Tumor microenvironment as the “regulator” and “target” for gene therapy

In this review, we focus on strategies for designing functional nano gene carriers, as well as choosing therapeutic genes targeting the tumor microenvironment. Gene mutations have a great impact on the occurrence of cancer. Thus, gene therapy plays a major role in cancer therapy and has the potential to cure cancer. Well‐designed gene therapy largely relies on effective gene carriers, which can be divided into viral carriers and non‐viral carriers. A gene carrier delivers functional genes to their intracellular target and avoids nucleic acids being degraded by nucleases in the serum. Most conventional cancer gene therapies only target cancer cells and do not appear to be sufficintly efficient to pass clinical trials. Accumulating evidence has shown that extending the therapeutic strategies to the tumor microenvironment, rather than the tumor cell itself, can allow more options for achieving robust anti‐cancer efficiency. In addition, unusual features between tumor microenvironment and normal tissues, such as a lower pH, higher glutathione and reactive oxygen species concentrations, and overexpression of some enzymes, facilitate the design of smart stimuli‐responsive gene carriers regulated by the tumor microenvironment. These carriers interact with nucleic acids and then form stable nanoparticles under physiological conditions. By regulation of the tumor microenvironment, stimuli‐responsive gene carriers are able to change their properties and achieve high gene delivery efficiency. Considering the tumor microenvironment as the “regulator” and “target” when designing gene carriers and choosing therapeutic genes shows significant benefit with respect to improving the accuracy and efficiency of cancer gene therapy.     

“Capacity”, “best interests”, “will and preferences” and the UN Convention on the Rights of Persons with Disabilities

The United Nations (UN) Convention on the Rights of Persons with Disabilities (CRPD) is the most up‐to‐date international legal instrument concerning the rights of persons with disabilities. Such persons are taken to include those with serious mental disorders. According to an authoritative interpretation of a crucial Article (Article 12 ‐ Equal recognition before the law) by the UN CRPD Committee, involuntary detention and treatment of people with mental health disabilities are prohibited under the Convention. Both conventional mental health law and “capacity‐based” law are deemed to violate the Convention. However, some other UN bodies are not in full agreement (for example, the UN Human Rights Committee and the Subcommittee on Prevention of Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment), while others are less explicitly absolutist (for example, the Human Rights Council). Furthermore, strong criticisms of the position of the CRPD Committee have been mounted from a number of academic quarters. These criticisms center on whether the role of a person's ability to make a decision can be ignored, no matter the circumstances. Much of the above debate turns on the concept of “legal capacity” and the now often‐repeated precept that one must always respect the “will and preferences” of the person with a disability. However, “will and preferences” remains undefined. In this paper, I offer an analysis of “will and preferences” that can clarify interventions that may be acceptable or non‐acceptable under the terms of the UN Convention.     

Distribution of the Character States “Early Sympetaly” and “Late Sympetaly” Within the “Sympetalae Tetracyclicae” and Presumably Allied Groups*

Within the Asteridae (“Sympetalae Tetracyclicae”) two main developmental patterns can be distinguished as regards the formation of corolla tubes, namely “early” and “late sympetaly”. Since the character “ontogeny of sympetaly”, after intensive studies, proved to be valuable for systematic considerations, we now recognize two blocks of orders within the Asteridae (and related groups): the Asteridae A-block and the Asteridae B-block (Figs. 82 and 83). By and large this bipartition referring mainly to the corolla tube development corresponds well with major lineages indentified by recent molecular data (see, e.g., Chase et al., 1993). Asteridae A-block is characterized predominantely by “late sympetaly” the “early sympetaly” in Rubiales and Oleales can be interpreted as derived within this block or can be linked with that in Asteridae B-block. Asteridae B-block is uniform throughout in its “early sympetaly”. In this block it is a primitive character, as judged from its occasional occurrence in the choripetalous Cornales and Apiales (Apiaceae, Araliaceae, Pittosporaceae), which can be regarded as ancestral for block B.     

“Laughter” and “Smile” in Barbary Macaques (Macaca sylvanus)

In an observational study on semi-free Barbary macaques it was investigated whether the phylogenetic roots of human laughter and smile can be traced back to the genus Macaca. On the basis of morphological similarity a ‘relaxed open-mouth display’ as the phylogenetic precursor of the laughter, and a ‘silent bared-teeth display’ as the possible ancestor of the smile can be distinguished in the repertory of the Barbary macaque. Behavioural sequences from focal animal protocols were analyzed in order to establish message and meaning of both displays. Relaxed open-mouth display is regularly observed in the play interactions of juveniles. It is associated with partner-directed behaviour, it is frequently answered by a relaxed open-mouth display of the receiver, and accompanied by a special vocalization. Although up to 50% of the juvenile's play partners were higher ranking than themselves voluntary participation was the rule. Most characteristically, the behaviour patterns shown by both play partners are highly symmetrical and synchronized. Silent bared-teeth display is typically accompanied by evasive or submissive body movements, and occurs primarily in dyadic interactions, mainly by the lower ranking individual. It is not an unidirectional sign of a linear dominance hierarchy, though. Silent bared-teeth display is a frequent answer to aggressive behaviour shown by the receiver. After its performance, an increase of body contact between sender and receiver was observed. Behavioural sequences of senders and receivers are complementary, but lose their asymmetry after occurrence of the display. It is concluded that these results further support Van Hooff 's (1972) view that human laughter and smile have different phylogenetic roots: while silent bared-teeth display is a signal of submission and appeasement, relaxed open-mouth display is rightly called the ‘play face’, and is an expression of fun.     

“Active” and “passive” ecological restoration strategies in meta‐analysis

One of the means of creating a more robust methodology for ecological restoration involves reducing the gap between ecological theory and restoration practices. A common strategy to do so is using meta‐analysis to understand key drivers of restoration outcomes. “Active” and “passive” is a dichotomy often used to separate restoration strategies in such meta‐analyses. We investigate previously raised concerns about selection bias and subjective categorization of strategies. We promote a paired experimental design in future empirical research and propose the use of three categories of restoration strategy in lieu of “passive” and “active” to alleviate inconsistency in definitions and categorization.     

MorphoBank: phylophenomics in the “cloud”

A highly interoperable informatics infrastructure rapidly emerged to handle genomic data used for phylogenetics and was instrumental in the growth of molecular systematics. Parallel growth in software and databases to address needs peculiar to phylophenomics has been relatively slow and fragmented. Systematists currently face the challenge that Earth may hold tens of millions of species (living and fossil) to be described and classified. Grappling with research on this scale has increasingly resulted in work by teams, many constructing large phenomic supermatrices. Until now, phylogeneticists have managed data in single‐user, file‐based desktop software wholly unsuitable for real‐time, team‐based collaborative work. Furthermore, phenomic data often differ from genomic data in readily lending themselves to media representation (e.g. 2D and 3D images, video, sound). Phenomic data are a growing component of phylogenetics, and thus teams require the ability to record homology hypotheses using media and to share and archive these data. Here we describe MorphoBank, a web application and database leveraging software as a service methodology compatible with “cloud” computing technology for the construction of matrices of phenomic data. In its tenth year, and fully available to the scientific community at‐large since inception, MorphoBank enables interactive collaboration not possible with desktop software, permitting self‐assembling teams to develop matrices, in real time, with linked media in a secure web environment. MorphoBank also provides any user with tools to build character and media ontologies (rule sets) within matrices, and to display these as directed acyclic graphs. These rule sets record the phylogenetic interrelatedness of characters (e.g. if X is absent, Y is inapplicable, or X–Z characters share a media view). MorphoBank has enabled an order of magnitude increase in phylophenomic data collection: a recent collaboration by more than 25 researchers has produced a database of > 4500 phenomic characters supported by > 10 000 media.
© The Willi Hennig Society 2011.     

A critique of the “ultra‐high risk” and “transition” paradigm

The transdiagnostic expression of psychotic experiences in common mental disorder (anxiety/depression/substance use disorder) is associated with a poorer prognosis, and a small minority of people may indeed develop a clinical picture that meets criteria for schizophrenia. However, it appears neither useful nor valid to observe early states of multidimensional psychopathology in young people through the “schizo”‐prism, and apply misleadingly simple, unnecessary and inefficient binary concepts of “risk” and “transition”. A review of the “ultra‐high risk” (UHR) or “clinical high risk” (CHR) literature indicates that UHR/CHR samples are highly heterogeneous and represent individuals diagnosed with common mental disorder (anxiety/depression/substance use disorder) and a degree of psychotic experiences. Epidemiological research has shown that psychotic experiences are a (possibly non‐causal) marker of the severity of multidimensional psychopathology, driving poor outcome, yet notions of “risk” and “transition” in UHR/CHR research are restrictively defined on the basis of positive psychotic phenomena alone, ignoring how baseline differences in multidimensional psychopathology may differentially impact course and outcome. The concepts of “risk” and “transition” in UHR/CHR research are measured on the same dimensional scale, yet are used to produce artificial diagnostic shifts. In fact, “transition” in UHR/CHR research occurs mainly as a function of variable sample enrichment strategies rather than the UHR/CHR “criteria” themselves. Furthermore, transition rates in UHR/CHR research are inflated as they do not exclude false positives associated with the natural fluctuation of dimensional expression of psychosis. Biological associations with “transition” thus likely represent false positive findings, as was the initial claim of strong effects of omega‐3 polyunsatured fatty acids in UHR samples. A large body of UHR/CHR intervention research has focused on the questionable outcome of “transition”, which shows lack of correlation with functional outcome. It may be more productive to consider the full range of person‐specific psychopathology in all young individuals who seek help for mental health problems, instead of “policing” youngsters for the transdiagnostic dimension of psychosis. Instead of the relatively inefficient medical high‐risk approach, a public health perspective, focusing on improved access to a low‐stigma, high‐hope, small scale and youth‐specific environment with acceptable language and interventions may represent a more useful and efficient strategy.     

“Inflammatory” Cytokines

If cytokines are constitutively expressed by and act on neurons in normal adult brain, then we may have to modify our current view that they are predominantly inflammatory mediators. We critically reviewed the literature to determine whether we could find experimental basis for such a modification. We focused on two "proinflammatory" cytokines, interleukin (IL)-1 and tumor necrosis factor-alpha (TNFalpha) because they have been most thoroughly investigated in shaping our current thinking. Evidence, although equivocal, indicates that the genes coding for these cytokines and their accessory proteins are expressed by neurons, in addition to glial cells, in normal brain. Their expression is region- and cell type-specific. Furthermore, bioactive cytokines have been extracted from various regions of normal brain. The cytokines' receptors selectively are present on all neural cell types, rendering them responsive to cytokine signaling. Blocking their action modifies multiple neural "housekeeping" functions. For example, blocking IL-1 or TNFalpha by several independent means alters regulation of sleep. This indicates that these cytokines likely modulate in the brain behavior of a normal organism. In addition, these cytokines are likely involved in synaptic plasticity, neural transmission, and Ca2+ signaling. Thus, the evidence strongly suggests that these cytokines perform neural functions in normal brain. We therefore propose that they should be thought of as neuromodulators in addition to inflammatory mediators.     

Various strategies for obtaining artificial hemoproteins: From “hemoabzymes” to “hemozymes”

The design of artificial hemoproteins that could lead to new biocatalysts for selective oxidation reactions of organic compounds presents a huge interest especially in pharmacology, both for a better understanding of the metabolic profile of drugs and for the synthesis of enantiomerically pure molecules that could be involved in the design of drugs.The present results show that the so-called “host-guest strategy” that involves the non-covalent incorporation of anionic water-soluble iron-porphyrins into xylanase A from Streptomyces lividans, a low cost protein, leads to such an artificial hemoprotein that is able to perform the stereoselective oxidation of sulfides.     

“How” and “what” matters: Sampling method affects biodiversity estimates of reef fishes

Understanding changes in biodiversity requires the implementation of monitoring programs encompassing different dimensions of biodiversity through varying sampling techniques. In this work, fish assemblages associated with the “outer” and “inner” sides of four marinas, two at the Canary Islands and two at southern Portugal, were investigated using three complementary sampling techniques: underwater visual censuses (UVCs), baited cameras (BCs), and fish traps (FTs). We firstly investigated the complementarity of these sampling methods to describe species composition. Then, we investigated differences in taxonomic (TD), phylogenetic (PD) and functional diversity (FD) between sides of the marinas according to each sampling method. Finally, we explored the applicability/reproducibility of each sampling technique to characterize fish assemblages according to these metrics of diversity. UVCs and BCs provided complementary information, in terms of the number and abundances of species, while FTs sampled a particular assemblage. Patterns of TD, PD, and FD between sides of the marinas varied depending on the sampling method. UVC was the most cost‐efficient technique, in terms of personnel hours, and it is recommended for local studies. However, for large‐scale studies, BCs are recommended, as it covers greater spatio‐temporal scales by a lower cost. Our study highlights the need to implement complementary sampling techniques to monitor ecological change, at various dimensions of biodiversity. The results presented here will be useful for optimizing future monitoring programs.     

Evolution of Protein Targeting into “Complex” Plastids: The “Secretory Transport Hypothesis”

Abstract: In algae different types of plastids are known, which vary in pigment content and ultrastructure, providing an opportunity to study their evolutionary origin. One interesting feature is the number of envelope membranes surrounding the plastids. Red algae, green algae and glaucophytes have plastids with two membranes. They are thought to originate from a primary endocytobiosis event, a process in which a prokaryotic cyanobacterium was engulfed by a eukaryotic host cell and transformed into a plastid. Several other algal groups, like euglenophytes and heterokont algae (diatoms, brown algae, etc.), have plastids with three or four surrounding membranes, respectively, probably reflecting the evolution of these organisms by so‐called secondary endocytobiosis, which is the uptake of a eukaryotic alga by a eukaryotic host cell. A prerequisite for the successful establishment of primary or secondary endocytobiosis must be the development of suitable protein targeting machineries to allow the transport of nucleus‐encoded plastid proteins across the various plastid envelope membranes. Here, we discuss the possible evolution of such protein transport systems. We propose that the secretory system of the respective host cell might have been the essential tool to establish protein transport into primary as well as into secondary plastids.     

Heterogeneous Single Atom Electrocatalysis,Where “Singles” Are “Married”

There is an intensive search for heterogeneous single atom catalysts (SACs) of high activity, efficiency, durability, and selectivity for a wide variety of electrocatalytic conversion and chemical reactions, such as the hydrogen evolution reaction (HER), oxygen evolution/reduction reaction (OER and ORR), CO₂ reduction reaction (CO₂ RR), and nitrogen reduction reaction (NRR). With the downsizing from nanoparticles and clusters to single atoms, there are steady changes in the bond and coordination environment for each and every atom involved. Indeed, the single atoms in these electrocatalysts are not “singles”; they are “married” to the supporting surfaces, and their performance is controlled by the bonding and coordination with the substrate surfaces. Herein, an overview is presented on the brief history leading to the rapid development of SACs and their current status, by focusing on their synthesis, control of composition, strategies to realize single atoms with the desired bonds and coordination, and targeted performance in selected reactions. Their applications in the selected spectrum of energy conversion and chemical reactions are discussed, in relation to their structures at varying length scales down to the atomic level. A particular emphasis is placed on on‐going research activities, together with the future perspectives and particular challenges for SACs.