Characterization of a Dipartite Iron Uptake System from Uropathogenic \u3ci\u3eEscherichia coli\u3c/i\u3e Strain

In the uropathogenic Escherichia coli strain F11, in silico genome analysis revealed the dicistronic iron uptake operon fetMP, which is under iron-regulated control mediated by the Fur regulator. The expression of fetMP in a mutant strain lacking known iron uptake systems improved growth under iron depletion and increased cellular iron accumulation. FetM is a member of the iron/lead transporter superfamily and is essential for iron uptake by the Fet system. FetP is a periplasmic protein that enhanced iron uptake by FetM. Recombinant FetP bound Cu(II) and the iron analog Mn(II) at distinct sites. The crystal structure of the FetP dimer reveals a copper site in each FetP subunit that adopts two conformations: CuA with a tetrahedral geometry composed of His44, Met90, His97, and His127, and CuB, a second degenerate octahedral geometry with the addition of Glu46. The copper ions of each site occupy distinct positions and are separated by 1.3A . Nearby, a putative additional Cu(I) binding site is proposed as an electron source that may function with CuA/CuB displacement to reduce Fe(III) for transport by FetM. Together, these data indicate that FetMP is an additional iron uptake system composed of a putative iron permease and an iron-scavenging and potentially iron-reducing periplasmic protein

Integrating CT-based radiomic model with clinical features improves long-term prognostication itpden high-risk prostate cancer

ObjectiveHigh-risk prostate cancer (PCa) is often treated by prostate-only radiotherapy (PORT) owing to its favourable toxicity profile compared to whole-pelvic radiotherapy. Unfortunately, more than 50% patients still developed disease progression following PORT. Conventional clinical factors may be unable to identify at-risk subgroups in the era of precision medicine. In this study, we aimed to investigate the prognostic value of pre-treatment planning computed tomography (pCT)-based radiomic features and clinical attributes to predict 5-year progression-free survival (PFS) in high-risk PCa patients following PORT.Materials and methodsA total of 176 biopsy-confirmed PCa patients who were treated at the Hong Kong Princess Margaret Hospital were retrospectively screened for eligibility. Clinical data and pCT of one hundred eligible high-risk PCa patients were analysed. Radiomic features were extracted from the gross-tumour-volume (GTV) with and without applying Laplacian-of-Gaussian (LoG) filter. The entire patient cohort was temporally stratified into a training and an independent validation cohort in a ratio of 3:1. Radiomics (R), clinical (C) and radiomic-clinical (RC) combined models were developed by Ridge regression through 5-fold cross-validation with 100 iterations on the training cohort. A model score was calculated for each model based on the included features. Model classification performance on 5-year PFS was evaluated in the independent validation cohort by average area-under-curve (AUC) of receiver-operating-characteristics (ROC) curve and precision-recall curve (PRC). Delong’s test was used for model comparison.ResultsThe RC combined model which contains 6 predictive features (tumour flatness, root-mean-square on fine LoG-filtered image, prostate-specific antigen serum concentration, Gleason score, Roach score and GTV volume) was the best-performing model (AUC = 0.797, 95%CI = 0.768-0.826), which significantly outperformed the R-model (AUC = 0.795, 95%CI = 0.774-0.816) and C-model (AUC = 0.625, 95%CI = 0.585-0.665) in the independent validation cohort. Besides, only the RC model score significantly classified patients in both cohorts into progression and progression-free groups regarding their 5-year PFS (p< 0.05).ConclusionCombining pCT-based radiomic and clinical attributes provided superior prognostication value regarding 5-year PFS in high-risk PCa patients following PORT. A large multi-centre study will potentially aid clinicians in implementing personalised treatment for this vulnerable subgroup in the future

MicroRNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF

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Characterization of a Dipartite Iron Uptake System from Uropathogenic \u3ci\u3eEscherichia coli\u3c/i\u3e Strain

In the uropathogenic Escherichia coli strain F11, in silico genome analysis revealed the dicistronic iron uptake operon fetMP, which is under iron-regulated control mediated by the Fur regulator. The expression of fetMP in a mutant strain lacking known iron uptake systems improved growth under iron depletion and increased cellular iron accumulation. FetM is a member of the iron/lead transporter superfamily and is essential for iron uptake by the Fet system. FetP is a periplasmic protein that enhanced iron uptake by FetM. Recombinant FetP bound Cu(II) and the iron analog Mn(II) at distinct sites. The crystal structure of the FetP dimer reveals a copper site in each FetP subunit that adopts two conformations: CuA with a tetrahedral geometry composed of His44, Met90, His97, and His127, and CuB, a second degenerate octahedral geometry with the addition of Glu46. The copper ions of each site occupy distinct positions and are separated by 1.3A . Nearby, a putative additional Cu(I) binding site is proposed as an electron source that may function with CuA/CuB displacement to reduce Fe(III) for transport by FetM. Together, these data indicate that FetMP is an additional iron uptake system composed of a putative iron permease and an iron-scavenging and potentially iron-reducing periplasmic protein

Reliability and validity of a new building environmental quality questionnaire

This study aimed to develop and then test the reliability and validity of a new self-report questionnaire method called the building environmental quality questionnaire (BEQQ) designed to assess the perceived environmental quality in residential apartments in Hong Kong. A total of 108 (46 men and 62 women) Chinese-speaking residents, between 16 and 81 years of age, took part and completed the questionnaire study. The subjects were recruited from 12 different buildings of three distinct quality ratings (low, medium and high) assigned by the building assessment tool called the building health and hygiene index (BHHI). The study was evaluated to determine reliability and this was assessed involving 20 of the participants (18% of the total sample size). The BEQQ was found to have good test-retest reliability, with intra-class correlation coefficient (ICC) values typically around 0.70. The validity testing, also using ICCs, generated moderate to high values for all BEQQ sub-categories (the mean value was around 0.80), indicating a good consistency among residents living within the same building. Finally, the summary BEQQ scores were significantly correlated (—0.68) with the BHHI ratings as the criterion standard. It is concluded that this eight-dimension instrument would provide a short and efficient questionnaire method to obtain self-reported information to determine the perceived residential building quality. The method was shown to yield adequate reliability and has been validated for use in empirical research

A network analysis on the relationship between loneliness and schizotypy

Background: Schizotypy is a multidimensional personality trait related to the heightened risk for the development of schizophrenia spectrum disorders. While it has been suggested that loneliness may be associated with schizotypy in general, whether it relates to the specific schizotypal traits differentially remains unknown. Be-sides, as loneliness often co-occurs with depression and anxiety, it is important to delineate its relationship with schizotypy in consideration of these co-occurring emotional disturbances. Methods: A demographically diverse sample of young people was obtained from multiple sources. The validated sample consisted of 2089 participants (68.4% female, age range: 18-30). The structural relationship between loneliness and schizotypy was modelled using a network analytic approach. The Gaussian graphical model with loneliness and nine schizotypal traits as nodes was first estimated without, and then with adjustment for the levels of depressive and anxiety symptoms. Edges were estimated as unique associations between nodes. Results: 'Suspiciousness', 'odd beliefs or magical thinking', 'no close friends', 'constricted affect' and 'excessive social anxiety' were linked to loneliness directly. Loneliness was found to be more strongly associated with 'suspiciousness' and 'no close friends' than other schizotypal traits. After adjustment for the levels of depressive and anxiety symptoms, the above direct edges remained robust. Limitations: The use of cross-sectional data indicated only undirected associations between variables. Conclusions: Loneliness was more strongly linked to some schizotypal traits than others, with the relationships maintaining above and beyond the effects of anxiety and depression. These findings warrant further investigation of the specific relationships between loneliness and individual schizotypal traits

The co-occurrence of multidimensional loneliness with depression, social anxiety and paranoia in non-clinical young adults: A latent profile analysis

IntroductionLoneliness is a negative experience arising from a mismatch between perceived and actual social relationships. Several dimensions of loneliness have been suggested, namely intimate, relational and collective loneliness. Loneliness has been linked to poorer mental health, with its co-occurrence with depression, social anxiety, and paranoia most widely reported. While expressions of these symptoms are heterogeneous across individuals in the non-clinical population, it remains unclear how these symptoms co-occur with one another and with various dimensions of loneliness. It is also of interest how trait factors such as core schemas about self/others may moderate these relationships between loneliness and co-occurring symptoms. MethodsA demographically diverse sample of young adults was recruited from multiple sources. The validated sample consisted of 2,089 participants (68.4% female), who completed an online survey consisting of questionnaires assessing levels of multidimensional loneliness, depression, social anxiety, paranoia, core schemas, and demographic characteristics. Latent profile analysis (LPA) was used to identify distinct profiles of loneliness and the three symptoms. Positive and negative core schemas about self and others were modeled as predictors of these profiles. ResultsFive distinct profiles were identified. Profile 1 had low levels across all symptoms and dimensions of loneliness (n = 1,273, 60.9%). Profiles 2-5 were elevated on dimensions of loneliness, and were heightened in depression (n = 189, 9.0%), social anxiety (n = 206, 9.9%), paranoia (n = 198, 9.5%), and all symptoms (n = 223, 10.7%), respectively. Relative to Profile 1, the other four profiles scored higher on negative-self (adjusted ORs = 1.36-1.49, ps < 0.001) and negative-other schemas (adjusted ORs = 1.24-1.44, ps < 0.001), and lower on positive-self (adjusted ORs = 0.82-0.85, ps < 0.001) and positive-other schemas (adjusted ORs = 0.81-0.90, ps < 0.001). ConclusionMore marked intimate, relational and collective loneliness were evident across profiles that had heightened depression, social anxiety and/or paranoia, suggesting that loneliness may serve as a general risk factor for these psychopathologies. Our findings shed light on the heterogeneity of the co-occurrence of loneliness and various mental health difficulties in non-clinical young adults. Core schemas are suggested to be putative psychological mechanisms underlying their co-occurrence and even development

A Bacterial Cell Shape-Determining Inhibitor

<i>Helicobacter pylori</i> and <i>Campylobacter jejuni</i> are human pathogens and causative agents of gastric ulcers/cancer and gastroenteritis, respectively. Recent studies have uncovered a series of proteases that are responsible for maintaining the helical shape of these organisms. The <i>H. pylori</i> metalloprotease Csd4 and its <i>C. jejuni</i> homologue Pgp1 cleave the amide bond between <i>meso</i>-diaminopimelate and <i>iso</i>-d-glutamic acid in truncated peptidoglycan side chains. Deletion of either <i>csd4</i> or <i>pgp1</i> results in bacteria with a straight rod phenotype, a reduced ability to move in viscous media, and reduced pathogenicity. In this work, a phosphinic acid-based pseudodipeptide inhibitor was designed to act as a tetrahedral intermediate analog against the Csd4 enzyme. The phosphinic acid was shown to inhibit the cleavage of the alternate substrate, Ac-l-Ala-<i>iso</i>-d-Glu-<i>meso</i>-Dap, with a <i>K</i>_i value of 1.5 μM. Structural analysis of the Csd4-inhibitor complex shows that the phosphinic acid displaces the zinc-bound water and chelates the metal in a bidentate fashion. The phosphinate oxygens also interact with the key acid/base residue, Glu222, and the oxyanion-stabilizing residue, Arg86. The results are consistent with the “promoted-water pathway” mechanism for carboxypeptidase A catalysis. Studies on cultured bacteria showed that the inhibitor causes significant cell straightening when incubated with <i>H. pylori</i> at millimolar concentrations. A diminished, yet observable, effect on the morphology of <i>C. jejuni</i> was also apparent. Cell straightening was more pronounced with an acapsular <i>C. jejuni</i> mutant strain compared to the wild type, suggesting that the capsule impaired inhibitor accessibility. These studies demonstrate that a highly polar compound is capable of crossing the outer membrane and altering cell shape, presumably by inhibiting cell shape determinant proteases. Peptidoglycan proteases acting as cell shape determinants represent novel targets for the development of antimicrobials against these human pathogens