Identification of a Novel Five-Gene Signature as a Prognostic and Diagnostic Biomarker in Colorectal Cancers

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The current TNM (Tumor, Node, and Metastasis) classification approach is suboptimal in determining the prognosis of CRC patients. The prognosis for CRC is affected by a variety of features that are present at the initial diagnosis. Herein, we performed a systematic exploration and established a novel five-panel gene signature as a prognostic and early diagnosis biomarker after performing differential gene expression analyses in five independent in silico CRCs cohort and independently validating it in one clinical cohort, using immunohistochemistry. Four genes (BDNF, PTGS2, GSK3B, and CTNNB1) were significantly upregulated and one gene (HPGD) was significantly downregulated in primary tumor tissues compared with adjacent normal tissues throughout all the five in silico datasets. The univariate CoxPH analysis yielded a five-gene signature that accurately predicted overall survival (OS) and recurrence-free survival (RFS) in the in silico training (AUC = 0.73 and 0.69, respectively) and one independent in silico validation cohort (AUC = 0.69 and 0.74, respectively). This five-gene signature demonstrated significant associations with poor OS in independent clinical validation cohorts of colon cancer (CC) patients (AUC = 0.82). Intriguingly, a risk stratification model comprising of the five-gene signature together with TNM stage and gender status achieved an even superior AUC of 0.89 in the clinical cohorts. On the other hand, the circulating mRNA expression of the upregulated four-gene signature achieved a robust AUC = 0.83 with high sensitivity and specificity as a diagnosis marker in plasma from CRC patients. We have identified a novel, five-gene signature as an independent predictor of OS, which in combination with TNM stage and gender offers an easy-to-translate and facile assay for the personalized risk-assessment in CRC patients.

Urea Gel Electrophoresis in Studies of Conformational Changes of Transferrin on Binding and Transport of Non-Ferric Metal Ions

Transferrin (Tf) is a crucial transporter protein for Fe(III), but its biological role in binding other metal ions and their delivery into cells remain highly controversial. The first systematic exploration of the effect of non-Fe(III) metal ion binding on Tf conformation has been performed by urea-polyacrylamide gel electrophoresis (urea-PAGE), which is commonly used for nucleic acids but rarely for proteins. Closed Tf conformation, similar to that caused by Fe(III)-Tf binding, was formed for In(III), V(III) or Cr(III) binding to Tf. In all these cases, metal distribution between Tf lobes and/or the rate of metal release under acidic conditions differed from that of Fe(III)-Tf. By contrast, Ga(III) and V(IV) did not form closed Tf conformation under urea-PAGE conditions. Apart from Fe(III), only In(III) was able to increase the proportion of closed Tf conformation in whole serum. These results suggest that Tf is unlikely to act as a natural carrier of any metal ion, except Fe(III), into cells but can reduce toxicity of exogenous metal ions by binding them in serum and preventing their entry into cells.

A regional approach to ancient urban studies in Greece through multi-settlement geophysical survey

The systematic exploration of large archaeological sites in the Mediterranean has evolved considerably since the “big dig” excavations. Pedestrian field surveying and remote sensing applications, including satellite and airborne image analysis, are now practical and relatively cost-efficient methods of characterizing large and diachronically diverse landscapes on regional scales. However, the use of geophysical techniques as a means for exploring manifold archaeological contexts is still in its infancy. In this paper, we highlight the advantages of archaeological geophysics to conduct regional surveys in the Mediterranean. Through a multi-site geophysical fieldwork campaign to investigate the patterns and dynamics of ancient cities in Greece, we show how geophysics offer new opportunities for characterizing the spatial attributes and regional dynamics of urban landscapes, and, in doing so, we make an argument for its wider adoption on regional survey projects.

Indications of Goal Displacement in Regulatory Enforcement Agencies: An Empirical Exploration

This paper describes indications of goal displacement in regulatory enforcement agencies as reported by enforcement professionals from a range of regulatory domains. The findings suggest that the occurrence of this phenomenon in these agencies may be more prevalent and multifaceted than expected. Among the goal-displacement types reported as most impactful were goal narrowing, induced by calamities, goal diversion through ongoing organizational reform, and goal diversion brought upon by strict regimes of output management. A systematic exploration of these various goal-displacement types as conducted here sheds light onto the intricate nature of goal alignment of these agencies.

Systematic exploration of prognostic alternative splicing events related to immune microenvironment of Clear Cell Renal Cell Carcinoma

Background Clear cell renal cell carcinoma (ccRCC) accounts for almost 75% of all renal cancers, with high heterogeneity and poor prognosis. There is increasing evidence that alternative splicing (AS) is associated with tumorigenesis and immune microenvironment. However, studies on the relationship between AS events and immunity in ccRCC are still few but needed. Methods The transcriptional data and clinicopathological information of ccRCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. We grouped patients according to the ESTIMATE algorithm and identified for differentially expressed AS events (DEASs). The functional enrichment analysis and unsupervised consensus analysis were performed to investigate the association between AS events and immune features. The regulatory network of survival-related AS events and intersection SFs was used to explore potential mechanisms. Results In total, 515 ccRCC patients were included in the present study. The low immune-score group had longer overall survival (OS) than the high low immune-score group. 861 AS events were identified as DEASs, and they were enriched in immune-related pathways. Unsupervised clustering analysis revealed that AS-based clusters significantly corelated with prognosis and immune features of ccRCC. Finally, MBNL1 was identified as a hub SF, and it was shown to inhibit proliferation and metastasis, promote apoptosis, and block cells in G2/M phase in 786O and A498 cells. Conclusion The present systematic exploration elaborated that not only some critical AS events were related to prognosis and immune microenvironment of ccRCC, but also the hub SF, such as MBNL1, could affect the development and progression of ccRCC.

Only ‘Time’ will ‘Tell’: Influence of temporality on the interpretation of narrative discourses

The notion of language has been broadly understood in different ways with respect to existing literatures revolving around form, meaning, sound & context. Although overtly these understandings do try to integrate with the functionality of a complex organic system, they glaringly lack reference to the basis for its realization, i.e., time. Approaches to problematize the understanding of language have overlooked the issue of time. Temporality introduces a distinct fuzziness in qualitative and abstract expressions beyond just the action or the state. It is also evident in the context of names in a diachronic sense. A systematic exploration of this gap can lead us to a time-oriented understanding of the faculty of language.

QFT, EFT and GFT

We explore the correspondence between geometric function theory (GFT) and quantum field theory (QFT). The crossing symmetric dispersion relation provides the necessary tool to examine the connection between GFT, QFT, and effective field theories (EFTs), enabling us to connect with the crossing-symmetric EFT-hedron. Several existing mathematical bounds on the Taylor coefficients of Typically Real functions are summarized and shown to be of enormous use in bounding Wilson coefficients in the context of 2-2 scattering. We prove that two-sided bounds on Wilson coefficients are guaranteed to exist quite generally for the fully crossing symmetric situation. Numerical implementation of the GFT constraints (Bieberbach-Rogosinski inequalities) is straightforward and allows a systematic exploration. A comparison of our findings obtained using GFT techniques and other results in the literature is made. We study both the three-channel as well as the two-channel crossing-symmetric cases, the latter having some crucial differences. We also consider bound state poles as well as massless poles in EFTs. Finally, we consider nonlinear constraints arising from the positivity of certain Toeplitz determinants, which occur in the trigonometric moment problem.

Systematic exploration of Escherichia coli phage–host interactions with the BASEL phage collection

Bacteriophages, the viruses infecting bacteria, hold great potential for the treatment of multidrug-resistant bacterial infections and other applications due to their unparalleled diversity and recent breakthroughs in their genetic engineering. However, fundamental knowledge of the molecular mechanisms underlying phage–host interactions is mostly confined to a few traditional model systems and did not keep pace with the recent massive expansion of the field. The true potential of molecular biology encoded by these viruses has therefore remained largely untapped, and phages for therapy or other applications are often still selected empirically. We therefore sought to promote a systematic exploration of phage–host interactions by composing a well-assorted library of 68 newly isolated phages infecting the model organism Escherichia coli that we share with the community as the BASEL (BActeriophage SElection for your Laboratory) collection. This collection is largely representative of natural E. coli phage diversity and was intensively characterized phenotypically and genomically alongside 10 well-studied traditional model phages. We experimentally determined essential host receptors of all phages, quantified their sensitivity to 11 defense systems across different layers of bacterial immunity, and matched these results to the phages’ host range across a panel of pathogenic enterobacterial strains. Clear patterns in the distribution of phage phenotypes and genomic features highlighted systematic differences in the potency of different immunity systems and suggested the molecular basis of receptor specificity in several phage groups. Our results also indicate strong trade-offs between fitness traits like broad host recognition and resistance to bacterial immunity that might drive the divergent adaptation of different phage groups to specific ecological niches. We envision that the BASEL collection will inspire future work exploring the biology of bacteriophages and their hosts by facilitating the discovery of underlying molecular mechanisms as the basis for an effective translation into biotechnology or therapeutic applications.