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Background Pseudocirrhosis is an imaging finding of malignancies with liver metastasis with or without clinical liver cirrhosis-related portal hypertension (pHTN). This study defined evident pHTN by the presence of esophageal or gastric varices and compared patients’ outcomes of metastatic breast cancer with imaging-diagnosed pseudocirrhosis with or without varices. Methods The medical records from patients with metastatic breast cancer and pseudocirrhosis between 2005 and 2017 were retrospectively analyzed. Survival outcomes were compared based on endoscopic evidence of esophageal or gastric varices. Results Among 106 patients with pseudocirrhosis, 33 (31%) had de novo stage IV disease, and 66 (62%) had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Eighty-one (76%) had initial metastases in both hepatic lobes, and 32 (30%) had esophageal or gastric varices. The median overall survival (OS) was 5 and 13 months in patients with and without varices (P = .002). The median OS in patients with HER2-positive, HR-positive/HER2-negative, and triple-negative subtype was 16, 9, and 2 months, respectively (P = .001). Patients with varices usually had cirrhotic complications, including gastrointestinal bleeding, hyperbilirubinemia, hyperammonemia, and coagulopathy. Despite their challenging clinical conditions, 7 patients with varices had OS exceeding 1 year. In multivariate analysis, evident varices (P = .007) and triple-negative subtype (P = .013) were associated with poor OS. Conclusions Patients with pseudocirrhosis and evident varices had a significantly shorter median OS, and were usually associated with clinical cirrhosis-related complications. To maximize OS, early identification and meticulous supportive care are warranted.

Transcription factor-based whole-cell biosensors have recently become promising alternatives to conventional analytical methods due to their advantage of simplicity, cost-effectiveness, and environmental friendliness. In this study, we used genetic engineering to develop a whole-cell biosensor based on the activation of promoters by CupR via interactions with gold ions, leading to the expression of reporter genes that yield output signals. Altering the promoter sequences was shown to significantly improve the performance of the biosensor strain in terms of gold-specificity. The detection sensitivity of our engineered strains was 42-fold higher than that of wild-type strains. The linear range of the purposed sensor was 125-1000 nM with a limit of detection at 46.5 nM. The effectiveness of the sensor strain was verified in wastewater samples.

Reference: Lie et al, 2013. Small-scale temporal and spatial variations in protistan community composition at the San Pedro Ocean Time-series station off the coast of southern California. Aquatic Microbial Ecology 70, 93-110.

Biological nitrogen fixation, the conversion of N2 gas into a more bioavailable form, is vital to sustaining marine primary production. Studies have shifted beyond traditionally studied tropical diazotrophs.CandidatusAtelocyanobacterium thalassa (or UCYN-A) has emerged as a research focal point due to its streamlined metabolism, intimate partnership with a haptophyte host, and broad distribution. Here, we explore the abiotic factors that govern UCYN-A’s presence at the San Pedro Ocean Time-series (SPOT), its partner fidelity, and statistical interactions with non-symbiotic eukaryotes. 16S and 18S rRNA sequences were amplified by “universal primers” from monthly samples and resolved into Amplicon Sequence Variants, allowing us to observe multiple UCYN-A symbioses. UCYN-A1 relative abundances increased following the 2015-2016 El Niño event. When this “open ocean ecotype” was present, coastal upwelling ceased, and Ekman transport brought tropical waters into the region. Network analyses reveal all strains of UCYN-A co-occur with dinoflagellates includingLepidodinium, a potential predator, and parasiticSyndiniales. UCYN-A2 appeared to pair with multiple hosts and was not tightly coupled to its predominate host, while UCYN-A1 maintained a strong host-symbiont relationship. These biological relationships are particularly important to study in the context of climate change, which will alter UCYN-A distribution patterns both locally and globally.

This cross-sectional study assessed the moderating effects of self-esteem and perceived support from friends on the association between self-stigma and suicide risk in individuals with schizophrenia. We included 300 participants (267 with schizophrenia and 33 with schizoaffective disorder). Suicide risk was assessed using items adopted from the suicide module of the Mini-International Neuropsychiatric Interview; self-stigma was assessed using the Self-Stigma Scale–Short; perceived support from friends was assessed using the Friend Adaptation, Partnership, Growth, Affection, and Resolve Index; and self-esteem was assessed using the Rosenberg Self-Esteem Scale. A moderation analysis was performed to examine the moderating effects of self-esteem and perceived support from friends on the association between self-stigma and suicide risk. The results indicated that self-stigma was positively associated with suicide risk after the effects of other factors were controlled for. Both perceived support from friends and self-esteem significantly reduced the magnitude of suicide risk in participants with self-stigma. Our findings highlight the value of interventions geared toward ameliorating self-stigma and enhancing self-esteem in order to reduce suicide risk in individuals with schizophrenia.

Background: The Mild Behavioral Impairment Checklist (MBI-C) has been developed to assess mild behavioral impairment (MBI). However, no study has validated the use of MBI-C using a promising translation method in Taiwan. Thus, consistency and discrepancy between informant-rated and self-rated scores have not been extensively researched. Objective: This study validated and compared the informant- and self-rated versions of the MBI-C among community-dwelling people in Taiwan. Method: We recruited 202 pairs of individuals without dementia aged ≥50 years and their cohabitating informants. The participants completed the MBI-C (MBI-C-self), and the informants completed the MBI-C (MBI-C-informant) and the Neuropsychiatric Inventory Questionnaire (NPI-Q) independently. Internal consistency, inter-rater reliability, and convergent validity were examined. Results: Both MBI-C-self and MBI-C-informant exhibited satisfactory Cronbach’s α values (0.92 and 0.88, respectively). The MBI-C-informant total scorewas correlated with the NPI-Q total score (r = 0.83, p < 0.001). Inter-rater reliability between the two versions, as represented by the inter-rater correlation coefficient, was 0.57 (p < 0.001). The prevalence of MBI based on the MBI-C-informant scores was 1.5% higher than that based on the MBI-C-self scores according to the suggested cut-off score of 8.5. The affective dysregulation domain score of MBI-C-informant was significantly lower than that of MBI-C-self. Conclusion: MBI-C-informant exhibited both high reliability and validity. Discrepancies between MBI-C-informant and MBI-C-self related to the detection rates and affective dysregulation domain scores were noted. The level of consistency and discrepancy between these two versions provide implications for the use of MBI-C in clinical practice and future research.

Oxidase-mimicking (catechol oxidase/laccase) nanozymes provide outstanding specificity in the detection of epinephrine (Epi) for the assessment of pheochromocytoma; however, epinephrine (Epi) and norepinephrine (NE) co-existing in the same systems will reduce the selectivity of the biosensor. In the current study, we synthesized copper-based coordination polymer (Cu-CP) nanozymes capable of accelerating the oxidation of Epi with high specificity. Furthermore, the Cu-CP is able to detect Epi over a wide linear range of 0.5-100 μM with a low detection limit of 0.36 μM while providing excellent stability and recyclability. Furthermore, we employed colorimetric and fluorescence signals for sequential detection of the coexistence of Epi and NE for use in tracking the treatment outcomes of patients with pheochromocytoma. Experiments using artificial urine further confirmed the efficacy of the proposed system.

In this study, we developed a simple and economical method for the green synthesis of Cu

The neurotransmitter phenylethylamine (PEA) is highly susceptible to oxidation to produce phenylacetic acid (PA). The fact that PEA and PA are both metabolites of phenylalanine (Phe) in humans makes them important indicators in the diagnosis of phenylketonuria. In this work, three-color whole-cell biosensors were developed to simultaneously detect these analytes (Phe, PEA, and PA). The tyrosine-responsive promoter was used to control the production of green fluorescent protein signals in response to Phe levels. The FeaR regulon was first used to indicate the presence of PEA, whereas the Paa regulon was used for the detection of PA. The combination of three sensor strains together made it possible to semiquantify the three analytes according to unique color outputs without cross-interference. We sought to optimize various modular components (ribosomal binding sites and fluorescent proteins) to ensure the rapid generation of fluorescent signals. Finally, the biosensors were implemented within a microchannel device to reduce sample consumption in point-of-care assays.

In this study, we report on a bi-metal organic framework, MOF-919 (Fe-Cu), capable of bifunctional-enzyme mimicking activity with oxidase- and peroxidase-like activities. The catalytic activities were examined by using

Transcription factor-based whole-cell biosensors have recently become promising alternatives to conventional analytical methods due to their advantage of simplicity, cost-effectiveness, and environmental friendliness. In this study, we used genetic engineering to develop a whole-cell biosensor based on the activation of promoters by CupR via interactions with gold ions, leading to the expression of reporter genes that yield output signals. Altering the promoter sequences was shown to significantly improve the performance of the biosensor strain in terms of gold-specificity. The detection sensitivity of our engineered strains was 42-fold higher than that of wild-type strains. The linear range of the purposed sensor was 125-1000 nM with a limit of detection at 46.5 nM. The effectiveness of the sensor strain was verified in wastewater samples.

Summary Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2's recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins.

Background: Pseudocirrhosis is an imaging finding of malignancies with liver metastasis with or without clinical liver cirrhosis–related complications such as portal hypertension (pHTN). This study compared the outcomes of metastatic breast cancer in patients with imaging-diagnosed pseudocirrhosis with or without pHTN. Methods: The medical records from patients with metastatic breast cancer and pseudocirrhosis between 2005 and 2017 were retrospectively analyzed. Clinical pHTN was defined based on endoscopic evidence of esophageal or gastric varices. Results: Among 106 patients with pseudocirrhosis, 33 (31%) had de novo stage IV disease, and 66 (62%) had hormone receptor (HR)–positive and human epidermal growth factor receptor 2 (HER2)–negative breast cancer. In total, 81 (76%) had initial metastases in both hepatic lobes, 91 (86%) had 4 or more liver metastases, and 32 (30%) had pHTN. The median overall survival (OS) was 5 and 13 months in patients with and without pHTN, respectively (p = .002). The median OS in patients with HER2-positive, HR-positive/HER2-negative, and triple-negative breast cancer was 16, 9, and 2 months, respectively (p = .001). Patients with pHTN generally had cirrhotic complications, including gastrointestinal bleeding, hyperbilirubinemia, hyperammonemia, and coagulopathy. Despite their challenging clinical conditions, 7 patients with pHTN had OS exceeding 1 year. In multivariate analysis, pHTN (p = .007) and triple-negative breast cancer (p = .013) were associated with poor OS. Conclusions: For patients with pseudocirrhosis, clinical pHTN was associated with liver cirrhosis–related complications and shorter median OS. A few patients with pHTN had prolonged OS with effective systemic treatment and aggressive supportive care.

We examined the association between statin use and hepatocellular carcinoma (HCC) incidence in patients with diabetes using marginal structural models (MSMs) estimated by inverse probability weight (IPW), which adjusts for time-varying confounders that are also mediators, and we compared the results with conventional regression methods.This retrospective cohort study included 245,122 patients with type 2 diabetes who were new users of lipid-lowering drugs identified using the claims data of a universal health insurance program. Statin exposure was time-updated every three months during the follow-up period. Stabilized IPW was calculated and accounted for chronic liver diseases considering as time-dependent confounders affected by past statin exposure.Over a median follow-up of 5.2 years, 1,694 patients developed HCC. In the conventional regression analysis, the hazard ratio of HCC associated with statin use was 0.88 (95% confidence interval CI: 0.79-0.97) after adjusting for baseline covariates and 0.97 (95% CI: 0.87-1.08) after additionally adjusting for time-varying covariates. The hazard ratio increased to 1.11 (95% CI: 0.94-1.31) using the MSM approach.Statin use was not associated with the risk of developing HCC in patients with diabetes. Our findings highlight the importance of controlling time-varying confounders in observational studies.

Trade-offs between competition ability and invulnerability to predation are important mechanisms explaining how predation promotes bacterial diversity. However, existence of these trade-offs has apparently not been investigated in natural marine bacterial communities. Here, we address this question with growth-based measurements for each marine bacterial taxon by conducting on-board dilution experiments to manipulate predation pressure and using high-throughput sequencing to assess the response of bacterial communities. We determined that bacterial taxa with a higher predation-free growth rate were accompanied with higher predation-caused mortality, supporting existence of competitiveness-invulnerability trade-off. This trade-off was stronger and more consistent under viral lysis than protist grazing. In addition, predation generally flattened out the rank-abundance distribution and increased the evenness and richness of the bacterial community. These findings supported the “Kill-the-Winner” hypothesis. All experiments supported a significant competitiveness-invulnerability trade-off, but there was substantial variation among bacterial communities in response to predation across experiments conducted in various sites and seasons. Therefore, we inferred that the Kill-the-Winner hypothesis is important but likely not the only deterministic mechanism explaining how predation shapes bacterial assemblages in natural marine systems.

Hexavalent chromium ions (Cr(VI)) are highly toxic and prone to bioaccumulation in the natural environment. This study sought to develop a facile and cost-effective approach to on-site monitoring Cr(VI) content in diverse environmental samples. We synthesized copper-based MOF nanozymes (Cu-PyC MOF) and developed a simple colorimetric method by which to detect Cr(VI) on paper-based devices. The colorimetric product is obtained using the MOF nanozyme as a catalyst, Cr(VI) as an oxidant, 3,3',5,5'-tetramethylbenzidine (TMB) as a chromogenic substrate to produce a bluish-green color observable by the naked eye or a UV-visible spectrophotometer. After Cu-PyC MOF was suspended in an acidic buffer, it remained stable and showed oxidoreductase-like catalytic activity, which in turn boosts Cr(VI) reduction. The proposed scheme enables the detection of Cr(VI) within 3 min over a linear range of 0.5-50 μM with a low detection limit of 0.051 μM. The proposed nanozyme-based colorimetric method exhibits excellent reusability and selectivity over other 27 interference ions and can be used in real sample analysis.

The UCLA Loneliness Scale (Version 3; UCLA-LSV3) is widely used for assessing loneliness. Nevertheless, the validity of this scale for assessing loneliness in individuals with schizophrenia or schizoaffective disorder has not been determined. Additionally, studies validating the eight-item and three-item versions of UCLA-LSV3 have not included individuals with severe mental illness; therefore, whether the short versions are comparable to the full 20-item version of UCLA-LSV3 for this population is unclear. The present study examined the unidimensional structure, internal consistency, concurrent validity, and test–retest reliability of the Chinese versions of UCLA-LSV3 (i.e., 20-item, 8-item, and 3-item versions) to determine which version is most appropriate for assessing loneliness in individuals with schizophrenia or schizoaffective disorder in Taiwan. A total of 300 participants (267 with schizophrenia and 33 with schizoaffective disorder) completed the scales, comprising UCLA-LSV3, the Center for Epidemiological Studies Depression Scale (CES-D), the suicidality module of the Kiddie Schedule for Affective Disorders and Schizophrenia–Epidemiological Version (K-SADS-E), and the family and peer Adaptation, Partnership, Growth, Affection, and Resolve (APGAR) index. Construct validity was evaluated through confirmatory factor analysis. The three versions of UCLA-LSV3 were compared with the CES-D, the suicidality module of the K-SADS-E, and the family and peer APGAR index to establish concurrent validity. The results indicated that all three versions of UCLA-LSV3 exhibited acceptable to satisfactory psychometric properties in terms of unidimensional constructs, concurrent validity, and test–retest reliability. The full version of UCLA-LSV3 had the best performance, followed by the eight-item version and the three-item version. Moreover, the three versions had relatively strong associations with each other. Therefore, when deliberating which version of UCLA-LSV3 is the best choice for assessing loneliness in individuals with schizophrenia or schizoaffective disorder, healthcare providers and therapists should consider time availability and practicality.

A variety of enzyme-based colorimetric biosensors have been developed for clinical practice; however, these methods will only become cost-effective when they are able to process multiple samples with a high degree of sensitivity. In this study, a novel heat-stable enzyme, 2,3-dopa-dioxygenase from the thermophilic bacterium Streptomyces sclerotialus (SsDDO), was used in the development of a protein- and cell-based biosensor for the detection of L-DOPA for the first time. SsDDO catalyzes the oxidative cleavage of L-DOPA forms linear semialdehyde (AHMS) and cyclizes to a 3-carboxy-3-hydroxyallylidene-3,4-dihydropyrrole-2-carboxylic acid (CHAPCA). We next derivatized CHAPCA by reacting with 3-aminobenzoic acid (MABA) to yield a red-fluorescent pigment. Overall, the detection of L-DOPA via the red fluorescent signal can be completed in only 30 min. We also developed a sequential analysis method to detect the coexistence of dopamine and L-DOPA with a high degree of sensitivity using the dual-fluorescent signals to monitor the therapy of patients with Parkinson's disease treated with L-DOPA. The robustness and applicability of the system were further validated in serum. In addition, paper microfluidics modified with chitosan was applied for fast and cost-effective analysis of dopamine and L-DOPA in the mixed solutions.

L-tyrosine hydroxylase (TH) is a critical enzyme and involved in the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) in the human body. TH deficiency is a rare autosomal recessive disorder which results in cerebral catecholamine deficiency and causes symptoms of depression, movement disorders, and impaired development. L-DOPA is the common precursor of catecholamine neurotransmitters, therefore how to rapidly and precisely determine the ratio of L-DOPA to L-tyrosine in the bio-matrix is important to the clinical diagnosis of disorder. To response the demand, a low-cost, user-friendly, and on-site detection system is developed herein, which includes a wax-printing paper microfluidics as reaction platform, surface modification with sodium periodate for improving detection performance, an additive manufactured enclosed case for maintaining identical detection environment, and an IOS application (APP) to drive smartphone’s imaging to facilitate high-throughput quantification of multiple biomarkers simultaneously. Multiple experiments were conducted to understand the detection limit, detection range, shelf-life, and specificity of this quantification system even with a complex bio-matrix such as artificial urine or Fetal Bovine Sera (FBS). The experiment results showed that L-DOPA, L-tyrosine, and creatinine can be easily and rapidly quantified with high reliability and repeatability, demonstrating an efficient tool for routine checkup of patients with TH deficiency.

l-dopa is a catecholamine neurotransmitter used to treat Parkinson's disease. This paper presents a low-cost paper-based biosensor aimed at enhancing the convenience of monitoring l-dopa concentrations. ZnO nanorods (ZnO-NRs) were synthesized on papers in less than 90 min using a microwave-assisted hydrothermal method. The ZnO-NRs amplify green fluorescence signals to enhance the detection sensitivity of l-dopa, best measured at excitation/emission wavelengths of 475/537 nm. We systematically characterized the effect of reaction conditions on the corresponding fluorescence enhancements. The proposed ZnO NRs-paper biosensor presented a ∼3-fold increase in green fluorescence compared to unmodified papers. The linear range of detection for l-dopa was 25-2000 nM, with a limit of detection of 24 nM, which meets the clinical requirements for the monitoring of l-dopa in Parkinson's patients.