS: Eleven randomized controlled studies were included, consisting of 5 cases of CC and 6 cases of IBS-C. Linaclotide reached the composite endpoint response approved by FDA in the treatment of CC (RR = 3.26, 95% CI: 2.45-4.33), and the composite endpoint response approved by FDA for the treatment of IBS-C (RR = 2.26, 95% CI: 1.86-2.74) was greater than the placebo (both p < 0.00001). The main adverse reactions of linaclotide were gastrointestinal, mostly diarrhea, which was higher than that of the placebo when treating CC (RR = 3.56, 95% CI: 2.76-4.60) and IBS-C (RR = 8.23, 95% CI: 5.69-11.90) (both p < 0.00001). CONCLUSION: Linaclotide proved to be effective and safe for the treatment of CC and IBS-C compared to the placebo. However, diarrhea is the primary adverse reaction.

Egg Protein Transferrin-Derived Peptides Irw (Lle-Arg-Trp) and Iqw (Lle-Gln-Trp) Prevent Obesity Mouse Model Induced by a High-Fat Diet via Reducing Lipid Deposition and Reprogramming Gut Microbiota.

Egg-derived peptides play important roles in insulin secretion and sensitivity, oxidative stress, and inflammation, suggesting their possible involvement in obesity management. Hence, the aim of this study is to explore the alleviating effects of IRW (lle-Arg-Trp) and IQW (lle-Gln-Trp) on obesity via the mouse model induced by a high-fat diet. The entire experimental period lasted eight weeks. The results demonstrated that IQW prevented weight gain (6.52%), decreased the glucose, low-density lipoprotein (LDL), malonaldehyde, triglycerides, total cholesterol (TC), and leptin levels, and increased the concentration of adiponectin (p < 0.05, n = 8). Although IRW failed to prevent weight gain, it reduced the concentration of glucose, high-density lipoprotein (HDL), LDL, and leptin, and increased the concentration of adiponectin (p < 0.05, n = 8). Moreover, IRW and IQW increased glucose tolerance and insulin resistance based on the results of the intraperitoneal glucose test and insulin tolerance test (p < 0.05, n = 8). The quantitative polymerase chain reaction results revealed that IRW and IQW downregulated the mRNA expression of DGAT1 (Diacylglycerol O-Acyltransferase 1), DGAT2 (Diacylglycerol O-Acyltransferase 2), TNF-α, IL-6, and IL-1ß of liver tissue (p < 0.05, n = 8). The results of the 16S ribosomal RNA amplicon sequencing showed that IQW and IRW tended to reduce the relative abundance of Firmicutes and Parabacteroides, and that IRW enhanced the abundance of Bacteroides (p < 0.05, n = 8). Collectively, IRW and IQW supplementation could alleviate the progression of obesity due to the fact that the supplementation reduced lipid deposition, maintained energy balance, and reprogrammed gut microbiota.

Salicylate Sodium Suppresses Monocyte Chemoattractant Protein-1 Production by Directly Inhibiting Phosphodiesterase 3B in TNF-α-Stimulated Adipocytes.

As a worldwide health issue, obesity is associated with the infiltration of monocytes/macrophages into the adipose tissue causing unresolved inflammation. Monocyte chemoattractant protein-1 (MCP-1) exerts a crucial effect on obesity-related monocytes/macrophages infiltration. Clinically, aspirin and salsalate are beneficial for the treatment of metabolic diseases in which adipose tissue inflammation plays an essential role. Herein, we investigated the effect and precise mechanism of their active metabolite salicylate on TNF-α-elevated MCP-1 in adipocytes. The results indicated that salicylate sodium (SAS) could lower the level of MCP-1 in TNF-α-stimulated adipocytes, which resulted from a previously unrecognized target phosphodiesterase (PDE), 3B (PDE3B), rather than its known targets IKKß and AMPK. The SAS directly bound to the PDE3B to inactivate it, thus elevating the intracellular cAMP level and activating PKA. Subsequently, the expression of MKP-1 was increased, which led to the decrease in p-EKR and p-p38. Both PDE3B silencing and the pharmacological inhibition of cAMP/PKA compromised the suppressive effect of SAS on MCP-1. In addition to PDE3B, the PDE3A and PDE4B activity was also inhibited by SAS. Our findings identify a previously unrecognized pathway through which SAS is capable of attenuating the inflammation of adipocytes.

Changes in Attitudes and Confidence in the Integration of Psychiatry in Other Areas of Medicine.

OBJECTIVE: The authors describe how attitudes and confidence in the integration of psychiatry into other areas of medicine change over time during clinical clerkship in medical school. METHODS: From January 2015 to December 2016, medical students from the University of Iowa were recruited for a prospective study of changes in the Attitudes and Confidence in the Integration of Psychiatry Scale (ACIP) scale. The survey instrument was completed before their psychiatry clerkship, after the clerkship, and at the end of the year following that and other clinical clerkships. Other information such as gender, time spent in clerkship, USMLE Step 1 score, and clerkship grades was also collected. RESULTS: A total of 172 surveys were completed by 138 students. The ACIP score was significantly higher at the end of the participants' clinical clerkship (67.2 to 76.6; t=-7.72, p<0.0001). Of the two ACIP subscales, confidence increased significantly (25.6 to 33.3; t=-9.82, p<0.0001), but attitudes toward integration of psychiatry did not (41.7 to 43.4; t=-1.96, p=0.059). Similar findings were seen in the subset of 34 students for whom pre- and post-clerkship data could be matched. CONCLUSIONS: At the end of their clinical clerkship, medical students feel more confident providing psychiatric care. The lack of significant increase in the ACIP scale's attitude subscale either demonstrates that attitude scores going into clerkship were already high and did not deteriorate, or highlights an area for clerkship curriculum development.

Highly Controllable Hierarchically Porous Ag/Ag2 S Heterostructure by Cation Exchange for Efficient Hydrogen Evolution.

Establishing the hierarchical porous architectures has been considered to be the most efficient approach to realize the efficient mass diffusion and large exposed active sites of designed micro/nanomaterial catalysts for hydrogen evolution reactions (HER). In this work, the nonequivalent cation exchange strategy is developed to fabricate the hierarchically porous Ag/Ag2 S heterostructure based on the rapid cation exchange by the metal-organic framework (MOF)-derived CoS. The as-prepared Ag/Ag2 S inherits the original 3D hollow morphology of CoS with porous nature, possessing abundant S-vacancies and lattice strain simultaneously due to the coordination loss and in-situ epitaxial growth of metallic Ag on the surface. Owing to the optimizations of lattice and electronic structures, the unique hierarchically porous Ag/Ag2 S heterostructure exhibits superior catalytic performance than previously reported catalysts derived from MOF. Theoretical calculations have confirmed that the co-existence of Ag cluster and sulfur vacancies activates the electroactivity of the interfacial defective region to boost the HER process. The binding strength of the proton and energetic trend of HER has been optimized with the formation of Ag/Ag2 S heterostructure, which guarantees the efficient generation of H2 . This study opens a new strategy for the utilization of the nonequivalent cation exchange strategy to efficiently synthesize advanced electrocatalysts with high performances.

A randomized controlled trial for symptoms of anxiety and depression: Effects of a 1-day acceptance and commitment training workshop.

BACKGROUND: Cognitive-behavioral therapies often are recommended for anxiety disorders. However, treatment adherence and compliance are major barriers for these treatments, which are often delivered in 10 to 12 sessions over several months. This randomized controlled trial (trial registration NCT02915874 at www.clinicaltrials.gov) examined the effectiveness and feasibility of a 1-day cognitive-behavioral intervention for mixed anxiety. METHODS: A total of 72 adults with moderate-to-high anxiety were randomized into a 1-day acceptance and commitment therapy (ACT) work-shop (n = 44) or treatment as usual (n = 28). Follow-up assessments were conducted 6 and 12 weeks after the workshop. Clinical outcomes were anxiety (primary) and depressive (secondary) symptoms, as measured by the Beck Anxiety Inventory and Beck Depression Inventory-II, respectively. Proposed mediators of ACT-psychological flexibility and commit-ted action-also were examined. RESULTS: Participants assigned to the ACT workshop showed significant improvements in anxiety (beta = -1.13; P = .02) and depression (beta = -1.09; P = .02) after 12 weeks. Consistent with the theoretical model, these clinical improvements were mediated by psychological flexibility and committed action. Notable limitations included the sample size, inability to blind to treatment condition, and a racially and ethnically homogeneous sample. CONCLUSIONS: Our 1-day ACT workshop was effective for anxiety with co-occurring depressive symptoms. One-day interventions are a promising alternative to weekly treatments.

Light Pollution Changes the Toxicological Effects of Cadmium on Microbial Community Structure and Function Associated with Leaf Litter Decomposition.

Artificial light at night (ALAN/A) can not only alter the behavior and communication of biological organisms, it can also interact with other stressors. Despite its widespread use and the numerous potential ecological effects, little is known about the impact of ALAN on plant litter decomposition under cadmium (Cd) pollution in aquatic ecosystems. In an indoor microcosm experiment, we tested single and combined effects of ALAN and Cd on the activities and community structure of fungi associated with plant litter. The results showed that ALAN and/or Cd can change both water and leaf litter characteristics. ALAN exposure not only altered fungal community structure and their correlations, but also increased the activities of alkaline phosphatase, ß-glucosidase, and cellobiohydrolase. The leaf litter decomposition rate was 71% higher in the A-Cd treatment than that in the N-Cd treatment, indicating that the presence of ALAN weakened the negative impact of Cd on leaf litter decomposition. These results suggested that ALAN exposure mitigated the negative effect of Cd on leaf litter decomposition, contributing to the duel effect of ALAN on leaf litter decomposition. Overall, the results expand our understanding of ALAN on the environment and highlight the contribution of ALAN to Cd toxicity in aquatic ecosystems.

The three members of the Vav family proteins form complexes that concur to foam cell formation and atherosclerosis.

During foam cell formation and atherosclerosis development, the scavenger receptor CD36 plays critical roles in lipid uptake and triggering of atherogenicity via the activation of Vav molecules. The Vav family includes three highly conserved members known as Vav1, Vav2, and Vav3. As Vav1 and Vav3 were found to exert function in atherosclerosis development, it remains thus to decipher whether Vav2 also plays a role in the development of atherosclerosis. In this study we found that Vav2 deficiency in RAW264.7 macrophages significantly diminished oxidized LDL uptake and CD36 signaling, demonstrating that each Vav protein family member was required for foam cell formation. Genetic disruption of Vav2 in ApoE-deficient C57BL/6 mice significantly inhibited the severity of atherosclerosis. Strikingly, we further found that the genetic deletion of each member of the Vav protein family by CRISPR/Cas9 resulted in a similar alteration of transcriptomic profiles of macrophages. The three members of the Vav proteins were found to form complexes, and genetic ablation of each single Vav molecule was sufficient to prevent endocytosis of CD36. The functional interdependence of the three Vav family members in foam cell formation was due to their indispensable roles in transcriptomic programing, lipid uptake, and activation of the JNK kinase in macrophages.

Changes in inflammation with treatment for bipolar II depression: Pilot trial data on differential effects of psychotherapy and medication.

OBJECTIVES: Limited prospective data, mostly focused on bipolar I disorder, suggests that pro-inflammatory cytokines are elevated in abnormal mood states. We evaluated whether treatment normalizes peripheral markers of inflammation in bipolar II disorder. METHODS: Using data from a randomized clinical trial of Interpersonal and Social Rhythm Therapy (IPSRT) + quetiapine vs. IPSRT + placebo for bipolar II depression, we examined whether these treatments for bipolar II depression impact inflammatory cytokines and whether observed changes in cytokines are associated with changes in depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD-17). RESULTS: Cytokine values were available for 33 participants who completed baseline and 20-week followup visits. After excluding those with CRP values >=10 mg/L, there were 27 patients available for analysis (IPSRT+quetiapine N=10, IPSRT+placebo N=17). Baseline measure of inflammation did not appear to moderate treatment response, nor was change in HRSD-17 score correlated with changes in cytokines. Those who received IPSRT+quetiapine had significantly greater increases in IL-6 (p=0.02) and TNF-α (p=0.04), even after adjusting for changes in body mass index, than the IPSRT alone group. Descriptively, the quetiapine group showed increases in pro-inflammatory and decreases in anti-inflammatory cytokines and the psychotherapy group showed reduced pro-inflammatory cytokines. CONCLUSIONS: Despite both groups showing depression improvement, this small study suggests a more pro-inflammatory cytokine profile over time with quetiapine plus psychotherapy compared to psychotherapy alone. Elevated risk of cardiovascular morbidity and mortality among those with bipolar II disorder underscores the importance of delivering treatments that do not exacerbate these risk factors.