Neurocomputational mechanisms underlying fear-biased adaptation learning in changing environments.

Humans are able to adapt to the fast-changing world by estimating statistical regularities of the environment. Although fear can profoundly impact adaptive behaviors, the computational and neural mechanisms underlying this phenomenon remain elusive. Here, we conducted a behavioral experiment (n = 21) and a functional magnetic resonance imaging experiment (n = 37) with a novel cue-biased adaptation learning task, during which we simultaneously manipulated emotional valence (fearful/neutral expressions of the cue) and environmental volatility (frequent/infrequent reversals of reward probabilities). Across 2 experiments, computational modeling consistently revealed a higher learning rate for the environment with frequent versus infrequent reversals following neutral cues. In contrast, this flexible adjustment was absent in the environment with fearful cues, suggesting a suppressive role of fear in adaptation to environmental volatility. This suppressive effect was underpinned by activity of the ventral striatum, hippocampus, and dorsal anterior cingulate cortex (dACC) as well as increased functional connectivity between the dACC and temporal-parietal junction (TPJ) for fear with environmental volatility. Dynamic causal modeling identified that the driving effect was located in the TPJ and was associated with dACC activation, suggesting that the suppression of fear on adaptive behaviors occurs at the early stage of bottom-up processing. These findings provide a neuro-computational account of how fear interferes with adaptation to volatility during dynamic environments.

Evaluation and Prognostication of Gd-EOB-DTPA MRI and CT in Patients With Macrotrabecular-Massive Hepatocellular Carcinoma.

BACKGROUND: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is highly aggressive. Comparing the diagnosis ability of CT and gadoxetate disodium (Gd-EOB-DTPA) MRI for MTM-HCC are lacking. PURPOSE: To compare the performance of Gd-EOB-DTPA MRI and CT for differentiating MTM-HCC from non-MTM-HCC, and determine the prognostic indicator. STUDY TYPE: Retrospective. SUBJECTS: Post-surgery HCC patients, divided into the training (N = 272) and external validation (N = 44) cohorts. FIELD STRENGTH/SEQUENCE: 3.0 T, T1-weighted imaging, in-opp phase, and T1-weighted volumetric interpolated breath-hold examination/liver acquisition with volume acceleration; enhanced CT. ASSESSMENT: Three radiologists evaluated clinical characteristics (sex, age, liver disease, liver function, blood routine, alpha-fetoprotein [AFP] and prothrombin time international normalization ratio [PT-INR]) and imaging features (tumor length, intratumor fat, hemorrhage, arterial phase peritumoral enhancement, intratumor necrosis or ischemia, capsule, and peritumoral hepatobiliary phase [HBP] hypointensity). Compared the performance of CT and MRI for diagnosing MTM-HCC. Follow-up occurred every 3-6 months, and nomogram demonstrated the probability of MTM-HCC. STATISTICAL TESTS: Fisher test, t-test or Wilcoxon rank-sum test, area under the curve (AUC), 95% confidence interval (CI), multivariable logistic regression, Kaplan-Meier curve, and Cox proportional hazards. Significance level: P < 0.05. RESULTS: Gd-EOB-DTPA MRI (AUC: 0.793; 95% CI, 0.740-0.839) outperformed CT (AUC: 0.747; 95% CI, 0.691-0.797) in the training cohort. The nomogram, incorporating AFP, PT-INR, and MRI features (non-intratumor fat, incomplete capsule, intratumor necrosis or ischemia, and peritumoral HBP hypointensity) demonstrated powerful performance for diagnosing MTM-HCC with an AUC of 0.826 (95% CI, 0.631-1.000) in the external validation cohort. Median follow-up was 347 days (interquartile range [IQR], 606 days) for the training cohort and 222 days (IQR, 441 days) for external validation cohort. Intratumor necrosis or ischemia was an independent indicator for poor prognosis. DATA CONCLUSION: Gd-EOB-DTPA MRI might assist in preoperative diagnosis of MTM-HCC, and intratumor necrosis or ischemia was associated with poor prognosis. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Neuroprotective Effects of Dammarane Sapogenins Against lipopolysaccharide-induced Cognitive Impairment, Neuroinflammation and Synaptic Dysfunction.

Neuroinflammation is a critical driver in the pathogenesis and progression of neurodegenerative disorders. Dammarane sapogenins (DS), a deglycosylated product of ginsenoside, possess a variety of potent biological activities. The present study aimed to explore the neuroprotective effects of DS in a rat model of neuroinflammation induced by intracerebroventricular injection of lipopolysaccharide (LPS). Our study revealed that DS pretreatment effectively improved LPS-induced associative learning and memory impairments in the active avoidance response test and spatial learning and memory in Morris water maze test. DS also remarkably inhibited LPS-induced neuroinflammation by suppressing microglia overactivation, pro-inflammatory cytok ine release (TNF-α and IL-1ß) and reducing neuronal loss in the CA1 and DG regions of the hippocampus. Importantly, pretreatment with DS reversed LPS-induced upregulation of HMGB1 and TLR4 and inhibited their downstream NF-κB signaling activation, as evidenced by increased IκBα and decreased p-NF-κB p65 levels. Furthermore, DS ameliorated LPS-induced synaptic dysfunction by decreasing MMP-9 and increasing NMDAR1 expression in the hippocampus. Taken together, this study suggests that DS could be a promising treatment for preventing cognitive impairments caused by neuroinflammation.

Lactic acid bacteria promoted soil quality and enhanced phytoextraction of Cd and Zn by mustard: A trial for bioengineering of toxic metal contaminated mining soils.

Microbial-assisted phytoremediation provides a green approach for remediation of metal contaminated soils. However, the impacts of mono and co-applications of lactic acid bacteria (LAB) on soil biochemical properties and phytoavailability of toxic metals in contaminated mining soils have not yet been sufficiently examined. Consequently, here we studied the effects of Lactobacillus plantarum (P), Lactobacillus acidophilus (A), and Lactobacillus rhamnosus (R) applications alone and in combination on soil enzyme activities and bioavailability and uptake of Cd and Zn by mustard (Brassica juncea) in a smelter-contaminated soil under greenhouse conditions. Among the studied bacteria, P was the most tolerant to Cd-and-Zn contamination. As compared to control, R increased the fresh and dry weight of mustard plants by 53.5% and 63.2%, respectively. Co-application of P + A increased the chlorophyll content by 28.6%, as compared to control. Addition of LAB to soil increased the activity of soil urease, alkaline phosphatase and ß-D glucosidase increased by 1.86-fold (P + R), 1.80-fold (R) and 55.16% (P + R), respectively. Application of P + A + R enhanced catalase activity (19.3%) and superoxide dismutase activity (51.2%), while addition of A alone increased peroxidase activity (POD: 15.7%). Addition of P alone and together with A (P + A) enhanced Cd and Zn phytoextraction by mustard shoots up to 51.5% and 52.5%, respectively. We conclude that the single and/or co-application of LAB decreased soil pH, promoted plant growth, antioxidant and enzyme activities, and enhanced the phytoavailability of Cd and Zn in the studied contaminated soil. These findings might be an aid for enhancing the phytoremediation of Cd and Zn using LAB and mustard as a bioenergy crop, which may offer new ideas for field treatment of toxic metals contaminated soils.

Prefrontal control of social influence in risk decision making.

To optimize our decisions, we may change our mind by utilizing social information. Here, we examined how changes of mind were modulated by Social Misalignment Sensitivity (SMS), egocentric tendency, and decision preferences in a decision-making paradigm including both risk and social information. Combining functional magnetic resonance imaging with computational modeling, we showed that both SMS and egocentric tendency modulated changes of mind under the influence of social information. While SMS was represented in the dorsal anterior cingulate cortex (dACC) and superior parietal gyrus (SPG) in the socially aligned situation, a distributed brain network was activated in the misaligned condition, including not only the dACC and SPG but also superior frontal gyrus and precuneus. These results suggest that SMS is related to a monitoring brain system, the scope of which varies according to the level of misalignment with social majority. The dorsolateral prefrontal cortex selectively interacted with SMS among the participants with a low switching threshold, indicating that its regulation on SMS may be sensitive to inter-individual variation. Our findings highlight the predominant roles of SMS and the prefrontal control system towards changes of mind under social influence.

Mechanism of [CO2] Enrichment Alleviated Drought Stress in the Roots of Cucumber Seedlings Revealed via Proteomic and Biochemical Analysis.

Cucumber is one of the most widely cultivated greenhouse vegetables, and its quality and yield are threatened by drought stress. Studies have shown that carbon dioxide concentration ([CO2]) enrichment can alleviate drought stress in cucumber seedlings; however the mechanism of this [CO2] enrichment effect on root drought stress is not clear. In this study, the effects of different drought stresses (simulated with 0, 5% and 10% PEG 6000, i.e., no, moderate, and severe drought stress) and [CO2] (400 µmol·mol-1 and 800 ± 40 µmol·mol-1) on the cucumber seedling root proteome were analyzed using the tandem mass tag (TMT) quantitative proteomics method. The results showed that after [CO2] enrichment, 346 differentially accumulating proteins (DAPs) were found only under moderate drought stress, 27 DAPs only under severe drought stress, and 34 DAPs under both moderate and severe drought stress. [CO2] enrichment promoted energy metabolism, amino acid metabolism, and secondary metabolism, induced the expression of proteins related to root cell wall and cytoskeleton metabolism, effectively maintained the balance of protein processing and degradation, and enhanced the cell wall regulation ability. However, the extent to which [CO2] enrichment alleviated drought stress in cucumber seedling roots was limited under severe drought stress, which may be due to excessive damage to the seedlings.

Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease.

BACKGROUND: BTC is an aggressive disease exacerbated by inflammation and immune suppression. Expansion of immunosuppressive cells occurs in biliary tract cancer (BTC), yet the role of BTC-derived cytokines in this process is unclear. METHODS: Activated signalling pathways and cytokine production were evaluated in a panel of human BTC cell lines. Human peripheral blood mononuclear cells (PBMCs) were cultured with BTC supernatants, with and without cytokine neutralising antibodies, and analysed by flow cytometry or immunoblot. A human BTC tissue microarray (TMA, n = 69) was stained for IL-6, GM-CSF, and CD33+S100a9+ cells and correlated with clinical outcomes. RESULTS: Immunomodulatory factors (IL-6, GM-CSF, MCP-1) were present in BTC supernatants. BTC supernatants expanded CD33dimCD11b+HLA-DRlow/- myeloid-derived suppressor cells (MDSCs) from human PBMCs. Neutralisation of IL-6 and GM-CSF in BTC supernatants inhibited activation of STAT3/5, respectively, in PBMCs, with heterogeneous effects on MDSC expansion in vitro. Staining of a BTC TMA revealed a positive correlation between IL-6 and GM-CSF, with each cytokine and more CD33+S100a9+ cells. Increased CD33+S100a9+ staining positively correlated with higher tumour grade, differentiation and the presence of satellite lesions. CONCLUSION: BTC-derived factors promote suppressive myeloid cell expansion, and higher numbers of CD33+S100a9+ cells in resectable BTC tumours correlates with more aggressive disease.

Demographic Characteristics, Experiences, and Beliefs Associated with Hand Hygiene Among Adults During the COVID-19 Pandemic - United States, June 24-30, 2020.

Frequent hand hygiene, including handwashing with soap and water or using a hand sanitizer containing ≥60% alcohol when soap and water are not readily available, is one of several critical prevention measures recommended to reduce the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19).* Previous studies identified demographic factors associated with handwashing among U.S. adults during the COVID-19 pandemic (1,2); however, demographic factors associated with hand sanitizing and experiences and beliefs associated with hand hygiene have not been well characterized. To evaluate these factors, an Internet-based survey was conducted among U.S. adults aged ≥18 years during June 24-30, 2020. Overall, 85.2% of respondents reported always or often engaging in hand hygiene following contact with high-touch public surfaces such as shopping carts, gas pumps, and automatic teller machines (ATMs).† Respondents who were male (versus female) and of younger age reported lower handwashing and hand sanitizing rates, as did respondents who reported lower concern about their own infection with SARS-CoV-2§ and respondents without personal experience with COVID-19. Focused health promotion efforts to increase hand hygiene adherence should include increasing visibility and accessibility of handwashing and hand sanitizing materials in public settings, along with targeted communication to males and younger adults with focused messages that address COVID-19 risk perception.

ER-localized protein-Herpud1 is a new mediator of IL-4-induced macrophage polarization and migration.

ER-localized proteins have been reported function in endoplasmic reticulum, unfolded protein degradation and destruction of misfolded proteins by the ER-associated protein degradation (ERAD) system, but their function in the chemotaxis of macrophage cells remained un-addressed. Here, we showed that ER protein with ubiquitin like domain 1(Herpud1) was upregulated in IL-4-treated M2 macrophage cells and its expression pattern was similar with macrophage polarization markers, such as Arg1, Mrc1 and Fizz1. Inhibition of Herpud1 by using specific target shRNA decreased these marker's expression at mRNA and protein level in IL-4-treated or -untreated M2 macrophage cells. IL-4 treatment promoted M2 macrophage cell migration and polarization, but this promotion was weakened by Herpud1 depletion and we got similar results by inhibition of ER stress response with chemical molecule 4-phenylbutyric acid (4-PBA) in IL-4-treated or untreated-M2 macrophage cells with Herpud1 overexpression. These results indicated that depending on ER-associated protein degradation (ERAD) to help unfolded protein degradation or destruction is not the only function of Herpud1 and acting as a mediator of IL-4 induced macrophage activation and polarization maybe another unrevealed function, elucidating the role of Herpud1-associated M2 macrophage cell polarization and activation are helpful for exploration the function of macrophage cells in immune response.

Application of wood biochar in polluted soils stabilized the toxic metals and enhanced wheat (Triticum aestivum) growth and soil enzymatic activity.

Biochar is a stable carbonaceous by-product of pyrolysis and can be used for toxic metals (TMs) retention in polluted soil. Wheat (Triticum aestivum) was grown in three polluted soils collected from Chenzhou (CZ), Tongguan (TG) and Fengxian (FX), China. Wood biochar (WBC) was applied at 0, 0.5, 1.0 and 2.0% to each pot filled with 2 kg polluted soil. The results showed that WBC was efficient to alter soil pH and electrical conductivity (EC). The changes in soil pH and EC had a direct relationship with the immobilization and phytostabilization of TMs in the three soils. The bioavailable TMs (Zn, Pb, Cd, and Cu) were reduced in the soil after WBC amendments due to ion exchange, precipitates of metal-carbonates and metal-phosphates, and chemisorption on WBC surface. The reduction in the bioavailable TMs content also resulted in the diminution in TMs shoot uptake in wheat. Similarly, the TMs uptake in wheat root were also reduced as a result of WBC application. The reduction in bioavailable TMs and the release of essential nutrients and base cations from the WBC also increased the wheat shoot and root dry biomasses production. The application of WBC in polluted soil also improved soil health and the urease and ß-glucosidase enzymes were also enhanced. The results concluded that WBC was efficient to reduce the bioavailability of TMs and shoot and root uptake, improved wheat dry biomasses production and soil enzymatic activities in industrial and smelter/mines polluted soils.

Effects of crop straw and its derived biochar on the mobility and bioavailability in Cd and Zn in two smelter-contaminated alkaline soils.

In this study, comparative investigations on the effects of crop straw and its derived biochars on soil Cd and Zn mobility and availability were conducted. Crop straws (i.e. maize straw, rapeseed straw, and wheat straw) and their derived biochars were incubated with two contaminated alkaline soils (FX and TG soils) at 2.5% (w/w). The changes of soil properties like pH, EC, organic matter content, and dissolved organic matter content were investigated along with metal mobility, speciation distribution, and accumulation in ryegrass (Lolium multiflorum Lam.). Results indicated biochar, especially those were high in pH, enhanced soil pH (>0.2 units, p < 0.05), whereas a continuous reduction of soil pH was observed among treatments with crop straws. Both soil EC and the organic matter content increased with the application of both crop straws and biochars. In term of metals, Cd and Zn mobility were reduced with 6-14%/1-5% and 6-27%/7-15% reduction in the DTPA extractable Cd and Zn contents in TG and FX soil treatments, respectively. Moreover, distinct changes of metals in different fractions were also observed (acid soluble and reducible fraction → oxidizable fraction in straw treatments; acid soluble fraction → reducible soluble fraction in biochar amendments). Furthermore, the biological analysis revealed that the growth of ryegrass was promoted, but the accumulation of metals in ryegrass shoots was reduced, especially in MS700 treatment. Apart from the amendments, metal immobilization efficiencies were negatively correlated with the contamination status. Despite that, a higher rate of biochar application (>10%) could dramatically reduce the amount of available metal in soil extracts, except for Zn in FX soil treatments. This present work demonstrated that biochars, especially those produced at a higher temperature, are superior to crop straws to immobilize metals in soils. However, the remediation efficiencies were strongly restricted by soil pH and contamination status.

Metabolomics analysis reveals that elevated atmospheric CO2 alleviates drought stress in cucumber seedling leaves.

Elevated atmospheric CO2 alleviates moderate to severe drought stresses at physiological level in cucumber. To investigate the underlying metabolic mechanisms, cucumber seedlings were treated with two [CO2] and three water treatments combinations, and their leaves were analyzed using a non-targeted metabolomics approach. The results showed that elevated [CO2] changed 79 differential metabolites which were mainly associated with alanine, aspartate and glutamate metabolism; arginine and proline metabolism; TCA cycle; and glycerophospholipid metabolism under moderate drought stress. Moreover, elevated [CO2] promoted the accumulation of secondary metabolites; including isoferulic acid, m-coumaric acid and salicyluric acid. Under severe drought stress, elevated [CO2] changed 26 differential metabolites which mainly involved in alanine, aspartate and glutamate metabolism; pyruvate metabolism; arginine and proline metabolism; glyoxylate and dicarboxylate metabolism; cysteine and methionine metabolism; starch and sucrose metabolism; glycolysis or gluconeogenesis; and pyrimidine metabolism. In addition, elevated [CO2] accumulated carbohydrates, 1,2,3-trihydroxybenzene, pyrocatechol, glutamate, and l-gulonolactone, to allow adaption to severe drought. In conclusion, the metabolites and metabolic pathways associated with the alleviation of drought stresses by elevated [CO2] were different according to the level of drought stress. Our results may provide a theoretical basis for CO2 fertilization and application of exogenous metabolites to enhance drought tolerance of cucumber.

Involvement of JNK signaling in IL4-induced M2 macrophage polarization.

It has been generally accepted that alternatively activated macrophages (M2), which can be induced by type 2 cytokines such as IL-4, is responsible for tissue repair. However, the function of JNK in IL-4-induced M2 macrophage polarization remains unclear. Here, we demonstrated that M0 macrophages can be polarized into M2 status in response to IL-4 stimulation with the increased expression of the M2-specific molecular markers. We also found that IL-4 induced higher expression of JNK and transcription factor c-Myc in M2 macrophages. Our Q-PCR and Western blot results showed that JNK increased the expression of c-Myc and M2 markers Arg1, Mrc1. We also demonstrated c-Myc was the downstream of IL-4-JNK pathway. Further, the depletion of c-Myc, Arg1 and Mrc1 could inhibit the migration ability of M2 macrophages. Taken together, our data establishes a new role for JNK signaling in IL-4-induced alternative activation of macrophages and may provide a novel strategy for immune therapy.

Apobec-1 Complementation Factor (A1CF) Inhibits Epithelial-Mesenchymal Transition and Migration of Normal Rat Kidney Proximal Tubular Epithelial Cells.

Apobec-1 complementation factor (A1CF) is a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family, which participates in site-specific posttranscriptional RNA editing of apolipoprotein B (apoB) transcript. The posttranscriptional editing of apoB mRNA by A1CF in the small intestine is required for lipid absorption. Apart from the intestine, A1CF mRNA is also reported to be highly expressed in the kidneys. However, it is remained unknown about the functions of A1CF in the kidneys. The aim of this paper is to explore the potential functions of A1CF in the kidneys. Our results demonstrated that in C57BL/6 mice A1CF was weakly expressed in embryonic kidneys from E15.5dpc while strongly expressed in mature kidneys after birth, and it mainly existed in the tubules of inner cortex. More importantly, we identified A1CF negatively regulated the process of epithelial-mesenchymal transition (EMT) in kidney tubular epithelial cells. Our results found ectopic expression of A1CF up-regulated the epithelial markers E-cadherin, and down-regulated the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) in NRK52e cells. In addition, knockdown of A1CF enhanced EMT contrary to the overexpression effect. Notably, the two A1CF variants led to the similar trend in the EMT process. Taken together, these data suggest that A1CF may be an antagonistic factor to the EMT process of kidney tubular epithelial cells.

EIYMNVPV Motif is Essential for A1CF Nucleus Localization and A1CF (-8aa) Promotes Proliferation of MDA-MB-231 Cells via Up-Regulation of IL-6.

Apobec-1 complementation factor (A1CF) is a heterogeneous nuclear ribonuceloprotein (hnRNP) and mediates apolipoprotein-B mRNA editing. A1CF can promote the regeneration of the liver by post-transcriptionally stabilizing Interleukin-6 (IL-6) mRNA. It also contains two transcriptional variants-A1CF64 and A1CF65, distinguished by the appearance of a 24-nucleotide motif which contributes to the corresponding eight-amino acid motif of EIYMNVPV. For the first time, we demonstrated that the EIYMNVPV motif was essential for A1CF nucleus localization, A1CF deficient of the EIYMNVPV motif, A1CF (-8aa) showed cytoplasm distribution. More importantly, we found that A1CF (-8aa), but not its full-length counterpart, can promote proliferation of MDA-MB-231 cells accompanied with increased level of IL-6 mRNA. Furthermore, silencing of IL-6 attenuated A1CF (-8aa)-induced proliferation in MDA-MB-231 cells. In conclusion, notably, these findings suggest that A1CF (-8aa) promoted proliferation of MDA-MB-231 cells in vitro viewing IL-6 as a target. Thus, the EIYMNVPV motif could be developed as a potential target for basal-like breast cancer therapy.

Zeb1 Is a Potential Regulator of Six2 in the Proliferation, Apoptosis and Migration of Metanephric Mesenchyme Cells.

Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks. It has been reported that Zeb1 regulates the proliferation of mesenchymal cells in mouse embryos. However, the role of Zeb1 in nephrons generation is not clear, especially in metanephric mesenchyme (MM). Here, we detected cell proliferation, apoptosis and migration in MM cells by EdU assay, flow cytometry assay and wound healing assay, respectively. Meanwhile, Western and RT-PCR were used to measure the expression level of Zeb1 and Six2 in MM cells and developing kidney. Besides, the dual-luciferase assay was conducted to study the molecular relationship between Zeb1 and Six2. We found that knock-down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data. Western-blot and RT-PCR results showed that knock-down of Zeb1 decreased the expression of Six2 in MM cells and Zeb1 overexpression contributed to the opposite results. Similarly, Zeb1 promoted Six2 promoter reporter activity in luciferase assays. However, double knock-down of Zeb1 and Six2 did not enhance the apoptosis of MM cells compared with control cells. Nevertheless, double silence of Zeb1 and Six2 repressed cell proliferation. In addition, we also found that Zeb1 and Six2 had an identical pattern in distinct developing phases of embryonic kidney. These results indicated that there may exist a complicated regulation network between Six2 and Zeb1. Together, we demonstrate Zeb1 promotes proliferation and apoptosis and inhibits the migration of MM cells, in association with Six2.

Six2 Is a Coordinator of LiCl-Induced Cell Proliferation and Apoptosis.

The metanephric mesenchyme (MM) cells are a subset of kidney progenitor cells and play an essential role in mesenchymal-epithelial transition (MET), the key step of nephron generation. Six2, a biological marker related to Wnt signaling pathway, promotes the proliferation, inhibits the apoptosis and maintains the un-differentiation of MM cells. Besides, LiCl is an activator of Wnt signaling pathway. However, the role of LiCl in cellular regulation of MM cells remains unclear, and the relationship between LiCl and Six2 in this process is also little known. Here, we performed EdU assay and flow cytometry assay to, respectively, detect the proliferation and apoptosis of MM cells treated with LiCl of increasing dosages. In addition, reverse transcription-PCR (RT-PCR) and Western-blot were conducted to measure the expression of Six2 and some maker genes of Wnt and bone-morphogenetic-protein (BMP) signaling pathway. Furthermore, luciferase assay was also carried out to detect the transcriptional regulation of Six2. Then we found LiCl promoted MM cell proliferation at low-concentration (10, 20, 30, and 40 mM). The expression of Six2 was dose-dependently increased in low-concentration (10, 20, 30, and 40 mM) at both mRNA and protein level. In addition, both of cell proliferation and Six2 expression in MM cells declined when dosage reached high-concentration (50 mM). However, Six2 knock-down converted the proliferation reduction at 50 mM. Furthermore, Six2 deficiency increased the apoptosis of MM cells, compared with negative control cells at relative LiCl concentration. However, the abnormal rise of apoptosis at 30 mM of LiCl concentration implies that it might be the reduction of GSK3ß that increased cell apoptosis. Together, these demonstrate that LiCl can induce the proliferation and apoptosis of MM cells coordinating with Six2.

MiR542-3p Regulates the Epithelial-Mesenchymal Transition by Directly Targeting BMP7 in NRK52e.

Accumulating evidence demonstrated that miRNAs are highly involved in kidney fibrosis and Epithelial-Eesenchymal Transition (EMT), however, the mechanisms of miRNAs in kidney fibrosis are poorly understood. In this work, we identified that miR542-3p could promote EMT through down-regulating bone morphogenetic protein 7 (BMP7) expression by targeting BMP7 3'UTR. Firstly, real-time PCR results showed that miR542-3p was significantly up-regulated in kidney fibrosis in vitro and in vivo. Moreover, Western blot results demonstrated that miR542-3p may promote EMT in the NRK52e cell line. In addition, we confirmed that BMP7, which played a crucial role in anti-kidney fibrosis and suppressed the progression of EMT, was a target of miR542-3p through Dual-Luciferase reporter assay, as did Western blot analysis. The effects of miR542-3p on regulating EMT could also be suppressed by transiently overexpressing BMP7 in NRK52e cells. Taken together, miR542-3p may be a critical mediator of the induction of EMT via directly targeting BMP7.

The first case of Odoribacter splanchnicus bacteremia isolated from a patient in China.

Background: Odoribacter splanchnicus is an extremely rare pathogen of human infection. This case reports bacteremia infection of O. splanchnicus, which is highly likely to result in misdiagnosis if inappropriate diagnostic method are used. Case presentation: A 29-year-old Chinese male patient with no underlying disease was hospitalized twice for injuries caused by a car accident. During the second hospitalization, abdominal surgery was performed and high fever developed after the surgery. A strain of O. splanchnicus was isolated from the blood and confirmed by MALDI-TOF-MS and 16S rRNA gene analysis. Finally, the patient recovered successfully by using antibiotics, fluid replacement and albumin input. Conclusions: This is the first case of O. splanchnicus bacteremia in China. We present a brief review of the cases concerning O. splanchnicus infection in humans. O. splanchnicus, as part of the normal intestinal flora, is well known for its anti-tumor and immune regulating properties, it is rarely isolated from clinical samples. This case illustrates the potential of O. splanchnicus as a pathogen and suggests attention to the use of new and advanced methods like MALDI-TOF MS and 16S rRNA gene sequencing to identify rarely isolated species from clinical samples.

Syrosingopine and UK5099 synergistically suppress non-small cell lung cancer by activating the integrated stress response.

Non-small cell lung cancer (NSCLC) presents a global health challenge due to its low five-year survival rates, underscoring the need for novel therapeutic strategies. Our research explored the synergistic mechanisms of syrosingopine and UK-5099 in treating NSCLC. In vitro experiments showed that the combination of syrosingopine and UK-5099 significantly synergized to suppress NSCLC proliferation. Further experiments revealed that this combination induced cell cycle arrest and promoted apoptosis in NSCLC cells. In vivo experiments demonstrated that the combination of syrosingopine and UK-5099 markedly inhibited tumor growth. Mechanistic studies revealed that this drug combination promoted mitochondrial damage by inducing lactate accumulation and oxidative stress. Additionally, the combination triggered an integrated stress response (ISR) through the activation of heme-regulated inhibitor kinase (HRI). Importantly, our findings suggested that the synergistic suppression of NSCLC by syrosingopine and UK-5099 was dependent on ISR activation. In summary, our study proposed a promising therapeutic approach that involved the combination of Syrosingopine and UK-5099 to activate ISR, significantly hindering NSCLC growth and proliferation.