Binary Expression Enhances Reliability of Messaging in Gene Networks.

The promoter state of a gene and its expression levels are modulated by the amounts of transcription factors interacting with its regulatory regions. Hence, one may interpret a gene network as a communicating system in which the state of the promoter of a gene (the source) is communicated by the amounts of transcription factors that it expresses (the message) to modulate the state of the promoter and expression levels of another gene (the receptor). The reliability of the gene network dynamics can be quantified by Shannon's entropy of the message and the mutual information between the message and the promoter state. Here we consider a stochastic model for a binary gene and use its exact steady state solutions to calculate the entropy and mutual information. We show that a slow switching promoter with long and equally standing ON and OFF states maximizes the mutual information and reduces entropy. That is a binary gene expression regime generating a high variance message governed by a bimodal probability distribution with peaks of the same height. Our results indicate that Shannon's theory can be a powerful framework for understanding how bursty gene expression conciliates with the striking spatio-temporal precision exhibited in pattern formation of developing organisms.

Post-COVID-19 condition: systemic inflammation and low functional exercise capacity.

Introduction: Post-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported. Methods: In this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6-12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group (n = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment. Results: SRPF presented lower IL-4 concentration compared with Control (q = 0.0018) and with SR (q = 0.030), and lower IFN-α2 serum content compared with Control (q = 0.007). In addition, SRPF presented higher MIP-1ß serum concentration compared with SR (q = 0.029). SR presented lower CCL11 (q = 0.012 and q = 0.001, respectively) and MCP-1 levels (q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control (q = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF (q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group (q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes.

A Stochastic Binary Model for the Regulation of Gene Expression to Investigate Responses to Gene Therapy.

In this manuscript, we use an exactly solvable stochastic binary model for the regulation of gene expression to analyze the dynamics of response to a treatment aiming to modulate the number of transcripts of a master regulatory switching gene. The challenge is to combine multiple processes with different time scales to control the treatment response by a switching gene in an unavoidable noisy environment. To establish biologically relevant timescales for the parameters of the model, we select the RKIP gene and two non-specific drugs already known for changing RKIP levels in cancer cells. We demonstrate the usefulness of our method simulating three treatment scenarios aiming to reestablish RKIP gene expression dynamics toward a pre-cancerous state: (1) to increase the promoter's ON state duration; (2) to increase the mRNAs' synthesis rate; and (3) to increase both rates. We show that the pre-treatment kinetic rates of ON and OFF promoter switching speeds and mRNA synthesis and degradation will affect the heterogeneity and time for treatment response. Hence, we present a strategy for reaching increased average mRNA levels with diminished heterogeneity while reducing drug dosage by simultaneously targeting multiple kinetic rates that effectively represent the chemical processes underlying the regulation of gene expression. The decrease in heterogeneity of treatment response by a target gene helps to lower the chances of emergence of resistance. Our approach may be useful for inferring kinetic constants related to the expression of antimetastatic genes or oncogenes and for the design of multi-drug therapeutic strategies targeting the processes underpinning the expression of master regulatory genes.

Myokines in treatment-naïve patients with cancer-associated cachexia.

Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naïve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways.

Hyperplastic polyposis: a case report / Polipose hiperplásica: relato de caso

OBJECTIVE: The authors present a case report of hyperplastic polyposis syndrome from the Coloproctology Service, Vitória Apart Hospital, Vitória-ES. CASE STUDY: Our case is a 24-year-old man who suffered from fatigue, malaise and microcytic and hypochromic anemia, whose upper digestive endoscopy presented several hyperplastic polyps in the stomach and whose colonoscopy revealed colonic polyposis mainly in the right colon; the histopathology showed tubular adenoma with moderate atypia in the ascending colon. Thus, a videolaparoscopic right colectomy was performed; the analysis of the surgical fragment showed multiple (more than 30) polyps distributed through the cecum and ascending colon. CONCLUSION: The histopathological diagnosis of hyperplastic polyposis is a challenging task. In general, most polyps are hyperplastic, but serrated and classic adenomas also occur. These associated adenomatous injuries can be the cause of malignant transformation. So far, there is no consensus about the appropriate treatment; however, a colectomy procedure may be beneficial in a scenario of a large number of hyperplastic polyps, concurrent serrated adenomas, or multiple high-risk adenomatous lesions. (AU)

A Síndrome Polipose Hiperplásica (HPS), descrita em 1980, é considerada como a presença de pólipos hiperplásicos múltiplos, grandes e/ou proximais e, ocasionalmente, um número menor de adenomas serrados, adenomas clássicos e pólipos mistos. A grande maioria dos pacientes são assintomáticos, sendo o diagnóstico um achado incidental da colonoscopia. No tocante ao prognóstico, a maioria dos autores considera HPS um achado incidental sem potencial de malignização, porém, estudos recentes têm descrito lesões genéticas sincrônicas à HPS e ao câncer colorretal. OBJETIVO: Os autores apresentam um relato de caso de Síndrome Polipose Hiperplásica do serviço de coloproctologia do Vitória Apart Hospital, Vitória-ES. CASO CLÍNICO: Trata-se de um paciente de 24 anos, masculino, que apresentava fadiga, adinamia e anemia microcitica e hipocrômica que apresentou na Endoscopia Digestiva Alta: diversos pólipos hiperplásicos no estômago e na Colonoscopia: polipose colônica principalmente em cólon direito cujo histopatológico demonstrou adenoma tubular com atipia moderada no ascendente. Para tal foi realizado colectomia direita videolaparoscópica em que a análise da peça mostrou múltiplos pólipos hiperplásicos distribuídos pelo ceco e cólon ascendente, superior a 30. CONCLUSÃO: O diagnóstico histopatológico de HPS é desafiador. Em geral, a maioria dos pólipos são hiperplásicos, mas também ocorrem adenomas serrados e adenomas clássicos. Tais lesões adenomatosas associadas podem ser a causa de transformações malignas. Ainda não há consenso do tratamento adequado, porém, a colectomia pode ser benéfica quando há grande número de pólipos hiperplásicos, adenomas serrados concomitantes ou múltiplas lesões adenomatosas de alto risco. (AU)