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ABSTRACTBackgroundDespite achieving endoscopic remission, over 20% of inflammatory bowel disease (IBD) patients experience chronic abdominal pain. Visceral pain and the microbiome exhibit sex-dependent interactions, while visceral pain in IBD shows a sex bias. Our aim was to evaluate whether post-inflammatory microbial perturbations contribute to visceral hypersensitivity in a sex-dependent manner.MethodsMales, cycling females, ovariectomized, and sham-operated females were given dextran sodium sulfate to induce colitis and allowed to recover. Germ-free recipients received sex-appropriate and cross-sex fecal microbial transplants (FMT) from post-inflammatory donor mice. Visceral sensitivity was assessed by recording visceromotor responses to colorectal distention. The composition of the microbiota was evaluated via 16S rRNA gene V4 amplicon sequencing, while the metabolome was assessed using targeted (short chain fatty acids – SCFA) and semi-targeted mass spectrometry.ResultsPost-inflammatory cycling females developed visceral hyperalgesia when compared to males. This effect was reversed by ovariectomy. Both post-inflammatory males and females exhibited increased SCFA-producing species, but only males had elevated fecal SCFA content. FMT from post-inflammatory females transferred visceral hyperalgesia to both males and females, while FMT from post-inflammatory males could only transfer visceral hyperalgesia to males.ConclusionsFemale sex, hormonal status as well as the gut microbiota play a role in pain modulation. Our data highlight the importance of considering biological sex in the evaluation of visceral pain.

Aberrant Notch activation has been implicated in multiple malignancies and the identification of NOTCH receptors and related pathways is critical for targeted therapy. In this study, we aim to delineate the most prominent dysregulated NOTCH receptor and comprehensively reveal its deregulation in gastric cancer (GC). In the four Notch members, NOTCH3 was found uniformly upregulated and associated with poor clinical outcomes in multiple GC datasets. siRNA-mediated NOTCH3 knockdown demonstrated antitumor effects by suppressing cell proliferation, inhibiting monolayer formation, and impairing cell invasion abilities. Its depletion also induced early and late apoptosis. NOTCH3 was confirmed to be a direct target of two tumor suppressor microRNAs (miRNAs), namely miR-491-5p and miR-875-5p. The activation of NOTCH3 is partly due to the silence of these two miRNAs. Through RNA-seq profiling and functional validation, PHLDB2 was identified as a potent functional downstream modulator for NOTCH3 in gastric carcinogenesis. PHLDB2 expression demonstrated a positive correlation with NOTCH3, but was negatively correlated with miR-491-5p. Akt-mTOR was revealed as the downstream signaling of PHLDB2. The NOTCH3-PHLDB2-Akt co-activation was found in 33.7% GC patients and the activation of this axis predicted poor clinical outcome. GC cells treated with siNOTCH3, siPHLDB2, miR-491-5p, miR-875-5p, were more sensitive to Cisplatin and 5-FU. Taken together, the NOTCH3-PHLDB2-Akt cascade plays oncogenic role in gastric carcinogenesis and serves as a therapeutic target. Our study provided insights into Notch-mediated underlying molecular mechanisms and implied translational potential.

Fibroblast growth factor receptor type 2 (FGFR2) has emerged as a key oncogenic factor that regulates gastric cancer (GC) progression, but the underlying mechanism of FGF–FGFR2 signaling pathway remains largely unknown. To identify the potential molecular mechanisms of the oncogenic FGFR2 in gastric carcinogenesis and convey a novel therapeutic strategy, we profiled the FGFR alterations and analyzed their clinical associations in TCGA and Hong Kong GC cohorts. We found that FGFR2 overexpression in GC cell lines and primary tumors predicted poor survival and was associated with advanced stages of GC. Functionally, growth abilities and cell cycle progression of GC were inhibited by inactivation of ERK–MAPK signal transduction after FGFR2 knockdown, while apoptosis was promoted. Meanwhile, the first-line anti-cancer drug sensitivity was enhanced. RNA-seq analysis further revealed that YAP1 signaling serves as a significant downstream modulator and mediates the oncogenic signaling of FGFR2. When stimulating FGFR2 by rhFGF18, we observed intensified F-actin, nuclear accumulation of YAP1, and overexpression of YAP1 targets, but these effects were attenuated by either FGFR2 depletion or AZD4547 administration. Additionally, the FGF18–FGFR2 signaling upregulated YAP1 expression through activating c-Jun, an effector of MAPK signaling. In our cohort, 28.94% of GC cases were characterized as FGFR2, c-Jun, and YAP1 co-positive and demonstrated worse clinical outcomes. Remarkably, we also found that co-targeting FGFR2 and YAP1 by AZD4547 and Verteporfin synergistically enhanced the antitumor effects in vitro and in vivo. In conclusion, we have identified the oncogenic FGF–FGFR2 regulates YAP1 signaling in GC. The findings also highlight the translational potential of FGFR2–c-Jun–YAP1 axis, which may serve as a prognostic biomarker and therapeutic target for GC.

Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset (n= 3,473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNTbut did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

ObjectivesIndividual neuroimaging features of small vessel disease (SVD) have been reported to influence poststroke cognition. This study aimed to investigate the joint contribution and strategic distribution patterns of multiple types of SVD imaging features in poststroke cognitive impairment.MethodsWe studied 145 first-ever ischaemic stroke patients with MRI and Montreal Cognitive Assessment (MoCA) examined at baseline. The local burdens of acute ischaemic lesion (AIL), white matter hyperintensity, lacune, enlarged perivascular space and cross-sectional atrophy were quantified and entered into support vector regression (SVR) models to associate with the global and domain scores of MoCA. The SVR models were optimised with feature selection through 10-fold cross-validations. The contribution of SVD features to MoCA scores was measured by the prediction accuracy in the corresponding SVR model after optimisation.ResultsThe combination of the neuroimaging features of SVD contributed much more to the MoCA deficits on top of AILs compared with individual SVD features, and the cognitive impact of different individual SVD features was generally similar. As identified by the optimal SVR models, the important SVD-affected regions were mainly located in the basal ganglia and white matter around it, although the specific regions varied for MoCA and its domains.ConclusionsMultiple types of SVD neuroimaging features jointly had a significant impact on global and domain cognitive functionings after stroke on top of AILs. The map of strategic cognitive-relevant regions of SVD features may help clinicians to understand their complementary impact on poststroke cognition.

ABSTRACTRecent loss-of-function studies in tissue-specific as well as global Tspo(Translocator Protein 18 kDa) knockout mice have not confirmed its long assumed indispensability for the translocation of cholesterol across the mitochondrial inter-membrane space, a rate-limiting step in steroid biosynthesis. Instead, recent studies in global Tspoknockout mice indicate that TSPO may play a more fundamental role in cellular bioenergetics, which may include the indirect down-stream regulation of transport or metabolic functions. To examine whether overexpression of the TSPO protein alters the cellular bioenergetic profile, Jurkat cells with low to absent endogenous expression were transfected with a TSPOconstruct to create a stable cell line with de novoexpression of exogenous TSPO protein. Expression of TSPO was confirmed by RT-qPCR, radioligand binding with [3H]PK11195 and immunocytochemistry with a TSPO antibody. We demonstrate that TSPOgene insertion causes increased transcription of genes involved in the mitochondrial electron transport chain. Furthermore, TSPOinsertion increased mitochondrial ATP production as well as cell excitability, reflected in a decrease in patch clamp recorded rectified K channel currents. These functional changes were accompanied by an increase in cell proliferation and motility, which were inhibited by PK11195, a selective ligand for TSPO. We suggest that TSPO may serve a range of functions that can be viewed as downstream regulatory effects of its primary, evolutionary conserved role in cell metabolism and energy production.

?-Gliadins were purified from wheat (Triticum aestivumL. ‘Butte’) flour and characterized. Although reversed-phase HPLC (RP-HPLC) separated the 1B-encoded ?-gliadins into two fractions, 1B1 and 1B2, these fractions had nearly identical amino acid compositions, three similar protein bands in SDS-PAGE, 10 similar spots in two-dimensional PAGE, and two similar N-terminal amino acid sequences. The main components had a range in mass of 48,900–51,500 when estimated by mass spectrometry, significantly less than the mass estimated by SDS-PAGE. The 1B fractions were digested with thermolysin, the peptides were separated by RP-HPLC, the peptide mass was determined, and nine peptides from each fraction were sequenced with nearly identical results for the 1B1 and 1B2 digests. A possible consensus sequence of the 1B-encoded ?-gliadin internal repeat was QQQXP, where X was F, I, or L in descending order of occurrence. The 1D-encoded ?-gliadins were purified by RP-HPLC as a single fraction that had one band in SDS-PAGE, two spots in two-dimensional PAGE, two components with mass of 41,923 and 42,770 detected by mass spectrometry, and two N-terminal sequences. Circular dichroism (CD) spectra for the 1B and 1D ?-gliadins were similar and were suggestive of mainly flexible random structure with a significant amount of the left-handed polyproline II helical conformation in the 1D components.

Idiopathic granulomatous mastitis (IGM) is a benign mimic of breast carcinomas. It is defined histologically by the presence of granulomas and inflammation. The closely related cystic neutrophilic granulomatous mastitis (CNGM) shows lipogranulomas, with a reported association with corynebacteria. A large cohort of IGM was reviewed to compare clinical, microbiological and histological features between non-CNGM IGM and CNGM.

PURPOSE. Little is known about the nature of biochemical disturbances during reperfusion after retinal ischemia. Previous studies have suggested that adenosine is responsible for regulation of retinal blood flow soon after ischemia has ended. Therefore, in this study we measured concentrations of adenosine and its metabolites in the rat retina/choroid after brief (10 min) or prolonged (60 min) periods of ischemia, and the functional consequences of inhibiting adenosine metabolism. METHODS. Ischemia was produced in anesthetized rats by ligation of the central retinal artery. The eyes were frozen in situ and purine nucleoside concentration was determined by high performance liquid chromatography. The functional effects of pre-ischemic inhibition of xanthine dehydrogenase/xanthine oxidase were assessed by measurement of the electroretinogram before, during, and up to 7 days following 60 min ischemia. RESULTS. Changes in the concentrations of adenosine and its metabolites were significant early in the reperfusion period, and were greater in magnitude and occurred earlier in prolonged, compared to brief, ischemic periods. Concentrations of adenosine, inosine, and hypoxanthine remained elevated for 30 min following the end of 60 min ischemia, and xanthine concentration was significantly elevated until 60 min after the end of either 10 or 60 min of ischemia. The onset of its peak value after ischemia was delayed in comparison to that of adenosine. Ischemia-evoked increases in xanthine concentration were attenuated by inhibition of adenosine deaminase or xanthine oxidase/xanthine dehydrogenase. Pre-ischemic inhibition of xanthine oxidase/xanthine dehydrogenase by oxypurinol (40 or 80 mg/kg intraperitoneally [IP]) resulted in a significant improvement in recovery of the a and b waves of the electro-retinogram in comparison to a saline-treated control group. CONCLUSIONS. These results indicate that adenosine is a major component of the biochemical changes that occur after retinal ischemia. Long-lasting increases in xanthine concentration during reperfusion after ischemia could be a source of oxygen free radicals that may contribute to delayed injury of the retina; attempts to decrease xanthine concentration would ideally be initiated within one hour after the end of ischemia.

(Bloomberg Opinion) -- China's REITs Plan Fuels Hong Kong Pipe Dreams: Ronald W. Chan This will boost trading volume on the Hong Kong stock exchange and spur increasing demand for Hong Kong-listed property trusts among mainland investors. [Extracted from the article]

(Bloomberg Opinion) -- Hong Kong Has a Haven From Trade-War Jolts: Ronald W. Chan Supporters believe that, in addition to stimulating the Chinese economy overall, the Greater Bay Area will be especially beneficial to Hong Kong millennials who have had difficulty finding affordable housing and high-paying jobs in the city. [Extracted from the article]

(Bloomberg Opinion) -- Investors Might Want to Buy Tickets to Indonesia: Ronald W. Chan Movies featuring local actors have grown in popularity throughout Indonesia, giving producers greater incentive to shoot such films. [Extracted from the article]

(Bloomberg Opinion) -- Thai Growth Will Ride Out Any Election Unrest: Ronald W. Chan Thailand's long-delayed elections to be held on March 24 have stirred concern among some analysts that we will see a fresh round of protests and social unrest. [Extracted from the article]

(Bloomberg Opinion) -- Hong Kong Malls Offer Shelter From Retail Gloom: Ronald W. Chan Hong Kong Malls Offer Shelter From the Retail Gloom The company, with a market cap of about $2.4 billion, operates 16 malls and shopping centers in Hong Kong. [Extracted from the article]

Mainland Chinese have poured roughly $10 billion into condos in Thailand over the past three years, helping to drive annual price increases of 20 percent in major cities such as Bangkok. Analysts estimate that one out of every five condos in Thailand is sold to a Chinese buyer. With Thailand's benchmark interest rate at 1.75 percent and inflation at about 0.4 percent, developers are able to obtain construction loans at a reasonable cost. [Extracted from the article]

(Bloomberg Opinion) -- Japan Stocks Can Be the Haven in a Bleak World: Ronald W. Chan Global equity investors have reason to be concerned: The economic outlook is worsening, interest rates are rising and tensions in the U.S.-China relationship could further harm growth. [Extracted from the article]

(Bloomberg Opinion) -- Hong Kong Should Cut Stock-Trading Taxes: Ronald W. Chan While the stamp duty on Hong Kong stocks is high, there may not be much incentive to reduce it, as this tax contributes about 8 percent of total government revenue. [Extracted from the article]

(Bloomberg Opinion) -- A New World Where Art and Property Collide: Ronald W. Chan Ten years ago, when New World Development Co. vice chairman and heir apparent Adrian Cheng wanted to infuse art into his property projects to add value, Hong Kong critics were skeptical. [Extracted from the article]

The richest man in Hong Kong, Li Ka-shing, hosted his final shareholder meeting as founder and chairman of the Cheung Kong group last week. While Li's and Buffett's investment results are almost identical, the Oracle of Omaha's longer and slightly better track record enabled him to provide a return of 24,000 times. When Buffett tells investors to seek a "margin of safety" in an investment, Li warns them in Chinese of the "risk of failure.". [Extracted from the article]