Helicobacter hepaticus promotes liver fibrosis through oxidative stress induced by hydrogenase in BALB/c mice.

BACKGROUND: It has been documented that Helicobacter hepaticus produces a nickel-containing hydrogen-oxidizing hydrogenase enzyme, which is necessary for hydrogen-supported amino acid uptake. Although H. hepaticus infection has been shown to promote liver inflammation and fibrosis in BALB/c mice, the impact of hydrogenase on the progression of liver fibrosis induced by H. hepaticus has not been explored. MATERIALS AND METHODS: BALB/c mice were inoculated with hydrogenase mutant (ΔHyaB) or wild type (WT) H. hepaticus 3B1 for 12 and 24 weeks. H. hepaticus colonization, hepatic histopathology, serum biochemistry, expression of inflammatory cytokines, and oxidative stress signaling pathways were detected. RESULTS: We found that ΔHyaB had no influence on the colonization of H. hepaticus in the liver of mice at 12 and 24 weeks post infection (WPI). However, mice infected by ΔHyaB strains developed significantly alleviated liver inflammation and fibrosis compared with WT infection. Moreover, ΔHyaB infection remarkably increased the expression of hepatic GSH, SOD, and GSH-Px, and decreased the liver levels of MDA, ALT, and AST compared to WT H. hepaticus infected group from 12 to 24 WPI. Furthermore, mRNA levels of Il-6, Tnf-α, iNos, Hmox-1, and α-SMA were significantly decreased with an increase of Nfe2l2 in the liver of mice infected by ΔHyaB strains. In addition, ΔHyaB H. hepaticus restored the activation of the Nrf2/HO-1 signaling pathway, which is inhibited by H. hepaticus infection. CONCLUSIONS: These data demonstrated that H. hepaticus hydrogenase promoted liver inflammation and fibrosis development mediated by oxidative stress in male BALB/c mice.

Apoptosis triggered by cytolethal distending toxin B subunit of Helicobacter hepaticus is aggravated by autophagy inhibition in mouse hepatocytes.

Hepatocytes injury caused by cytolethal distending toxin (CDT) are major events during helicobacter hepaticus (H.hepaticus) infection. Recent study showed that pre-survival autophagy was promoted against CdtB subunit induced DNA damage. In the present study, we demonstrated that inflammatory cytokines IL-6, IL-1ß, TNF-α, IFN-α, IFN-γ expression and STAT phosphorylation were promoted by CdtB. Besides, CdtB decreased cell viability while promote apoptosis in mouse liver (AML12) cells. Especially, apoptotic protein caspase-9, caspase-3 and PARP were activated while the ratio of Bcl-2/Bax was decreased after CdtB treatment. Moreover, apoptosis induced by CdtB was inhibited due to Erk/p38 MAPK signaling pathway suppression performed with SB203580 or U0126. Meanwhile, we found that CdtB increased autophagic marker levels accompanied by Akt/mTOR/P70S6K signaling pathway in a dose dependent manner. To assess the correlation between autophagy and apoptosis induced by H.hepaticus, chloroquine (CQ, 50 µM) was employed to inhibit autophagy. The result showed that inhibition of autophagy with CQ treatment promoted apoptosis induced by CdtB. Altogether, all these results suggest that CdtB triggers apoptosis via MAPK/Erk/p38 signaling pathway in caspase dependent manner, which was prevented by autophagy in AML12 cells. Collectively, our findings provide new insights into the virulence potential of CdtB on the molecular pathogenesis throughout H.hepaticus infection.

Helicobacter hepaticus Induce Colitis in Male IL-10-/- Mice Dependent by Cytolethal Distending Toxin B and via the Activation of Jak/Stat Signaling Pathway.

It has been well documented that cytolethal distending toxin (CDT) from Helicobacter hepaticus (H. hepaticus), Campylobacter jejuni (C. jejuni) and other Gram-negative intestinal pathogens is linked to the inflammatory bowel disease (IBD). However, the mechanisms underlying the progression of H. hepaticus induced colitis remains unclear. In this study, male B6.129P2-IL10tm1Cgn /J mice were infected by H. hepaticus and ΔCdtB H. hepaticus for 6, 12, 18, and 24 weeks. Histopathology, H. hepaticus colonization levels, expression of inflammatory cytokines, signaling pathways, and content of NO in proximal colon were examined. We found that Cytolethal distending toxin subunit B (CdtB) deletion had no influence on colonization ability of H. hepaticus in colon of B6.129P2-IL10tm1cgn/J mice, and there was no significant difference in abundance of colonic H. hepaticus over infection duration. H. hepaticus aggravated rectocele and proximal colonic inflammation, especially at 24 WPI, while ΔCdtB H. hepaticus could not cause significant symptom. Furthermore, mRNA levels of Il-6, Tnf-α, Il-1ß, and iNOS significantly increased in the proximal colon of H. hepaticus-infected mice compared to ΔCdtB H. hepaticus infected group from 12 WPI to 24 WPI. In addition, the elevated content of NO and activated Stat3 and Jak2 in colon were observed in H. hepaticus infected mice. These data demonstrated that CdtB promote colitis development in male B6.129P2-IL10tm1Cgn /J mice by induction of inflammatory response and activation of Jak-Stat signaling pathway.

Helicobacter hepaticus Infection Promotes the Progression of Liver Preneoplasia in BALB/c Mice via the Activation and Accumulation of High-Mobility Group Box-1.

It has been documented that Helicobacter hepaticus (H. hepaticus) infection is linked to chronic hepatitis and fibrosis in male BALB/c mice. However, the mechanism underlying the mice model of H. hepaticus-induced hepatocellular carcinoma is not fully known. In this study, male BALB/c mice were infected with H. hepaticus for 3, 6, 12, and 18 months. H. hepaticus colonization, histopathology, expression of proinflammatory cytokines, key signaling pathways, and protein downstream high-mobility group box-1 (HMGB1) in the liver were examined. Our data suggested that the H. hepaticus colonization level in the colon and liver progressively increased over the duration of the infection. H. hepaticus-induced hepatic inflammation and fibrosis were aggravated during the infection, and hepatic preneoplasia developed in the liver of infected mice at 12 and 18 months post-inoculation (MPI). H. hepaticus infection increased the levels of alanine aminotransferase and aspartate aminotransferase in the infected mice. In addition, the mRNA levels of IL-6, Tnf-α, Tgf-ß, and HMGB1 were significantly elevated in the liver of H. hepaticus-infected mice from 3 to 18 MPI as compared to the controls. In addition, Ki67 was increased throughout the duration of the infection. Furthermore, HMGB1 protein was activated and translocated from the nucleus to the cytoplasm in the hepatocytes and activated the proteins of signal transducers and activators of transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) [extracellular regulated protein kinases 1/2 (Erk1/2) and mitogen-activated protein kinase p38 (p38)] upon H. hepaticus infection. In conclusions, these data demonstrated that male BALB/c mice infected with H. hepaticus are prone to suffering hepatitis and developing into hepatic preneoplasia. To verify the effect of HMGB1 in the progression of liver preneoplasia, mice were infected by H. hepaticus for 2 months before additional HMGB1 recombinant adenovirus treatment. All mice were sacrificed at 4 MPI, and the sera and liver tissues from all of the mice were collected. Immunology and histopathology evaluation showed that HMGB1 knockdown attenuated the H. hepaticus-induced hepatic and fibrosis at 4 MPI. Therefore, we showed that H. hepaticus-induced liver preneoplasia is closely correlated with the activation and accumulation of HMGB1.

Helicobacter hepaticus infection-induced IL-33 promotes hepatic inflammation and fibrosis through ST2 signaling pathways in BALB/c mice.

It has been documented that Helicobacter hepaticus (H. hepaticus) infection is linked to hepatic inflammation and fibrosis. Interleukin 33 (IL-33) is a cytokine involved in inflammatory and fibrotic diseases, but its relevance to H. hepaticus infection-induced liver inflammation and fibrosis is unknown. In this study, we found that the expression of IL-33 in mice liver was significantly induced by H. hepaticus infection at 24 weeks post infection (WPI). Immunohistochemistry analysis revealed that IL-33 was transferred from the nucleus to the cytoplasm due to infection. The quantitation of inflammatory cytokine and histopathology evaluation showed that IL-33 knockdown attenuated the H. hepaticus-induced hepatic inflammation and fibrosis. More importantly, H. hepaticus promoted the expression of the IL-33 receptor ST2 on cell surfaces, and the expression of ST2 then activated the expression nuclear factor-κB (p65), α-SMA, and Erk1/2. These observations provide novel insights into the pathogenic mechanism of hepatic inflammation and fibrosis during H. hepaticus infection.

Helicobacter hepaticus infection induces chronic hepatitis and fibrosis in male BALB/c mice via the activation of NF-κB, Stat3, and MAPK signaling pathways.

BACKGROUND: It has been documented that Helicobacter hepaticus (H hepaticus) infection is linked to chronic hepatitis and liver cancer. However, our understanding of the molecular mechanisms underlying progression of the H hepaticus-induced hepatic inflammation to cellular hepatocarcinoma is still limited. MATERIALS AND METHODS: In our study, male BALB/c mice were infected by H hepaticus for 8, 12, 16, 20, and 24 weeks. Histopathology, H hepaticus colonization dynamics, select signaling pathways, and expression of key inflammatory cytokines in the liver were examined. RESULTS: We found that H hepaticus was detectible in feces of mice at 7 days postinfection (DPI) by PCR, but it was not detected in the livers by PCR until 8 weeks postinfection (WPI). In addition, abundance of colonic and hepatic H hepaticus was progressively increased over the infection duration. H hepaticus-induced hepatic inflammation and fibrosis were aggravated over the infection duration, and necrosis or cirrhosis developed in the infected liver at 24 WPI H hepaticus infection increased levels of alanine aminotransferase and aspartate aminotransferase. Moreover, mRNA levels of Il-6 and Tnf-α were significantly elevated in the livers of H hepaticus-infected mice compared to uninfected control from 8 WPI to 24 WPI. Furthermore, Stat3, nuclear factor-κB (p65), and MAPK (Erk1/2 and p38) were activated by H hepaticus infection. CONCLUSIONS: These data demonstrated that male BALB/c mice can be used as a new mouse model of H hepaticus-induced liver diseases and that the H hepaticus-induced liver injury is triggered by NF-κB, Jak-Stat, and MAPK signaling pathways.

Mr2DNM: A Novel Mutual Information-Based Dendritic Neuron Model.

By employing a neuron plasticity mechanism, the original dendritic neuron model (DNM) has been succeeded in the classification tasks with not only an encouraging accuracy but also a simple learning rule. However, the data collected in real world contain a lot of redundancy, which causes the process of analyzing data by DNM become complicated and time-consuming. This paper proposes a reliable hybrid model which combines a maximum relevance minimum redundancy (Mr2) feature selection technique with DNM (namely, Mr2DNM) for classifying the practical classification problems. The mutual information-based Mr2 is applied to evaluate and rank the most informative and discriminative features for the given dataset. The obtained optimal feature subset is used to train and test the DNM for classifying five different problems arisen from medical, physical, and social scenarios. Experimental results suggest that the proposed Mr2DNM outperforms DNM and other six classification algorithms in terms of accuracy and computational efficiency.

Extraction and identification of noise patterns for ultracold atoms in an optical lattice.

To extract useful information about quantum effects in cold atom experiments, one central task is to identify the intrinsic fluctuations from extrinsic system noises of various kinds. As a data processing method, principal component analysis can decompose fluctuations in experimental data into eigenmodes, and give a chance to separate noises originated from different physical sources. In this paper, we demonstrate for Bose-Einstein condensates in one-dimensional optical lattices that the principal component analysis can be applied to time-of-flight images to successfully separate and identify noises from different origins of leading contribution, and can help to reduce or even eliminate noises via corresponding data processing procedures. The attribution of noise modes to their physical origins is also confirmed by numerical analysis within a mean-field theory. As the method does not rely on any a priori knowledge of the system properties, it is potentially applicable to the study of other quantum states and quantum critical regions.

ERK-mediated autophagy promotes inactivated Sendai virus (HVJ-E)-induced apoptosis in HeLa cells in an Atg3-dependent manner.

BACKGROUND: Apoptosis and autophagy are known to play important roles in cancer development. It has been reported that HVJ-E induces apoptosis in cancer cells, thereby inhibiting the development of tumors. To define the mechanism by which HVJ-E induces cell death, we examined whether HVJ-E activates autophagic and apoptotic signaling pathways in HeLa cells. METHODS: Cells were treated with chloroquine (CQ) and rapamycin to determine whether autophagy is involved in HVJ-E-induced apoptosis. Treatment with the ERK inhibitor, U0126, was used to determine whether autophagy and apoptosis are mediated by the ERK pathway. Activators of the PI3K/Akt/mTOR/p70S6K pathway, 740 Y-P and SC79, were used to characterize its role in HVJ-E-induced autophagy. siRNA against Atg3 was used to knock down the protein and determine whether it plays a role in HVJ-E-induced apoptosis in HeLa cells. RESULTS: We found that HVJ-E infection inhibited cell viability and induced apoptosis through the mitochondrial pathway, as evidenced by the expression of caspase proteins. This process was promoted by rapamycin treatment and inhibited by CQ treatment. HVJ-E-induced autophagy was further blocked by 740 Y-P, SC79, and U0126, indicating that both the ERK- and the PI3K/Akt/mTOR/p70S6K-pathways were involved. Finally, autophagy-mediated apoptosis induced by HVJ-E was inhibited by siRNA-mediated Atg3 knockdown. CONCLUSION: In HeLa cells, HVJ-E infection triggered autophagy through the PI3K/Akt/mTOR/p70S6K pathway in an ERK1/2-dependent manner, and the induction of autophagy promoted apoptosis in an Atg3-dependent manner.

Voice-associated static face image releases speech from informational masking.

In noisy, multipeople talking environments such as a cocktail party, listeners can use various perceptual and/or cognitive cues to improve recognition of target speech against masking, particularly informational masking. Previous studies have shown that temporally prepresented voice cues (voice primes) improve recognition of target speech against speech masking but not noise masking. This study investigated whether static face image primes that have become target-voice associated (i.e., facial images linked through associative learning with voices reciting the target speech) can be used by listeners to unmask speech. The results showed that in 32 normal-hearing younger adults, temporally prepresenting a voice-priming sentence with the same voice reciting the target sentence significantly improved the recognition of target speech that was masked by irrelevant two-talker speech. When a person's face photograph image became associated with the voice reciting the target speech by learning, temporally prepresenting the target-voice-associated face image significantly improved recognition of target speech against speech masking, particularly for the last two keywords in the target sentence. Moreover, speech-recognition performance under the voice-priming condition was significantly correlated to that under the face-priming condition. The results suggest that learned facial information on talker identity plays an important role in identifying the target-talker's voice and facilitating selective attention to the target-speech stream against the masking-speech stream.

Temporally pre-presented lipreading cues release speech from informational masking.

Listeners can use temporally pre-presented content cues and concurrently presented lipreading cues to improve speech recognition under masking conditions. This study investigated whether temporally pre-presented lipreading cues also unmask speech. In a test trial, before the target sentence was co-presented with the masker, either target-matched (priming) lipreading video or static face (priming-control) video was presented in quiet. Participants' target-recognition performance was improved by a shift from the priming-control condition to the priming condition when the masker was speech but not noise. This release from informational masking suggests a combined effect of working memory and cross-modal integration on selective attention to target speech.

Aging effects on detection of spectral changes induced by a break in sound correlation.

OBJECTIVES: Previous studies have shown that both younger adults and older adults with clinically normal hearing are able to detect a break in correlation (BIC) between interaurally correlated sounds presented over headphones. This ability to detect a BIC improved when the correlated sounds were presented over left and right loudspeakers rather than over left and right headphones, suggesting that additional spectral cues provided by comb filtering (caused by interference between the two channels) facilitate detection of the BIC. However, older adults receive significantly less benefit than younger adults from a switch to loudspeaker presentation. It is hypothesized that this is a result of an age-related reduction in the sensitivity to the monaural spectral cues provided by comb filtering. DESIGN: Two experiments were conducted in this study. Correlated white noises with a BIC in the temporal middle were presented from two spatially separated loudspeakers (positioned at ±45-degree azimuth) and recorded at the right ear of a Knowles Electronic Manikin for Acoustic Research (KEMAR). In Experiment 1, the waveforms recorded at the KEMAR's right ear were presented to the participant's right ear over a headphone in 14 younger adults and 24 older adults with clinically normal hearing. In Experiment 2, 8 of the 14 younger participants participated. Under the monaurally cueing condition, the waveforms recorded at the KEMAR's right ear were presented to the participant's right ear as Experiment 1. Under the binaurally cueing condition, waveforms delivered from the left loudspeaker and those from the right loudspeaker were recorded at the KEMAR's left and right ear, respectively, thereby eliminating the spectral ripple cue, and were presented to the participant's left and right ears, respectively. For each of the two experiments, the break duration threshold for detecting the BIC was examined when the interloudspeaker interval (delay) (ILI) was 0, 1, 2, or 4 msec (left loudspeaker leading). RESULTS: In Experiment 1, both younger participants and older participants detected the BIC in the waveforms recorded by the right ear of KEMAR, but older participants had higher detection thresholds than younger participants when the ILI was 0, 2, or 4 msec without an effect of SPL shift between 59 and 71 dB. In Experiment 2, each of the eight younger participants was able to detect the occurrence of the BIC in either the monaurally cueing or binaural-cueing condition. In addition, the detection threshold under the monaurally cueing condition was substantially the same as that under the binaurally cueing condition at each of the four ILIs. CONCLUSIONS: Younger adults and older adults with clinically normal hearing are able to detect the monaural spectral changes arising from comb filtering when a sudden drop in intersound correlation is introduced. However, younger adults are more sensitive than older adults are, at detecting the BIC. The findings suggest that older adults are less able than younger adults to detect a periodic ripple in the sound spectrum. This age-related ability reduction may contribute to older adults' difficulties in hearing under noisy, reverberant conditions.

Masking of speech in people with first-episode schizophrenia and people with chronic schizophrenia.

In "cocktail-party" environments, although listeners feel it difficult to recognize attended speech due to both energetic masking and informational masking, they can use various perceptual/cognitive cues, such as content and voice primes, to facilitate their attention to target speech. In patients with schizophrenia, both speech-perception deficits and increased vulnerability to masking stimuli generally occur. This study investigated whether speech recognition in first-episode patients (FEPs) and chronic patients (CPs) of schizophrenia is more vulnerable to noise masking and/or speech masking than that in demographics-matched-healthy controls, and whether patients with schizophrenia can use primes to unmask speech. In a trial under the priming condition, before the target sentence containing three keywords was co-presented with a noise or speech masker, the prime (early part of the sentence including the first two keywords) was recited in quiet with the target-speaker's voice. The results show that in patients, target-speech recognition was more impaired under speech-masking conditions than noise-masking conditions, and the impairment in CPs (n=22) was larger than that in FEPs (n=12). Although working memory for holding prime-content information in patients, especially CPs, was more vulnerable to masking, especially speech masking, than that in healthy controls, patients were still able to use the prime to unmask the last keyword. Thus, in "cocktail-party" environments, speech recognition in people with schizophrenia is more vulnerable to masking, particularly informational masking, and the speech-recognition impairment augments as the illness progresses. However, people with schizophrenia can use the content/voice prime to reduce energetic masking and informational masking of target speech.

Improvement of intelligibility of ideal binary-masked noisy speech by adding background noise.

When a target-speech/masker mixture is processed with the signal-separation technique, ideal binary mask (IBM), intelligibility of target speech is remarkably improved in both normal-hearing listeners and hearing-impaired listeners. Intelligibility of speech can also be improved by filling in speech gaps with un-modulated broadband noise. This study investigated whether intelligibility of target speech in the IBM-treated target-speech/masker mixture can be further improved by adding a broadband-noise background. The results of this study show that following the IBM manipulation, which remarkably released target speech from speech-spectrum noise, foreign-speech, or native-speech masking (experiment 1), adding a broadband-noise background with the signal-to-noise ratio no less than 4 dB significantly improved intelligibility of target speech when the masker was either noise (experiment 2) or speech (experiment 3). The results suggest that since adding the noise background shallows the areas of silence in the time-frequency domain of the IBM-treated target-speech/masker mixture, the abruption of transient changes in the mixture is smoothed and the perceived continuity of target-speech components becomes enhanced, leading to improved target-speech intelligibility. The findings are useful for advancing computational auditory scene analysis, hearing-aid/cochlear-implant designs, and understanding of speech perception under "cocktail-party" conditions.