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Finally, we noticed that the most frequent MKK4 mutation observed in cancer, R134W, which role has not been disclosed to date, contributes to the dimer stability. Based on these data we postulate that MKK4 occurs as a dimer in its inactive autoinhibited state, providing an additional layer for its activity regulation.Protein-protein interactions regulate almost all cellular functions and rely on a fine tune of surface amino acids properties involved on both molecular partners. The disruption of a molecular association can be caused even by a single residue mutation, often leading to a pathological modification of a biochemical pathway. Therefore the evaluation of the effects of amino acid substitutions on binding, and the ad hoc design of protein-protein interfaces, is one of the biggest challenges in computational biology. Here, we present a novel strategy for computational mutation and optimization of protein-protein interfaces. Modeling the interaction surface properties using the Zernike polynomials, we describe the shape and electrostatics of binding sites with an ordered set of descriptors, making possible the evaluation of complementarity between interacting surfaces. With a Monte Carlo approach, we obtain protein mutants with controlled molecular complementarities. Applying this strategy to the relevant case of the interaction between Ferritin and Transferrin Receptor, we obtain a set of Ferritin mutants with increased or decreased complementarity. The extensive molecular dynamics validation of the method results confirms its efficacy, showing that this strategy represents a very promising approach in designing correct molecular interfaces.Extracellular vesicles (EVs) are membrane-coated particles secreted by virtually all cell types in response to different stimuli, both in physiological and pathological conditions. Their content generally reflects their biological functions and includes a variety of molecules, such as nucleic acids, proteins and cellular components. The role of EVs as signaling vehicles has been widely demonstrated. In particular, they are actively involved in the pathogenesis of several hematological malignancies (HM), mainly interacting with a number of target cells and inducing functional and epigenetic changes. In this regard, by releasing their cargo, EVs play a pivotal role in the bilateral cross-talk between tumor microenvironment and cancer cells, thus facilitating mechanisms of immune escape and supporting tumor growth and progression. Recent advances in high-throughput technologies have allowed the deep characterization and functional interpretation of EV content. In this review, the current knowledge on the high-throughput technology-based characterization of EV cargo in HM is summarized.Structures of protein-drug-complexes provide an atomic level profile of drug-target interactions. In this work, the three-dimensional arrangements of amino acid side chains in known drug binding sites (substructures) were used to search for similarly arranged sites in SARS-CoV-2 protein structures in the Protein Data Bank for the potential repositioning of approved compounds. We were able to identify 22 target sites for the repositioning of 16 approved drug compounds as potential therapeutics for COVID-19. Using the same approach, we were also able to investigate the potentially promiscuous binding of the 16 compounds to off-target sites that could be implicated in toxicity and side effects that had not been provided by any previous studies. The investigations of binding properties in disease-related proteins derived from the comparison of amino acid substructure arrangements allows for effective mechanism driven decision making to rank and select only the compounds with the highest potential for success and safety to be prioritized for clinical trials or treatments. Syrosingopine cost The intention of this work is not to explicitly identify candidate compounds but to present how an integrated drug repositioning and potential toxicity pipeline using side chain similarity searching algorithms are of great utility in epidemic scenarios involving novel pathogens. In the case of the COVID-19 pandemic caused by the SARS-CoV-2 virus, we demonstrate that the pipeline can identify candidate compounds quickly and sustainably in combination with associated risk factors derived from the analysis of potential off-target site binding by the compounds to be repurposed.Multicultural behavior analysts must stand together to address the issues of systemic racism collectively, show solidarity, and support Black lives. This article discusses the role of culturally and linguistically diverse behavior analysts, the mechanisms underlying barriers to showing solidarity, and the mechanisms required for cultural evolution to promote a compassionate and nurturing approach to racial equity. It is critical that non-Black people of color actively participate in antiracist advocacy to express solidarity with the Black Lives Matter movement.The COVID-19 pandemic has presented practitioners of applied behavior analysis (ABA) with new and uncharted challenges. Upholding ethical responsibilities while navigating an international public health crisis has opened areas of uncertainty that have no precedent. Although there is general guidance on how to respond ethically from the Behavior Analyst Certification Board (BACB) in their publication specific to the COVID-19 crisis (BACB, 2020, March 29, Ethics Guidance for ABA Providers During COVID-19 Pandemic, retrieved from https//www.bacb.com/ethics-guidance-for-aba-providers-during-covid-19-pandemic-2/), there remains a huge responsibility on the individual practitioner to make potentially life-changing decisions. In that regard, practitioners are urged to ensure that they rely on socially significant and valid decision-making processes. The goal of this article is to provide an exercise in accounting for stakeholder feedback and connecting with patients and families regarding their input on the acceptability of treatment during the COVID-19 pandemic. The exercise is in the form of a structured parent interview to help practitioners account for the setting variables and social validity of treatment during a crisis. It is our ethical responsibility to remember this critical dimension of our science and practice.At present, the earthquake-risk perception research in Aceh only focuses on the general public. Limited research examines earthquake-risk perceptions amongst students. This exploratory study is focused on geography education students because this study programme has integrated disaster education into its curriculum. This study aims to find the extent to which earthquake knowledge and fatalism beliefs affect earthquake-risk perception. The survey was conducted on 210 students using questionnaires. Using the Spearman correlation test, the results of this study revealed that there was a positive and significant relationship between earthquake knowledge and risk perception with coefficients (0.200) and significance (0.004). Meanwhile, fatalism beliefs have a negative and significant relationship to the perception of earthquake risk with correlation coefficient (-0.224) and significance (0.001). This means that the higher the fatalism attitude of students towards disasters, the lower the perception of earthquake risk. It is feared that fatalism will have an impact on the lack of disaster preparedness. Fatalism beliefs are complex issues that require joint efforts from governments, religious leaders, educational institutions and the media to reduce them.Collaborative governance and social capital can help to form a resilient community in the wake of a disaster, such as the eruptions of Mount Merapi in Indonesia. This study examines the successfulness of the handling of disasters in Indonesia, with particular focus on eruptions of Mount Merapi. Disasters foster a close relationship between the government and the community in response to the emergency. This study uses a mixed method to analyse social networks in evaluating the structure of disaster networks in Indonesia and their implications for disaster management. Data were collected via a survey of 100 respondents from 28 institutions representing, for practical purposes, each population identified by each institution (government, non-governmental organisations and volunteers) that participated in handling the Merapi eruption disaster. The findings revealed that considerable miscommunication between institutions reduced the effectiveness of disaster management so that close discussion about conflict resolution was needed to develop more mature and systematic planning. Inter-agency trust is also felt to be necessary in disaster management. Trust between agency members and other institutions strongly supports the success of systematic disaster management. Meanwhile, every institution must foster open leadership by giving individuals with precise knowledge of the situation and the condition of the disaster area a mandate to lead directly in the field. Disaster governance is carried out through the agreement of each institution formed in the Disaster Emergency Planning (Rencana Penanggulangan Kedaruratan Bencana - RPKB) guidelines. These guidelines expect the Government and the community to coordinate with each other in a structured and systematic manner in the process of disaster management.The purpose of this article is to analyse the results of a survey towards the architects and engineers of construction in order to estimate the perception of the anti-seismic protection amongst these professionals. It focuses more on the architects who design buildings and, in many cases, monitor their implementation. The main result is the observation of inadequacies and gaps in seismic culture amongst the professionals, especially architects. These difficulties require the reinforcement of earthquake-resistant training. This effort to upgrade skills is as important as other aspects of the preventive management of the seismic risk in Algeria.Despite annual climate variability threats, traditional farming in semi-arid Zimbabwe remains entrenched in unproductive, rain-fed agricultural practices. Adaptation strategies by farmers are seemingly failing to mitigate climate impacts, as evidenced by annual crop and livestock losses. Matabeleland South Province was a thriving livestock and small grain-producing province in the 1970s. Today, the province relies heavily on humanitarian assistance from government and humanitarian agencies. Through literature review, observations and focus group discussions with 129 farmers, the qualitative study established the perceptions of farmers around climate variability impacts in the past 20 years in Mangwe, Matobo and Gwanda districts in Zimbabwe. The study (1) analysed changes in climate and weather patterns in the past 20 years; (2) analysed climate impacts on traditional farming systems in the past 20 years in Gwanda, Mangwe and Matobo districts in Zimbabwe; and (3) established farmers' perceptions, experiences adern practices are highly recommended to enhance resilience to climate.
Accelerated partial breast irradiation (APBI) is an alternative approach to breast conserving therapy (BCT) where radiation (RT) is delivered over a shorter period of time compared with whole breast irradiation (WBI), resulting in improved patient convenience and cost savings. APBI can be delivered using brachytherapy, intraoperative RT, or conformal external beam radiation therapy (EBRT) techniques. In this review, the authors appraise the latest modern randomized controlled trials (RCTs) of APBI and discuss the application of the data to clinical practice.

The OCOG-RAPID and NSABP B-39/RTOG 0413 trials recently reported long-term outcomes of APBI. The OCOG-RAPID trial delivered 38.5Gy/10 fractions twice daily (at least 6h apart using EBRT) or WBI and demonstrated non-inferiority of APBI compared with WBI (8-year cumulative rate of ipsilateral breast tumor recurrence (IBTR) was 3% after APBI or 2.8% after WBI, HR 1.27, 90%CI 0.84-1.91). While acute toxicity was reduced, late toxicity and breast cosmesis were worse with APBI.
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