Darwin’s contributions to genetics

Darwin’s contributions to evolutionary biology are well known, but his contributions to genetics are much less known. His main contribution was the collection of a tremendous amount of genetic data, and an attempt to provide a theoretical framework for its interpretation. Darwin clearly described almost all genetic phenomena of fundamental importance, such as prepotency (Mendelian inheritance), bud variation (mutation), heterosis, reversion (atavism), graft hybridization (Michurinian inheritance), sex-limited inheritance, the direct action of the male element on the female (xenia and telegony), the effect of use and disuse, the inheritance of acquired characters (Lamarckian inheritance), and many other observations pertaining to variation, heredity and development. To explain all these observations, Darwin formulated a developmental theory of heredity — Pangenesis — which not only greatly influenced many subsequent theories, but also is supported by recent evidence.     

Upset in response to a Sibling’s partner’s infidelities

Using data collected from people with at least one brother and one sister, and consistent with an evolutionary perspective, we find that older men and women (a) are more upset by a brother’s partner’s sexual infidelity than by her emotional infidelity and (b) are more upset by a sister’s partner’s emotional infidelity than by his sexual infidelity. There were no effects of participant sex or sex of in-law on upset over a sibling’s partner’s infidelities, but there was an effect of participant sex on reports of upset over one’s own partner’s infidelities. The results suggest that the key variable among older participants is the sex of the sibling or, correspondingly, the sex of the sibling’s partner, as predicted from an evolutionary analysis of reproductive costs, and not the sex of the participant, as predicted from a socialization perspective. Discussion offers directions for future work on jealousy.     

Coronado’s Route to Quivira 1541

Abstract

The oft-discussed historical question as to Coronado’s route of march in 1541 from the Rio Grande pueblos to the settlements of Quivira is re-examined in light of documentary research, hitherto unpublished, by the late J. R. Swanton of the Bureau of American Ethnology. A collation of all available narratives casts strong doubt on Schroeder’s 1962 theory that the expedition at no time traveled south of the Canadian River, and instead supports older interpretations by Hodge, Bolton, and others who maintained that the expedition separated far south of that stream. The documentary evidence, like that from archaeology, supports the view that the 16th century province of Ouivira was the home of ancestral Wichita Indians residing in central Kansas along the great bend of the Arkansas River.     

From Peirce’s Semiotics to Information-Sign-Symbol

Peirce is the father of semiotics. However, his theory was developed long before the developments in information theory. The codification procedures studied by the latter turn out to be crucial also for biology. At the root of both information and semiosis there are equivalence classes. In the case of biological systems, we speak of functional equivalence classes. Equivalence classes represent the grid that organism impose on biochemical processes and signals of the external or internal environment. The whole feedback circuit that is built in this way allows information control. Symbolic systems represent another kind of dealing-with-information as far as they deal with the matching of our concepts with the world.     

From Formation to Ecosystem: Tansley’s Response to Clements’ Climax

Arthur G. Tansley never accepted Frederic E. Clements’ view that succession is a developmental process whose final stage, the climax formation, is determined primarily by regional climate and that all other types of vegetation are some kind of successional stage or arrested successional stage. Tansley was convinced that in a given region a variety of environmental factors could produce different kinds of climax formations. At the heart of their dispute was Clements’ organicist view of succession, i.e., the formation was a complex organism with an ontogeny and phylogeny. As early as 1905, Tansley offered an alternative to Clements’ complex organism, the quasi-organism, but Clements in private and public rejected this compromise. Tansley and other plant ecologists continued to criticize Clements’ theories for the next 20 years, but with no impact on Clements. John Phillips, a South African plant ecologist who was a follower of Clements, published a series of papers in 1934 and 1935 defending Clementsian ecology. These papers were triggered by the publication of a letter by another ecologist working in Africa who claimed that there was a strong correlation between soils and various kinds of climax vegetation, which was contrary to what was predicted by Phillips and Clements. In 1935, Tansley published an attack on Phillips and Clements and their developmental theory of succession. In it, he proposed the concept of the ecosystem as a way to get around Clements’ monoclimax theory by making the physical environment (e.g., soil chemistry, soil texture, soil moisture) as important a factor as climate, plants and other organisms in determining the composition and characteristics of ecological entities, i.e., ecosystems. Tansley’s ecosystem concept quickly replaced Clements’ monoclimax theory as a dominant paradigm in ecology.     

A Beginner’s Guide to Phylogenetics

Metagenomics and the development of high throughput next generation sequencing capabilities have forced significant development in the field of phylogenetics: the study of the evolutionary relatedness of the planet’s inhabitants. Herein, I review the major tree-building strategies, challenges and opportunities which exist in this rapidly expanding field of evolutionary biology.     

Systems biology approach to Wilson’s disease

Wilson’s disease (WD) is a severe disorder of copper misbalance, which manifests with a wide spectrum of liver pathology and/or neurologic and psychiatric symptoms. WD is caused by mutations in a gene encoding a copper-transporting ATPase ATP7B and is accompanied by accumulation of copper in tissues, especially in the liver. Copper-chelation therapy is available for treatment of WD symptoms and is often successful, however, significant challenges remain with respect to timely diagnostics and treatment of the disease. The lack of genotype-phenotype correlation remains unexplained, the causes of fulminant liver failure are not known, and the treatment of neurologic symptoms is only partially successful, underscoring the need for better understanding of WD mechanisms and factors that influence disease manifestations. Recent gene and protein profiling studies in animal models of WD began to uncover cellular processes that are primarily affected by copper accumulation in the liver. The results of such studies, summarized in this review, revealed new molecular players and pathways (cell cycle and cholesterol metabolism, mRNA splicing and nuclear receptor signaling) linked to copper misbalance. A systems biology approach promises to generate a comprehensive view of WD onset and progression, thus helping with a more fine-tune treatment and monitoring of the disorder.     

Proteomic approach to studying parkinson’s disease

Parkinson’s disease is a common age-related neurodegenerative disease characterized pathologically by a loss of dopaminergic neurons in the substantia nigra with resultant depletion of striatal dopamine and presence of Lewy bodies in the remaining neurons. The Lewy body contains numerous functional and structural proteins, including α-synuclein and ubiquitin; aggregation of α-synuclein is thought to be important in Lewy body formation as well as neurodegeneration, although the detailed mechanisms remain to be defined. Increasing evidence has suggested that mitochondrial dysfunction, increased oxidative stress, and dysfunction of the ubiquitin-proteasome system may be involved in α-synuclein aggregation, Lewy body formation, and neurodegeneration. However, how these processes are related to each other is not fully understood, given that there are Parkinsonian animal models as well as human diseases with significant nigral neurodegeneration regardless of whether Lewy bodies form or not. This review summarizes the current related research fields and proposes a proteomic approach to investigate the mechanisms that may dictate α-synuclein aggregation, Lewy body formation, and neurodegeneration.     

Multimodal retinal imaging to detect and understand Alzheimer’s and Parkinson’s disease

Retinal neurodegeneration and visual dysfunctions have been reported in a majority of Alzheimer’s and Parkinson’s patients, and, in light of the quest for novel biomarkers for these neurodegenerative proteinopathies, the retina has been receiving increasing attention as an organ for diagnosing, monitoring, and understanding disease. Thinning of retinal layers, abnormalities in vasculature, and protein deposition can be imaged at unprecedented resolution, which offers a unique systems biology view on the cellular and molecular changes underlying these pathologies. It makes the retina not only a promising target for biomarker development, but it also suggests that novel fundamental insights into the pathophysiology of Alzheimer’s and Parkinson’s disease can be obtained by studying the retina–brain axis.     

From Goethe’s plant archetype via Haeckel’s biogenetic law to plant evo-devo 2016

In 1790, the German poet Johann W. v. Goethe (1749–1832) proposed the concept of a hypothetical sessile organism known as the ‘Plant Archetype,’ which was subsequently reconstructed and depicted by 19th-century botanists, such as Franz Unger (1800–1870) and Julius Sachs (1832–1897), and can be considered one of the first expressions of Evo-Devo thinking. Here, we present the history of this concept in the context of Ernst Haeckel’s (1834–1919) biogenetic law espoused in his Generelle Morphologie der Organismen of 1866. We show that Haeckel’s idea of biological recapitulation may help to explain why various phenomena, such as the ontogenetic transformations in the stellar anatomy of lycopods and ferns, the transition from primary to secondary anatomy of seed plants, the presence of unfused juvenile cone scale segments in the Japanese cedar (Cryptomeria japonica), and the transition of C3- to C4-photosynthesis in the ontogeny of maize (Zea mays), appear to support his theories. In addition, we outline the current status of plant evolutionary developmental biology (Evo-Devo), which can be traced back to Haeckel's (1866) biogenetic law, with a focus on the model plant thale cress (Arabidopsis thaliana).     

Common Infections May Lead to Alzheimer’s Disease

正Alzheimer’s disease (AD), also known as Alzheimer’s, is a chronic neurodegenerative disorder with hallmark amyloid plaques in brain tissue. The diseases commences slowly and worsens over time (Sjogren et al. 1952). Although it has been investigated for over six decades, the cause of AD     

Traversing a wormhole to combat Parkinson’s disease

Human movement disorders represent a significant and unresolved societal burden. Among these, the most prevalent is Parkinson’s disease (PD), a disorder afflicting millions worldwide. Despite major advances, stemming primarily from human genetics, there remains a significant gap in our understanding of what factors underlie disease susceptibility, onset, and progression. Innovative strategies to discern specific intracellular targets for subsequent drug development are needed to more rapidly translate basic findings to the clinic. Here we briefly review the recent contributions of research using the nematode roundworm Caenorhabditis elegans as a model system for identifying and characterizing gene products associated with PD. As a microscopic but multicellular and genetically tractable animal with a well-defined nervous system and an experimentally tenable lifespan, C. elegans affords significant advantages to researchers attempting to determine causative and therapeutic factors that influence neuronal dysfunction and age-associated neurodegeneration. The rapidity with which traditional genetic, large-scale genomic, and pharmacological screening can be applied to C. elegans epitomizes the utility of this animal for disease research. Moreover, with mature bioinformatic and functional genomic data readily available, the nematode is well positioned to play an increasingly important role in PD-associated discoveries.Physicists and astronomers have long posited the concept of a ‘wormhole’ as a means of rapid interstellar travel by analogy with how a worm could eat a hole from one end of an apple, through the center to the other end, and create a shortcut through the intervening space. Unfortunately, bending the fabric of space and time is not typically considered a viable option to more rapidly explore cures for neurodegenerative diseases (and would likely result in a poorly received grant application). The biological equivalent of the space exploration program, the human genome project, has unleashed an age of genomic, proteomic, metabolomic, and bioinformatic analyses that has generated a wealth of datasets primed for subsequent discovery. This exponential growth demands the development of functional means for exploiting this treasure trove of biological information. In this regard, biomedical researchers are literally turning to a worm to accelerate the path toward therapeutic advances and get to the core of mechanisms underlying Parkinson’s disease (PD).While drugs to treat the symptoms of PD have been prescribed for decades (e.g. L-DOPA), an unmet need for innovative strategies to discern disease etiology and treatments that either halt or reverse progression remains. Application of a microscopic nematode roundworm toward gaining insights into a human neurodegenerative disorder may seem impractical; yet, C. elegans affords many advantages for such research, as it has a defined cell lineage, completed genome sequence, and lifespan of only 2 weeks. As opposed to the human brain, which is estimated to have over 100 billion nerve cells, this nematode contains precisely 302 neurons for which a defined neuronal connectivity map has been determined. In this regard, C. elegans is ideal for investigation of diseases associated with neuronal dysfunction and ageing, and represents a model system that is poised to bridge the gap between basic and translational research.Interpretation of disease-associated data obtained in invertebrate systems requires downstream validation in mammals prior to establishing the therapeutic significance of any findings. The likelihood of a positive outcome is significant, however, due to the evolutionary conservation of metazoan genomes. For example, human homologs have been identified for at least 50% of C. elegans genes. Remarkably, these include all orthologs of reported genes linked to familial forms of PD (Fig. 1), with the one exception being the gene encoding α-synuclein. Despite this difference, ectopic overexpression of both wildtype and mutant (A53T) human α-synuclein led to motor deficits or DA neuron loss in C. elegans (Lasko et al., 2003). Subsequent reports also demonstrated phenotypic changes associated with driving α-synuclein expression from a variety of pan-neuronal and specific neuronal promoters (Cao et al., 2005; Ved et al., 2005; Kuwahara et al., 2006). The translational utility of C. elegans is perhaps best demonstrated by the characterization of conserved neuroprotective genes that block α-synuclein-associated degeneration in nematodes (Cooper et al., 2006; Gitler et al., 2008; Hamamichi et al., 2008).Open in a separate windowFig. 1PD-associated gene products and their prospective sites of cellular functionPD is hypothesized to be a consequence of the dysfunction of intersecting and compensatory protein degradation components, including those associated with the lysosome and autophagy, as well as those associated with the ubiquitin proteasome system (UPS). Inefficient clearance and enhanced misfolding, or expression, of α-synuclein has been shown to block intracellular trafficking and increase cytotoxicity. Accordingly, mutations in Parkin (an E3 ubiquitin ligase), ubiquitin C-terminal hydrolase-1 (UCHL-1), as well as in a lysosomal ATPase termed ATP13A2 and the Gaucher’s disease-related protein glucocerebrosidase (GBA), have further implicated protein degradation pathways in PD. PD-associated mutations in genes linked with mitochondrial function, such as those encoding DJ-1 and the PTEN-induced kinase (PINK1), presumably affect the production of reactive oxygen species (ROS), which accelerate protein damage and neurodegeneration. While mutations in the leucine-rich repeat kinase 2 (LRRK2) protein now represent the most common heritable cause of PD, the function of this large, 2527 amino acid multidomain-containing protein remains undefined.The rich, 40-year history of C. elegans genetics provides a legacy of behavioral and neuroanatomical information that researchers draw upon to elucidate relationships between gene function and PD-associated mechanisms (Bargmann, 1998). Using traditional genetic suppressor and enhancer screening, investigators have begun to dissect genetic contributors to DA neuron development and function (Chase et al., 2004). A limbless simple invertebrate will certainly never recapitulate the phenotypic behaviors associated with the tremor and dyskinesia of PD, yet this nematode does afford opportunities for accurate quantification of factors that influence DA neuron survival. Loss of DA neurons in C. elegans is not lethal and leads only to a subtle behavioral deficit where affected animals display an inability to discriminate local mechanosensory cues (Sawin et al., 2000). Unfortunately, this behavior, while quantifiable, is not robust enough to be easily used in extensive screening paradigms.Mammalian and primate modeling approaches to PD have traditionally involved use of neurotoxins to induce DA neuron loss and evaluate the consequences of neurodegeneration. Among these toxins are 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), as well as the pesticides rotenone and paraquat. Worms are susceptible to these toxins (Nass et al., 2002; Braungart et al., 2004; Cao et al., 2005); moreover, the defined and transparent neuroanatomy of C. elegans includes precisely eight neurons that produce DA, thereby enabling an unparalleled level of quantitative analysis of neurodegeneration and protection by use of fluorescent protein labeling (Fig. 2). Furthermore, these animals can be evaluated in specific genetic or transgenic backgrounds to screen for factors that confer either neuroprotection or enhancement of degeneration. One neuroprotective gene product termed TOR-2, a human torsinA-related protein with molecular chaperone-like activity (Caldwell et al., 2008), was shown to deter multiple forms of toxic insults to DA neurons, including 6-OHDA, excess intracellular DA production, and α-synuclein overexpression (Cao et al., 2005). The neuroprotective capacity of torsin-like proteins renders them intriguing candidates for subsequent drug targeting and validation in mammalian systems, where human torsinA is endogenously expressed in DA neurons (Augood et al., 1998).Open in a separate windowFig. 2Anterior dopamine neurons of C. elegansCell bodies and processes of the six anterior DA neurons including two pairs of the CEP (cephalic) neurons and one pair of ADE (anterior deirid) neurons, as illuminated using GFP driven from the dopamine transporter promoter (P_dat-1::GFP). Two additional DA neurons (PDEs) are found in the posterior (not shown).Directed and comprehensive screens have been undertaken to define chemical and genetic effectors of worm DA neuron sensitivity to 6-OHDA (Nass et al., 2005; Maranova and Nichols, 2007). These studies identified a collection of intragenic mutations in the gene sequence encoding the key protein required for DA reuptake into presynaptic neurons, the DA transporter (DAT-1). Structural and functional relationships revealed through this work have implications not only for PD, but also for other disorders associated with DAT function (e.g. depression, ADHD). It has also been shown that worm dat-1 knockout mutants exhibit diminished α-synuclein-dependent degeneration, which indicates a possible role for DAT in maintaining an important balance of intraneuronal levels of DA, the dysregulation of which may contribute to cytotoxicity (Cao et al., 2005).Elegant studies in Drosophila have demonstrated the capacity for model systems to reveal unsuspected relationships between PD gene products, such as PINK1 and Parkin, and their impact on mitochondrial integrity and morphology (Clark et al., 2006; Park et al., 2006; Poole et al., 2008). Likewise, the ability of worm research to link genotype to phenotype in this manner is accelerating our understanding of the underlying nature of PD. Ved et al. investigated the functional consequences of rotenone-induced stress and reported that pan-neuronal overexpression of human αsynuclein (wild-type or A53T mutant), RNAi knockdown of a C. elegans DJ-1 ortholog (B0432.2), or a deletion mutant of the C. elegans parkin ortholog (pdr-1), all produced similar patterns of mitochondrial vulnerability in response to pharmacological challenges associated with complex I inhibition (Ved et al., 2005). Furthermore, the effect of rotenone, which led to mortality in these animals, was more severe in α-synuclein-expressing strains and the pdr-1 deletion mutant than in control animals of wild-type background. Initial work on worm PDR-1 revealed that this Parkin ortholog, an E3 ubiquitin ligase, cooperates with conserved degradation machinery to mediate ubiquitin conjugation (Springer et al., 2005). Co-expression of C. elegans pdr-1 and α-synuclein variants in human cell cultures showed that a truncated protein derived from an in-frame pdr-1 (lg103) deletion allele causes aggregation of α-synuclein, similar to Parkin variants isolated from PD patients. This altered gene product also resulted in proteotoxicity and hypersensitivity to ER stress (Springer et al., 2005). These examples demonstrate how mutant analysis in C. elegans offers a powerful strategy for uncovering functional relationships between gene products with key roles in PD pathogenesis in mammalian cells.C. elegans has been recently used to show a protective role for human LRRK2 (leucine-rich repeat kinase 2) against mitochondrial toxicity induced by rotenone, an effect potentiated by knockdown of an endogenous worm ortholog, lrk-1 (Wolozin et al., 2008). These data are surprising when considering a PD-associated G2019S mutant version of LRRK2 that exhibits increased kinase activity was also found to be protective; kinase activity has been suggested to contribute to the pathogenesis associated with LRRK2 neurotoxicity (West et al., 2007). An initial report on lrk-1 function in C. elegans indicated a role for the product of this gene in establishing neuronal polarity (Sakaguchi-Nakashima et al., 2007). As mutations in LRRK2 now represent the most common genetic cause of PD (Haugarvoll et al., 2008), further insights gleaned from C. elegans on this important, yet relatively uncharacterized, protein family will undoubtedly be informative.The capacity for genomic-scale screening has brought C. elegans to the forefront of modern functional analysis (Kamath and Ahringer, 2003). In contrast to mammals, where individual knockouts of mice are expensive and time consuming, worms are an efficient and economical alternative. Hamamichi et al. took a hypothesis-driven approach toward identification of putative genetic modifiers of PD via a multi-tiered screen for C. elegans genes that impact the misfolding of transgenic human α-synuclein, as well as neuroprotection, in vivo (Hamamichi et al., 2008). This study encompassed RNAi knockdown of nearly 900 bioinformatically prioritized gene targets, comprising components of cellular pathways implicated in protein folding or degradation, as well as gene products that are either co-expressed or interact with worm orthologs of familial PD genes. From this varied, but biased, ‘guilt by association’ list of targets, 20 candidate genes emerged as having the greatest propensity to influence α-synuclein misfolding. Internal validation was evident within this short list, as included were the worm homologs of two established recessive PD genes (DJ-1, PINK1), as well as a gene (ULK2) shown to be one of only six identified in a genome-wide association study of polymorphisms in PD patients (Fung et al., 2006). Importantly, overexpression of select cDNAs in C. elegans DA neurons revealed that five of seven gene products tested, chosen from the primary effectors of α-synuclein misfolding identified in the RNAi screen, exhibited significant protection from age- and dose-dependent neurodegeneration induced by α-synuclein (Hamamichi et al., 2008). Thus, application of C. elegans in this context uncovered functionally evaluated targets identified by the two primary clinical criteria associated with PD: α-synuclein accumulation and DA neurodegeneration.These genes, which included uncharacterized proteins, as well as regulators of autophagy, lysosomal function, cellular trafficking, and G-protein signaling, now represent outstanding candidates for strategically targeted drug development and validation in mammalian systems. A more recently conducted unbiased genome-wide RNAi screen for genetic factors that influence αsynuclein inclusion formation in C. elegans also yielded an over-representation of genes encoding components of vesicular trafficking, as well as specific age-associated genes (e.g. sir-2.1) (van Ham et al., 2008). Similar validation of the effect that these additional targets may have on DA neuron survival will likely reveal functionally significant relationships as well. Associations between PD and lysosomal degradation are of growing interest following the identification of a lysosomal ATPase, ATP13A2 (PARK9), as a gene product linked to hereditary early-onset PD with dementia (Ramirez et al., 2006), in addition to the discovery of a higher incidence of PD in patients with mutations in the Gaucher’s disease-associated gene, GBA, encoding the lysosomal storage-enzyme glucocerebrosidase. (Aharon-Peretz et al., 2004; Clark et al., 2007). It is easy to envision an expansion of such gene-specific data and the application of C. elegans toward investigating the functional consequences of single-nucleotide polymorphisms (SNPs) found in human populations, as these may potentially lead to genetic biomarkers of disease susceptibility.The burgeoning promise that a microscopic worm may contribute toward the goal of drug discovery for PD has become a tangible reality. Containing a rudimentary nervous system, unlike single-celled organisms, but more amenable to transgenic analysis and drug screening than mammals, C. elegans serves as an excellent intermediary bottleneck in translational research pipelines to characterize therapeutic gene and drug targets across animal models. Concerted efforts toward therapeutic development have been initiated that exploit the high-throughput screening capabilities of yeast cells to define numerous gene targets of interest, followed by subsequent evaluation of their neuroprotective capacity in worms, fruit flies and rat neuronal cultures (Cooper et al., 2006; Gitler et al., 2008). This approach has already revealed that overproduction of αsynuclein leads to a cytotoxic blockage in intracellular vesicular trafficking that can be alleviated by specific members of the Rab protein family (Cooper et al., 2006; Gitler et al., 2008). Thus, through the employment of a combination of powerful model systems, not only has a prospective cellular cause of PD been illuminated, but targeted screens for small molecules that protect against underlying functional aspects of neurodegeneration are now possible.When envisioning future directions whereby C. elegans will benefit PD research, several inescapable advantages of this model system should be considered. The most obvious of these is the well-established use of the worm for investigating mechanisms of aging (Kenyon, 2005). Indeed, the only definitive risk factor for PD is aging, where PD symptomatically affects over 2% of people above age 65. Extensive studies on worm longevity mutants (e.g. daf-2 or age-1) have demonstrated that evolutionarily conserved mechanisms are shared between invertebrates and mammals. Microarray and genomic-scale RNAi analyses conducted in age-extending backgrounds have yielded significant insights into gene sets that implicate dietary restriction and insulin-like signaling pathways as crucial mediators of lifespan (Murphy et al., 2003; Panowski et al., 2007). The vital, but poorly understood, interface between aging and age-associated neurodegenerative disease represents an exciting frontier that is readily explored using C. elegans.Furthermore, in the advent of the microRNA (miRNA) revolution, our nascent understanding of putative regulatory roles for miRNAs in neuron function will likely soon interface with our understanding of neurological disease and PD (Kosik, 2006; Kim et al., 2007). Considering the pioneering role worm research has played in defining miRNA function, a universe of possibilities exist, as worm researchers are well-poised to explore relationships between miRNAs, ageing and neuroprotective gene activity (Ibanez-Ventoso, 2007).

Advantages of C. elegans as a model for Parkinson’s disease

• All orthologs of genes linked to familial PD have been identified in C. elegans, except α-synuclein
• Ectopic overexpression of α-synuclein has neurotoxic effects in C. elegans, which are blocked by neuroprotective genes
• C. elegans has a simple nervous system (302 neurons compared with over 100 billion in humans) that is amenable to quantitative analysis of neurodegeneration
• C. elegans is susceptible to toxins commonly used to model neurodegeneration
• C. elegans studies predict relationships between cellular signaling, trafficking and protein degradation pathways, which are being tested for their susceptibility to targeted drug development for PD

Finally, although the primary advances in PD etiology have come through human genetics, the largely idiopathic nature of PD remains linked to inexplicable environmental causes. C. elegans research into innate immunity and cellular stress response has already provided mechanistic insights into organismal defenses and environmental influences on homeostasis (Kim et al., 2002; Mohri-Shiomi and Garsin, 2008). An expansion of neurotoxicity studies conducted in C. elegans is warranted and may yield a greater understanding of the interplay between genetic composition and environmental factors such as heavy metals, pesticides and other untested exposures.The worm is unquestionably a powerful system, yet it has its limitations: the anatomical and functional connectivity of the neuronal circuitry within this simple nematode cannot recapitulate the complex features of mammalian dopamine neurons or mimic the precise behavioral deficits associated with their loss. Likewise, as a cautionary caveat to inferring conservation of function from genetic interaction data, Tischler et al. demonstrated that synthetic lethal gene interactions between yeast and worm genes are not significantly conserved (Tischler et al., 2008). In this context, as the march toward systems biology proceeds and integrated analyses of gene or protein activity continue to lead to an increasing number of complex datasets, our ability to eventually define causes and cures will depend on functional strategies for wading through the emerging ‘information overload’. Science will benefit from the efficient manner by which C. elegans research can contribute to the quest for translational and personalized medical breakthroughs, by boldly going where no worm has gone before.     

Exploring glia to better understand Alzheimer’s disease

The amyloid-β (Aβ) hypothesis has been the leading explanation for the pathogenesis of Alzheimer’s disease (AD). The most common traits of AD are cognitive impairments and memory loss, which are associated with the accumulation of Aβ. Aβ aggregates activate glial cells, which in turn remove Aβ. Because microglia act as immune cells in the brain, most glia-related studies of AD have focused primarily on this cell type. However, astrocytes, another type of glial cell, also participate in the brain immune system, synaptic formation, brain homeostasis, and various other brain functions. Accordingly, many studies on the underlying mechanisms of AD have investigated not only neurons but also glial cells. Although these studies suggest that microglia and astrocytes are effective targets for AD therapeutics, other recent studies have raised questions regarding whether microglial cells and/or astrocytes serve a neuroprotective or neurotoxic function in AD. To gain a better understanding of the mechanisms of AD and identify novel targets for AD treatment, in this review, we consider the role of both microglia and astrocytes in AD.     

Florida’s efforts to assume section 404 permitting

Wetlands Ecology and Management - Section 404 of the federal Clean Water Act prohibits disposing of dredged and fill materials into the waters of the United States (WOTUS) absent a permit...     

Synucleins and their relationship to Parkinson’s disease

Parkinsons disease (PD) is one of the most common neurodegenerative motor disorders, marked by chronic progressive loss of neurons in the substantia nigra. It has long been believed that PD is caused by environmental factors. The discovery of genetic factors involved in PD has improved the understanding of the pathology of the disease. The first gene found to be mutated in PD encodes for the presynaptic protein -synuclein. -Synuclein is a major component of Lewy bodies and Lewy neurites, which represent the morphological hallmarks of the disease. The mechanisms by which -synuclein is involved in nigral cell death remain poorly understood. Moreover, the factors triggering the formation of -synuclein-positive inclusion bodies remain enigmatic. Indeed, even the normal cellular functions of -synuclein and of the other synucleins (-synuclein and -synuclein) are still unknown. Several lines of evidence suggest that they play a role in the regulation of vesicular turnover under normal nonpathological conditions.The work of O. von Bohlen und Halbach is supported by the DFG (Forschergruppe FOR 302 and SFB 636)     

A user’s guide to PDE models for chemotaxis

Mathematical modelling of chemotaxis (the movement of biological cells or organisms in response to chemical gradients) has developed into a large and diverse discipline, whose aspects include its mechanistic basis, the modelling of specific systems and the mathematical behaviour of the underlying equations. The Keller-Segel model of chemotaxis (Keller and Segel in J Theor Biol 26:399-415, 1970; 30:225-234, 1971) has provided a cornerstone for much of this work, its success being a consequence of its intuitive simplicity, analytical tractability and capacity to replicate key behaviour of chemotactic populations. One such property, the ability to display "auto-aggregation", has led to its prominence as a mechanism for self-organisation of biological systems. This phenomenon has been shown to lead to finite-time blow-up under certain formulations of the model, and a large body of work has been devoted to determining when blow-up occurs or whether globally existing solutions exist. In this paper, we explore in detail a number of variations of the original Keller-Segel model. We review their formulation from a biological perspective, contrast their patterning properties, summarise key results on their analytical properties and classify their solution form. We conclude with a brief discussion and expand on some of the outstanding issues revealed as a result of this work.