There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?

/pdf/antimicrobial-peptides-of-multicellular-organisms-24vvoqtunk.pdf

Antimicrobial peptides of multicellular organisms

The use of and search for drugs and dietary supplements derived from plants have accelerated in recent years. Ethnopharmacologists, botanists, microbiologists, and natural-products chemists are combing the Earth for phytochemicals and “leads” which could be developed for treatment of infectious diseases. While 25 to 50% of current pharmaceuticals are derived from plants, none are used as antimicrobials. Traditional healers have long used plants to prevent or cure infectious conditions; Western medicine is trying to duplicate their successes. Plants are rich in a wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have been found in vitro to have antimicrobial properties. This review attempts to summarize the current status of botanical screening efforts, as well as in vivo studies of their effectiveness and toxicity. The structure and antimicrobial properties of phytochemicals are also addressed. Since many of these compounds are currently available as unregulated botanical preparations and their use by the public is increasing rapidly, clinicians need to consider the consequences of patients self-medicating with these preparations.

Plant Products as Antimicrobial Agents

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.

For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.

Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

/pdf/guidelines-for-the-use-and-interpretation-of-assays-for-ijf2t30pbq.pdf

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Since the discovery of amphotericin B in 1955 the armamentarium of antimycotic drugs now embraces many new chemical classes: azoles, allylamines and candins. However, despite the wide variety in chemical structure, there is a lack of diversity in terms of mechanism of action. The mechanism of action of the main classes of antimycotics as well as the therapeutic value of some representatives is discussed. Some challenges to innovation will be highlighted that when overcome will herald more effective therapeutic interventions. Finally, we will list antimycotics that are at a late stage of development.

/pdf/a-general-overview-on-past-present-and-future-antimycotics-3h1o9cny0l.pdf

A General Overview on Past, Present and Future Antimycotics

Invasive fungal infections caused by opportunistic fungal pathogens are associated with high mortality rates, mainly due to the occurrence of genotypic and/or phenotypic resistance. One of the causes of phenotypic resistance is the preferred growth of various fungal pathogens as biofilms, which are tolerant or resistant to most classes of antifungal agents. Moreover, increasing evidence points to biofilm formation as a general prerequisite for the development of systemic infections. Therefore, new antibiofilm agents are urgently needed to reduce the incidence of biofilm-associated infections. Nowadays, antimicrobial peptides (AMPs) are considered as valuable alternatives for or complements to the classical antifungal agents to combat fungal infections. Many review reports describe activity of AMPs against free-living planktonic fungal pathogens. In contrast, this review summarizes the antibiofilm properties of natural or synthetic AMPs against fungal biofilms and their potential to enhance the antibiofilm activity of existing antifungal agents.

Antimicrobial Peptides as a Strategy to Combat Fungal Biofilms.

Despite the availability of various classes of antimycotics, the treatment of patients with systemic fungal infections is challenging. Therefore the development of new antifungals is urgently required. Promising new antifungal candidates are antimicrobial peptides. In the present review, we provide an overview of antifungal peptides isolated from plants, insects, amphibians and mammals that induce apoptosis. Their antifungal spectrum, mode of action and toxicity are discussed in more detail.

Apoptosis-inducing antifungal peptides and proteins.

The protein kinase Sch9 is proposed to be a downstream effector of TORC1 that is required for activation of ribosome biogenesis and repression of entry into G(0). However, Sch9 apparently functions antagonistically to TORC1, when considering the induction of several stress defence genes that are normally repressed by TORC1. To further investigate the relationship between Sch9 and TORC1, we compared the rapamycin-induced transcriptional responses in an sch9 Delta mutant and the isogenic wild type. The data indicate that Sch9 is necessary for proper integration of the rapamycin-induced stress signal, i.e. in sch9 Delta cells, typical effects of rapamycin-like repression of ribosomal protein genes and induction of stress response genes are diminished or abolished. Moreover, they reveal for the first time a direct link between Sch9 and nitrogen metabolism. A sch9 Delta mutant has an increased basal activation of targets of the general amino acid control pathway and of the nitrogen discrimination pathway, including the ammonium permease MEP2 and the amino acid permease GAP1. The mutant also shows enhanced expression of the transcription factor Gcn4 required for amino acid biosynthesis. Our data favour a model in which (1) the role of Sch9 in the general stress response switches depending on TORC1 activity and (2) Sch9 and TORC1 have independent and additive effects on genes induced upon nitrogen and amino acid starvation.

Genome-wide expression analysis reveals TORC1-dependent and -independent functions of Sch9.

Both bacterial cyclic lipodepsipeptide syringomycin E and plant defensin DmAMP1 were shown previously to require expression of the yeast gene IPT1 for fungicidal action against Saccharomyces cerevisiae. IPT1 encodes a sphingolipid biosynthetic pathway glycotransferase that produces the terminal sphingolipid mannosyldiinositolphosphoceramide. However, when grown in half-strength potato dextrose medium, an ipt1 deletion mutant of S. cerevisiae was observed to be sensitive to syringomycin E and DmAMP1 and to produce small amounts of mannosyldiinositolphosphoceramide. These results show that the terminal sphingolipid but not IPT1 expression is required for fungicidal activity, and they suggest an IPT1-independent route for mannosyldiinositolphosphoceramide biosynthesis.

Karin Thevissen

Papers

A General Overview on Past, Present and Future Antimycotics

Antimicrobial Peptides as a Strategy to Combat Fungal Biofilms.

Apoptosis-inducing antifungal peptides and proteins.

Genome-wide expression analysis reveals TORC1-dependent and -independent functions of Sch9.

IPT1-independent sphingolipid biosynthesis and yeast inhibition by syringomycin E and plant defensin DmAMP1.