Toll Like Receptors as Sensors of the Tumor Microbial Dysbiosis: Implications in Cancer Progression

The microbiota is a complex ecosystem of active microorganisms resident in the body of mammals. Although the majority of these microorganisms resides in the distal gastrointestinal tract, high-throughput DNA sequencing technology has made possible to understand that several other tissues of the human body host their own microbiota, even those once considered sterile, such as lung tissue. These bacterial communities have important functions in maintaining a healthy body state, preserving symbiosis with the host immune system, which generates protective responses against pathogens and regulatory pathways that sustain the tolerance to commensal microbes. Toll-like receptors (TLRs) are critical in sensing the microbiota, maintaining the tolerance or triggering an immune response through the direct recognition of ligands derived from commensal microbiota or pathogenic microbes. Lately, it has been highlighted that the resident microbiota influences the initiation and development of cancer and its response to therapies and that specific changes in the number and distribution of taxa correlate with the existence of cancers in various tissues. However, the knowledge of functional activity and the meaning of microbiome changes remain limited. This review summarizes the current findings on the function of TLRs as sensors of the microbiota and highlighted their modulation as a reflection of tumor-associated changes in commensal microbiota. The data available to date suggest that commensal “onco-microbes” might be able to break the tolerance of TLRs and become complicit in cancer by sustaining its growth.

Plasticity in AAA+ proteases reveals ATP-dependent substrate specificity principles

SummaryIn bacteria, AAA+ proteases such as Lon and ClpXP specifically degrade substrates to promote growth and stress responses. Here, we find that an ATP-binding mutant of ClpX suppresses physiological defects of a Lon-deficient strain by shifting ClpXP protease specificity toward normally Lon-restricted substrates and away from normal ClpXP targets. Reconstitution with purified proteins assigns these effects to changes in direct recognition and processing of substrates. We show that wildtype ClpXP specificity can be similarly altered when ATP hydrolysis is reduced, which unexpectedly accelerates degradation of some substrates. This activation corresponds with changes in ClpX conformation, leading to a model where ClpX cycles between ‘capture’ and ‘processive’ states depending on ATP loading. Limiting ATP binding alters dynamics between states affording better recognition of unorthodox substrates, but worse degradation of proteins specifically bound by the processive state. Thus, AAA+ protease specificities can be directly tuned by differences in ATP hydrolysis rates.HighlightsA mutation in the Walker B region of ClpX induces recognition of new substrates.Proteases are optimized for specific functions but barrier to recognize new substrates is easily overcome.Expanding substrate recognition by a protease comes at the cost of reducing native substrate degradation.Decreasing ATP enhances ClpXP mediated degradation of certain classes of substrates.ClpX adopts distinct conformational states to favor better recognition of some substrates over others.Graphical AbstractIn a wildtype cell, AAA+ proteases Lon and ClpXP promote normal growth by degrading distinct substrates. ClpX*P can compensate for the absence of the Lon protease by tuning ClpXP substrate specificity to better degrade Lon-privileged substrates (such as DnaA, SciP, and misfolded proteins) but this comes at the cost of native ClpXP substrates (such as ssrA-tagged proteins and CtrA). We propose that ClpX alternates between a closed and open conformation and promoting one state over the other leads to alterations in substrate specificity. In the presence of ClpX* or in ATP-limited conditions, the open state is favored, allowing capture and recognition of substrates such as casein. The balance shifts to the closed state under high ATP conditions, allowing degradation of substrates such as GFP-ssrA, which preferentially bind the closed state.

Lessons in Innate and Allergic Immunity From Dust Mite Feces and Tick Bites

Allergic diseases represent a major cause of morbidity in modern industrialized and developing countries. The origins and development of allergic immune responses have proven difficult to unravel and remain an important scientific objective. House dust mites (HDM) and ticks represent two important causes of allergic disease. Investigations into HDM fecal particles and tick bites have revealed insights which have and will continue to shape our understanding of allergic immunity. In the present review, focus is given to the role of innate immunity in shaping the respective responses to HDM and ticks. The HDM fecal particle represents a rich milieu of molecules that can be recognized by pathogen-recognition receptors of the innate immune system. Factors in tick saliva and/or tissue damage resultant from tick feeding are thought to activate innate immune signaling that promotes allergic pathways. Recent evidence indicates that innate sensing involves not only the direct recognition of allergenic agents/organisms, but also indirect sensing of epithelial barrier disruption. Although fecal particles from HDM and bites from ticks represent two distinct causes of sensitization, both involve a complex array of molecules that contribute to an innate response. Identification of specific molecules will inform our understanding of the mechanisms that contribute to allergic immunity, however the key may lie in the combination of molecules delivered to specific sites in the body.

Lactoferrin Against SARS-CoV-2: In Vitro and In Silico Evidences

Lactoferrin (Lf) is a cationic glycoprotein synthetized by exocrine glands and is present in all human secretions. It is also secreted by neutrophils in infection and inflammation sites. This glycoprotein possesses antimicrobial activity due to its capability to chelate two ferric ions per molecule, as well as to interact with bacterial and viral anionic surface components. The cationic features of Lf bind to cells, protecting the host from bacterial and viral injuries. Its anti-inflammatory activity is mediated by the ability to enter inside the nucleus of host cells, thus inhibiting the synthesis of proinflammatory cytokine genes. In particular, Lf down-regulates the synthesis of IL-6, which is involved in iron homeostasis disorders and leads to intracellular iron overload, favoring viral replication and infection. The well-known antiviral activity of Lf has been demonstrated against DNA, RNA, and enveloped and naked viruses and, therefore, Lf could be efficient in counteracting also SARS-CoV-2 infection. For this purpose, we performed in vitro assays, proving that Lf exerts an antiviral activity against SARS-COV-2 through direct attachment to both SARS-CoV-2 and cell surface components. This activity varied according to concentration (100/500 μg/ml), multiplicity of infection (0.1/0.01), and cell type (Vero E6/Caco-2 cells). Interestingly, the in silico results strongly supported the hypothesis of a direct recognition between Lf and the spike S glycoprotein, which can thus hinder viral entry into the cells. These in vitro observations led us to speculate a potential supplementary role of Lf in the management of COVID-19 patients.

Characterization of the Anti-Inflammatory Capacity of IL-10-Producing Neutrophils in Response to Streptococcus pneumoniae Infection

Neutrophils are immune cells classically defined as pro-inflammatory effector cells. However, current accumulated evidence indicates that neutrophils have more versatile immune-modulating properties. During acute lung infection with Streptococcus pneumoniae in mice, interleukin-10 (IL-10) production is required to temper an excessive lung injury and to improve survival, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during S. pneumoniae infection remain unknown. Here we show that neutrophils are the main myeloid cells that produce IL-10 in the lungs during the first 48 h of infection. Importantly, in vitro assays with bone-marrow derived neutrophils confirmed that IL-10 can be induced by these cells by the direct recognition of pneumococcal antigens. In vivo, we identified the recruitment of two neutrophil subpopulations in the lungs following infection, which exhibited clear morphological differences and a distinctive profile of IL-10 production at 48 h post-infection. Furthermore, adoptive transfer of neutrophils from WT mice into IL-10 knockout mice (Il10-/-) fully restored IL-10 production in the lungs and reduced lung histopathology. These results suggest that IL-10 production by neutrophils induced by S. pneumoniae limits lung injury and is important to mediate an effective immune response required for host survival.

Inclusive Education in the Illusio Space. A Proposal to Research the School FIeld

This article describes planned research on the practice of inclusive education in Poland in the context of Pierre Bourdieu's [3] concept of society, in which field is one of the basic concepts. In using this term, the author intends to describe the social space of the school, the social space’s organization, and the state of the school’s social position; as well as to answer the question: What is the reality of inclusive education, as analyzed using the illusio category? It is necessary to analyze the state of the implementation of the assumptions made by inclusive education in primary schools, and to find out the opinions of teachers working with students covered by this type of education. In P. Bourdieu’s [3] concept of society, the field is the source of what is social, it shapes it in those who are within its area of influence. This “attitude” is called illusio [11, p. 188]. Illusio is a state of engrossment in a game that the participant is unaware of. This is the result of direct recognition of the field's requirements. Everyday educational life in the context of P. Bourdieu's concept falls within the field of activities of the Ministry of National Education. The teacher takes part in a game whose rules are set by the Ministry of National Education. In the context of the proposed research within the scope of the field, apart from teachers, there are also the parents of the children covered by inclusive education.

Islam and Art: An Overview

Modern terms like “religion” and “art” offer limited access to the ways in which nonverbal human creativity in the Islamic world engages the “way of life” indicated by the Arabic word din, often translated as religion. Islam emerged within existing paradigms of creativity and perception in the late antique world. Part of this inheritance was a Platonic and Judaic concern with the potentially misleading power to make images, often misinterpreted in the modern world as an “image prohibition.” Rather, the image function extended beyond replication of visual reality, including direct recognition of the Divine as manifest in the material and cultural world. Music, geometry, writing, poetry, painting, devotional space, gardens and intermedial practices engage people with the “way of life” imbued with awareness of the Divine. Rather than externally representing religious ideas, creativity fosters the subjective capacity to recognize the Divine. Flexible enough to transcend the conventions of time and place over the millennium and a half since the inception of Islam, these modes of engagement persist in forms that also communicate through the expressive practices of contemporary art. To consider religion and art in Islam means to think about how each of these categories perpetually embodies, resists, and recreates the others.

Fault Detection by Using Instance Segmentation

Fault detection is an important, but time-consuming task in seismic data interpretation. Traditionally, seismic attributes, such as coherency (Marfurt et al., 1998) and curvature (Al-Dossary et al., 2006) are used to detect faults. Recently, machine learning methods, such as convolution neural networks (CNNs) are used to detect faults, by applying various semantic segmentation algorithms to the seismic data (Wu et al., 2019). The most used algorithm is U-Net (Ronneberger et al., 2015), which can accurately and efficiently provide probability maps of faults. However, probabilities of faults generated by semantic segmentation algorithms are not sufficient for direct recognition of fault types and reconstruction of fault surfaces. To address this problem, we propose, for the first time, a workflow to use instance segmentation algorithm to detect different fault lines. Specifically, a modified CNN (LaneNet; Neven et al., 2018) is trained using automatically generated synthetic seismic images and corresponding labels. We then test the trained CNN using both synthetic and field collected seismic data. Results indicate that the proposed workflow is accurate and effective at detecting faults.

PERANCANGAN APLIKASI SISTEM INFORMASI DATA PRODUKSI PADA PT SHIROKI INDONESIA BERBASIS JAVA NETBEANS

Perancangan Aplikasi Sistem Informasi data produksi, bertujuan untuk mempermudah dalam mengelola data produksi yang terdapat pada PT. Shiroki Indonesia, sehingga pendataan menjadi efektif, efisien, tepat guna, dan dapat membantu menyelesaikan permasalahan yang berkenan dengan pengelolaan data produksi PT. Shiroki Indonesia. Metode penelitian yang digunkan untuk perancangan aplikasi data produksi ini adalah metode penilitian kualitatif dan metode pengumpulan data dengan cara pengenalan langsung (observasi). Selain itu penulis juga melakukan penelitian dengan metode kepustakaan berdasarkan refrensi dan berbagai media yang memuat informasi yang dibutuhkan, menganalisa kebutuhan , perancangan, pengujian, dan implementasi sistem. Perancangan Aplikasi data produksi ini tercipta dengan dukungan bahasa pemrograman Java dan database MySql Designing Production Data Information System Application, aims to make it easier to manage production data contained in PT. Shiroki Indonesia, so that the data collection becomes effective, efficient, effective, and can help solve problems that are pleased with the management of PT. Shiroki Indonesia. The research method used for the design of production data applications is a qualitative research method and data collection methods by direct recognition (observation). In addition, the authors also conduct research with library methods based on references and various media that contain information needed, analyze needs, design, test, and implement systems. The design of this production data application was created with the support of the Java programming language and MySql database.

Design and synthesis of purine nucleoside analogues for the formation of stable anti-parallel-type triplex DNA with duplex DNA bearing the 5mCG base pair

We herein demonstrated for the first time the direct recognition of duplex DNA bearing the 5-methyl-2′-deoxycytosine and 2′-deoxyguanosine base pair by triplex DNA formation.