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1.  The puzzling origin of the autophagosomal membrane 
Autophagy is one of the newest and fastest emerging research areas in biomedical life sciences. Autophagosomes, large double-membrane vesicles enclosing cytoplasmic components targeted for degradation, are the hallmark of this catabolic pathway. The origin of the lipid bilayers composing these transport carriers has been the central enigma of the field since the discovery of autophagy. A series of recent studies has implicated several cellular organelles as the possible source of the autophagosomal membranes, if anything further clouding our view. In this compendium, we will discuss these apparently contradictory results and briefly emphasize the relevance of determining the lipid source used for autophagy for future translational research, for example in drug discovery programs.
PMCID: PMC3229206  PMID: 22162728
2.  Structure and recognition of polyubiquitin chains of different lengths and linkage 
The polyubiquitin signal is post-translationally attached to a large number of proteins, often directing formation of macromolecular complexes resulting in the translocation, assembly or degradation of the attached protein. Recent structural and functional studies reveal general mechanisms by which different architectures and length of the signal are distinguished.
PMCID: PMC3229271  PMID: 22162729
3.  Gout, genetics and ABC transporters 
Gout is a chronic arthritic disease associated with high levels of urate in blood. Recent advances in research have permitted the identification of several new and common genetic factors underlying the disease. Among them, a polymorphism in the ABC transporter gene ATP-binding cassette transporter isoform G2 has been highlighted. ATP-binding cassette transporter isoform G2 was found to be involved in renal urate elimination, and the presence of the Q141K polymorphism to induce a 2-fold decrease in urate efflux. The Q141K variant has been shown to have impaired trafficking, leading to its intracellular retention, whereas the wild type protein is expressed on the cell surface. Several agents are being studied for the purpose of improving folding, trafficking and function of various ABC transporters, including ATP-binding cassette transporter isoform G2. If successful, this strategy opens doors to potential new therapies for gout.
PMCID: PMC3206739  PMID: 22065982
4.  Drugs for malaria: something old, something new, something borrowed 
Malaria was estimated to cause 800,000 deaths and 225 million cases worldwide in 2010. Worryingly, the first-line treatment currently relies on a single drug class called artemisinins, and there are signs that the parasite is becoming resistant to these drugs. The good news is that new technology has given us new approaches to drug discovery. New drugs generated this way are probably 10-15 years away from the clinic. Other antimalarials that may offer hope include those rehabilitated after not being used for some time, those that act as inhibitors of resistance mechanisms, those that limit infection while allowing protective immunity to develop, and those which are drugs borrowed from other disease treatments. All of these offer new hope of turning the tables on malaria. In parallel with the effort to develop vaccines that interrupt malaria transmission, drugs that target the parasite during transmission to the mosquito or during its pre-erythrocytic development in the liver, may allow us to terminate the parasite’s spread.
PMCID: PMC3206709  PMID: 22076126
5.  Adenosine receptors and fibrosis: a translational review 
Adenosine—a purine nucleoside generated extracellularly from adenine nucleotides released by cells as a result of direct stimulation, hypoxia, trauma, or metabolic stress—is a well-known physiologic and pharmacologic agent. Recent studies demonstrate that adenosine, acting at its receptors, promotes wound healing by stimulating both angiogenesis and matrix production. Subsequently, adenosine and its receptors have also been found to promote fibrosis (excess matrix production) in the skin, lungs, and liver, but to diminish cardiac fibrosis. A commonly ingested adenosine receptor antagonist, caffeine, blocks the development of hepatic fibrosis, an effect that likely explains the epidemiologic finding that coffee drinking, in a dose-dependent fashion, reduces the likelihood of death from liver disease. Accordingly, adenosine may be a good target for therapies that prevent fibrosis of the lungs, liver, and skin.
PMCID: PMC3186039  PMID: 22003368
6.  Secrets of aging: What does a normally aging brain look like? 
Over the past half century, remarkable progress has been made in understanding the biological basis of memory and how it changes over the lifespan. An important conceptual advance during this period was the realization that normative cognitive trajectories can exist independently of dementing illness. In fact, mammals as different as rats and monkeys, who do not spontaneously develop Alzheimer’s disease, show memory impairments at advanced ages in similar domains as those observed in older humans. Thus, animal models have been particularly helpful in revealing brain mechanisms responsible for the cognitive changes that occur in aging. During these past decades, a number of empirical and technical advances enabled the discoveries that began to link age-related changes in brain function to behavior. The pace of innovation continues to accelerate today, resulting in an expanded window through which the secrets of the aging brain are being deciphered.
PMCID: PMC3186042  PMID: 22003369
7.  Taste isn't just for taste buds anymore 
Taste is a discriminative sense involving specialized receptor cells of the oral cavity (taste buds) and at least two distinct families of G protein-coupled receptor molecules that detect nutritionally important substances or potential toxins. Yet the receptor mechanisms that drive taste also are utilized by numerous systems throughout the body. How and why these so-called taste receptors are used to regulate digestion and respiration is now a matter of intense study. In this article we provide a historical perspective and an overview of these systems, leading to speculations on directions for further research.
PMCID: PMC3169900  PMID: 21941599
8.  Amyotrophic lateral sclerosis: new genes, new models, and new mechanisms 
Research aimed at understanding amyotrophic lateral sclerosis (ALS) has seen exceptional growth in the past few years. New genes, new models, and new mechanisms have not only improved our understanding, but also contributed to the increasing complexity of ALS pathogenesis. The focus of this piece is to highlight some of the more notable developments in the field and to encourage a re-appreciation for the superoxide dismutase 1 (SOD1) mouse models.
PMCID: PMC3169903  PMID: 21941597
9.  Conformational selection or induced fit? 50 years of debate resolved 
Exactly 50 years ago, biochemists raised the question of the mechanism of the conformational change that mediates “allosteric” interactions between regulatory sites and biologically active sites in regulatory/receptor proteins. Do the different conformations involved already exist spontaneously in the absence of the regulatory ligands (Monod-Wyman-Changeux), such that the complementary protein conformation would be selected to mediate signal transduction, or do particular ligands induce the receptor to adopt the conformation best suited to them (Koshland-Nemethy-Filmer—induced fit)? This is not just a central question for biophysics, it also has enormous importance for drug design. Recent advances in techniques have allowed detailed experimental and theoretical comparisons with the formal models of both scenarios. Also, it has been shown that mutated receptors can adopt constitutively active confirmations in the absence of ligand. There have also been demonstrations that the atomic resolution structures of the same protein are essentially the same whether ligand is bound or not. These and other advances in past decades have produced a situation where the vast majority of the data using different categories of regulatory proteins (including regulatory enzymes, ligand-gated ion channels, G protein-coupled receptors, and nuclear receptors) support the conformational selection scheme of signal transduction.
PMCID: PMC3169905  PMID: 21941598
10.  Plant-soil interactions in a changing world 
Evidence is mounting to suggest that the transfer of carbon through roots of plants to the soil plays a primary role in regulating ecosystem responses to climate change and its mitigation. Future research is needed to improve understanding of the mechanisms involved in this phenomenon, its consequences for ecosystem carbon cycling, and the potential to exploit plant root traits and soil microbial processes that favor soil carbon sequestration.
PMCID: PMC3155187  PMID: 21876727
11.  Harnessing the immune system's arsenal: producing human monoclonal antibodies for therapeutics and investigating immune responses 
Monoclonal antibody technology has undergone rapid and innovative reinvention over the last 30 years. Application of these technologies to human samples revealed valuable therapeutic and experimental insights. These technologies, each with their own benefits and flaws, have proven indispensable for immunological research and in our fight to provide new treatments and improved vaccines for infectious disease.
PMCID: PMC3155207  PMID: 21876728
12.  Exosomes: secreted vesicles and intercellular communications 
Exosomes are small membrane vesicles of endocytic origin secreted by most cell types, and are thought to play important roles in intercellular communications. Although exosomes were originally described in 1983, interest in these vesicles has really increased dramatically in the last 3 years, after the finding that they contain mRNA and microRNA. This discovery sparked renewed interest for the general field of membrane vesicles involved in intercellular communications, and research on these structures has grown exponentially over the last few years, probing their composition and function, as well as their potential value as biomarkers.
PMCID: PMC3155154  PMID: 21876726
13.  Valuing ecological systems and services 
Making trade-offs between ecological services and other contributors to human well-being is a difficult but critical process that requires valuation. This allows both better recognition of the ecological, social, and economic trade-offs and also allows us to bill those who use up or destroy ecological services and reward those that produce or enhance them. It also aids improved ecosystems policy. In this paper we clarify some of the controversies in defining the contributions to human well-being from functioning ecosystems, many of which people are not even aware of. We go on to describe the applicability of the various valuation methods that can be used in estimating the benefits of ecosystem services. Finally, we describe some recent case studies and lay out the research agenda for ecosystem services analysis, modeling, and valuation going forward.
PMCID: PMC3155191  PMID: 21876725
14.  Bacteria, food, and cancer 
Gut microbes are essential components of the human organism—helping us metabolize food into energy, produce micronutrients, and shape our immune systems. Having a particular pattern of gut microbes is also increasingly being linked to medical conditions including obesity, inflammatory bowel disease, and diabetes. Recent studies now indicate that our resident intestinal bacteria may also play a critical role in determining one's risk of developing cancer, ranging from protection against cancer to promoting its initiation and progression. Gut bacteria are greatly influenced by diet and in this review we explore evidence that they may be the missing piece that explains how dietary intake influences cancer risk, and discuss possible prevention and treatment strategies.
PMCID: PMC3155156  PMID: 21876723
15.  Sweet memories: epigenetic control in flowering 
Many plants respond to winter with epigenetic factors that gradually dampen repression of flowering so that they can flower in spring. The study of this process was important for the identification of the plant Polycomb group (PcG) of proteins and their role in the epigenetic control of plant gene expression. Fittingly, these studies continue to illuminate our understanding of PcG function. We discuss recent advances, particularly the role of noncoding RNA in the recruitment of PcG to target genes, and the role of the PcG in regulating the stem cell pool in flowers.
PMCID: PMC3155212  PMID: 21876724
16.  Checkpoint recovery in cells: how a molecular understanding can help in the fight against cancer 
Dysregulation of the cell cycle is the underlying mechanism of neoplasia. Healthy cells prevent propagation of DNA mutations to progeny by activation of cellular checkpoints, which allows time for DNA repair. On the other hand, activation of the DNA damage response is also the general principle of many current cancer treatments. Thus, recent advances in understanding how checkpoints in the cell cycle work at the molecular level open the door to new approaches to antitumor therapy.
PMCID: PMC3100786  PMID: 21655336
17.  Epigenetic changes in cancer 
Interest in epigenetics is now booming in all the biomedical fields. Initially, interest was sparked within the field of cancer research with the finding of global DNA hypomethylation events in the 1980s, followed by the CpG island hypermethylation of tumor suppressor genes in the 1990s and the approval of DNA demethylating drugs and histone deactylase inhibitors in the 2000s. For transformed cells, the arena is also expanding to include the wide spectrum of histone modification changes and the interaction with noncoding RNAs. What lies ahead is even more exciting, with the imminent completion of many human cancer epigenomes that will form the basis of better biomarkers and epigenetic drugs.
PMCID: PMC3100810  PMID: 21655338
18.  A history of optogenetics: the development of tools for controlling brain circuits with light 
Understanding how different kinds of neuron in the brain work together to implement sensations, feelings, thoughts, and movements, and how deficits in specific kinds of neuron result in brain diseases, has long been a priority in basic and clinical neuroscience. “Optogenetic” tools are genetically encoded molecules that, when targeted to specific neurons in the brain, enable their activity to be driven or silenced by light. These molecules are microbial opsins, seven-transmembrane proteins adapted from organisms found throughout the world, which react to light by transporting ions across the lipid membranes of cells in which they are genetically expressed. These tools are enabling the causal assessment of the roles that different sets of neurons play within neural circuits, and are accordingly being used to reveal how different sets of neurons contribute to the emergent computational and behavioral functions of the brain. These tools are also being explored as components of prototype neural control prosthetics capable of correcting neural circuit computations that have gone awry in brain disorders. This review gives an account of the birth of optogenetics and discusses the technology and its applications.
PMCID: PMC3155186  PMID: 21876722
19.  New tools in membrane protein determination 
The determination of membrane structures presents the structural biologist with many challenges; however, the last two years have seen major advances in our ability to resolve these structures at atomic resolution. My goal here is to summarize some of the most recent advances that have enhanced our prospects for understanding membrane proteins at the level of atomic structure.
PMCID: PMC3100781  PMID: 21655333
20.  Physics, biology and the right chemistry 
Joint studies that involve biologists and physicists are becoming more frequent and have contributed to the identification and understanding of physical parameters underlying key biological processes. Here, we illustrate the main findings resulting from a 10-year collaboration between a cell biologist and an experimental physicist, both interested in the mechanisms of intracellular transport and membrane dynamics in eukaryotic cells.
PMCID: PMC3100792  PMID: 21655337
21.  Laminar fate specification in the cerebral cortex 
The cerebral cortex is composed of hundreds of different types of neurons, which underlie its ability to perform highly complex neural processes. How this astonishing cell diversity is generated during development constitutes a major challenge in developmental neurosciences, with important implications for neurological diseases. Here we review some recent and exciting advances in this field, from the description of the cellular processes at the origin of cortical neuron diversity, to the dissection of the molecular logic underlying fate selection in cortical neurons.
PMCID: PMC3100784  PMID: 21655334
22.  Medulloblastoma: advances and challenges 
Medulloblastoma, a cancer of the posterior fossa, is the most common malignant brain tumor in children. Although 80% of patients with average-risk medulloblastoma are cured, their quality of life is often compromised by treatment-related side effects. Recently, molecular and genomic studies have shown medulloblastoma to be a heterogeneous disease made up of distinct disease subtypes. The importance of this finding is that response to therapy appears to be subtype-specific. Nevertheless, most patients are still treated according to risk stratification methods based on the clinically defined presence or absence of disseminated disease, which take no account of these newly defined subtypes. The potential, however, to vastly reduce therapy-mediated toxicity to patients with tumor subtypes that have good outcomes, while improving therapy through targeting for the poor responders, is now palpable. Critical to this effort will be the ongoing refinement of our understanding of medulloblastoma subgroups at the molecular level and the development of mouse models that faithfully recapitulate tumor subtypes.
PMCID: PMC3100785  PMID: 21655335
23.  The coming health crisis: indirect health effects of global climate change 
Global climate change threatens the health of hundreds of millions of people. While much has been written about the direct impacts of climate change on health as a result of more severe storms, more intense heat stress, changes in the distribution of infectious disease, and reduced air quality, we are concerned that the indirect impacts of a disrupted climate system may be orders of magnitude more important in terms of the human suffering they cause. Because these indirect effects will result from changes in biophysical systems, which are inherently complex, there is significant uncertainty about their magnitude, timing, and location. However, the uncertainty that shrouds this issue should not be cause for complacency; rather it should serve as an organizing principle for adaptation to its ill effects.
PMCID: PMC3042309  PMID: 21399764
24.  Chemical signaling in the gastrointestinal tract 
Chemical signaling via the production of small molecules such as hormones has been studied in detail in higher organisms. These molecules have important functions in maintaining physiological homeostasis as well as allowing organisms to respond to external insults. Virtually every living cell produces hormone-like diffusible small molecules that can be used to convey messages to neighboring cells—a vital step in adaptation, development, and survival within populations. Although most of our knowledge on cellular chemical communication comes from studies of multicellular eukaryotes, it is now understood that bacteria can also communicate using sophisticated signaling systems, in a way analogous to those used by higher organisms. Many of these microbes live in close association with higher eukaryotes, in mutualistic or commensal relationships. We suggest that there may be a wealth of unidentified bioactive small molecules in the human body, originating from both microbial and human cells and that have important biological functions. Because chemical signaling has important roles for the biology of both microbes and humans, detecting, identifying, and studying these chemical signals can further our understanding of the chemical interplay between microbiota and their hosts and provide us with an unexplored source of molecules that could be used for human benefit.
PMCID: PMC3042312  PMID: 21399765
25.  At home with hostility: How do pathogenic bacteria evade mammalian immune surveillance to establish persistent infection? 
Bacterial persistence is of major concern as persistent bacterial infections involving bacteria such as Helicobacter pylori, Salmonella enterica serotype Typhi, and Mycobacterium tuberculosis pose significant public health problems worldwide. This report discusses the recent advances in understanding the strategies used by bacteria during persistent infection that allow them to colonize specific sites in the host and evade immune surveillance.
PMCID: PMC3042314  PMID: 21399762

Results 1-25 (26)