The Digital Agricultural Knowledge and Information System (DAKIS): Employing digitalisation to encourage diversified and multifunctional agricultural systems.

Multifunctional and diversified agriculture can address diverging pressures and demands by simultaneously enhancing productivity, biodiversity, and the provision of ecosystem services. The use of digital technologies can support this by designing and managing resource-efficient and context-specific agricultural systems. We present the Digital Agricultural Knowledge and Information System (DAKIS) to demonstrate an approach that employs digital technologies to enable decision-making towards diversified and sustainable agriculture. To develop the DAKIS, we specified, together with stakeholders, requirements for a knowledge-based decision-support tool and reviewed the literature to identify limitations in the current generation of tools. The results of the review point towards recurring challenges regarding the consideration of ecosystem services and biodiversity, the capacity to foster communication and cooperation between farmers and other actors, and the ability to link multiple spatiotemporal scales and sustainability levels. To overcome these challenges, the DAKIS provides a digital platform to support farmers' decision-making on land use and management via an integrative spatiotemporally explicit approach that analyses a wide range of data from various sources. The approach integrates remote and in situ sensors, artificial intelligence, modelling, stakeholder-stated demand for biodiversity and ecosystem services, and participatory sustainability impact assessment to address the diverse drivers affecting agricultural land use and management design, including natural and agronomic factors, economic and policy considerations, and socio-cultural preferences and settings. Ultimately, the DAKIS embeds the consideration of ecosystem services, biodiversity, and sustainability into farmers' decision-making and enables learning and progress towards site-adapted small-scale multifunctional and diversified agriculture while simultaneously supporting farmers' objectives and societal demands.

Lysosomes, growth factor activity, and carcinogenic implications.

The aim of this paper is to point out a body of literature which up to now has been largely ignored by investigators in the area of growth factors This paper will offer a response to the questions: Why is it that inhibition of endolysosomal proteases (by agents such as leupeptin, methylamine, etc.) or inhibition of endocytosis block the activities of all growth factors and carcinogens so far studied? What role therefore can endocytosis and endolysosomes (E/L) play in the signal transduction process? As will be detailed below, in many cases involving growth factors, inhibition of E/L proteases results in complete or very significant loss of growth factor activity. That is, treatment with inhibitors of E/L proteases (i.e., leupeptin, antipain methylamine, etc.) erases the normal activity of growth factors affecting systems of concern to immunologists, endocrinologists, and cardiologists. There are strong indications in the literature that suggest that in the nervous system (of obvious interest to neuroscientists) endocytosis plays a vital role in the induced proliferation of neurons as well (of interest to neurologists). This paper will explore the implications and offer an explanation for these findings. Thus this communication will travel from one growth factor to another in order to demonstrate the universality of the model offered in this paper.

Amino acid-anticodon binding specificity: rationale for a new class of therapeutic agent.

In this article a new class of anticancer and antiviral drugs is discussed. These new drugs consist of small di- and tri-peptides, designed to bind to single-stranded (ss) regions that are crucial for the expression of genes such as the c-myc oncogene in cancers and start sites (and other ss regions) of viral pathogenic genes. The components (i.e. the amino acids and the sequences they form) of these peptides could be dictated by the specific binding of amino acids to their ss anticodons in tRNA. Cancer cell viability depends on the continued overexpression of the c-myc oncogene, and thus this gene is a target of opportunity for anticancer agents. Sharply reducing the overexpression of c-myc leads to the death of cancer cells. To achieve this end the following rationale is suggested: crucial regions of the c-myc promoters (to which activating proteins must bind for expression to occur) are single stranded and thus strongly resemble the anticodon loop of tRNA. It was found that amino acids chemically bind to their cognate tRNA anticodons. Regarding the ss regions of c-myc as a series of adjacent 'anticodons', di- and tri-peptides are proposed to be aligned to their cognate 'anticodons' in the proper order. For example, if the ss region of a promoter is hypothetically TTT-GGG-CCC, the tripeptide Lys-Pro-Gly could be expected to bind to it and deny access of the promoter to all activating proteins, thereby blocking c-myc expression and all the cancers dependent on such overexpression. Similarly, it is reported that in the initial phase of gene expression the start sites of the genes are single stranded (before and after and spanning the start site). Thus, invoking the amino acid cognate anticodon binding specificity (ACABS) principle as described above, a series of small peptides are suggested that could span the start sites of pathogenic viral genes (e.g. the oris region of herpes simplex virus (HSV)) to deny access of the gene to the transcription elements. This would inactivate the toxic effect of the virus and thereby constitute a promising approach to antiviral therapy, where the start sites (or other ss regions of pathogenic genes) have been sequenced. The ACABS principle (for peptide-nucleic-acid interaction) enables us to focus on probable effective small peptides rather than having to screen a large number of randomly chosen small peptides to find probable anticancer and antiviral therapeutic agents.

Role of the endocytic pathway in carcinogenesis.

This commentary was prompted by many reports that carcinogenesis involving various carcinogens and various types of systems is blocked by inhibitors of endolysosomal proteases (i.e. leupeptin, antipain). These findings have been largely ignored by cancer investigators so far. In this commentary based on these reports a carcinogenesis model is suggested that does not involve direct attack by the carcinogen onto target cell DNA. This model proposes the following steps in the initial phase of carcinogenesis: interaction of a carcinogen with an appropriate cell surface receptor (i.e. possibly the receptor for the epidermal growth factor). This carcinogen­receptor complex is endocytosed and fragmented by various cathepsins to form small peptides (i.e. di-and tripeptides) some of which enter the nucleus and interact very specifically with the protein repressors that normally (during G0 phase) inhibit expression of oncogenes critical to the transformation process. This interaction causes removal of the repressors from these oncogenes. The oncogenes, freed from their repressors are then expressed, culminating in carcinogenesis. This then defines the G0/G1 transition comprising the initial phases of carcinogenesis. Note is taken of reports that the only cells transformed in a heterogeneous collection of cells comprising target organs are in the G0 stem cell subpopulation. The need for such an alternative mechanism is outlined in terms of reports that major kinases (i.e. MAPK and PI3K) operate only after entry into cell cycle (during G1). Thus an answer is provided as to what events occur before entry into cell cycle, the events that define the transition from G0 to G1. In addition, note it taken of the recent reports that suggest that epigenetic mechanisms operate in the carcinogenic process and an attempt is made to harmonize the model presented in this commentary with epigenetic mechanisms as proposed in recent years.