Can neuroscience be integrated into the DSM-V?

To date, the diagnosis of mental disorders has been based on clinical observation, specifically: the identification of symptoms that tend to cluster together, the timing of the symptoms' appearance, and their tendency to resolve, recur or become chronic. The Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Disease, the manuals that specify these diagnoses and the criteria for making them, are currently undergoing revision. It is thus timely to ask whether neuroscience has progressed to the point that the next editions of these manuals can usefully incorporate information about brain structure and function.     

Particle capture into the lung made simple?

Understanding the impact distribution of particles entering the human respiratory system is of primary importance as it concerns not only atmospheric pollutants or dusts of various kinds but also the efficiency of aerosol therapy and drug delivery. To model this process, current approaches consist of increasingly complex computations of the aerodynamics and particle capture phenomena, performed in geometries trying to mimic lungs in a more and more realistic manner for as many airway generations as possible. Their capture results from the complex interplay between the details of the aerodynamic streamlines and the particle drag mechanics in the resulting flow. In contrast, the present work proposes a major simplification valid for most airway generations at quiet breathing. Within this context, focusing on particle escape rather than capture reveals a simpler structure in the entire process. When gravity can be neglected, we show by computing the escape rates in various model geometries that, although still complicated, the escape process can be depicted as a multiplicative escape cascade in which each elementary step is associated with a single bifurcation. As a net result, understanding of the particle capture may not require computing particle deposition in the entire lung structure but can be abbreviated in some regions using our simpler approach of successive computations in single realistic bifurcations. Introducing gravity back into our model, we show that this multiplicative model can still be successfully applied on up to nine generations, depending on particle type and breathing conditions.     

Adult stem cells: the real root into the embryo?

During embryonic development, a pool of cells may become a reserve of undifferentiated cells, the embryo-stolen adult stem cells (ESASC). ESASC may be responsible for adult tissue homeostasis, as well as disease development. Transdifferentiation is a sort of reprogramming of ESASC from one germ layer-derived tissue towards another. Transdifferentiation has been described to take place from mesoderm to ectodermal- or endodermal-derived tissues and viceversa but not from ectodermal- to endodermal-derived tissues. We hypothesise that two different populations of ESASC could exist, the first ecto/mesoblast-committed and the second endo/mesoblast-committed. If confirmed, this hypothesis could lead to new studies on the molecular mechanisms of cell differentiation and to a better understanding of the pathogenesis of a number of diseases.     

Something in the air? New insights into mammalian pheromones

Olfaction is the dominant sensory modality for most animals and chemosensory communication is particularly well developed in many mammals. Our understanding of this form of communication has grown rapidly over the last ten years since the identification of the first olfactory receptor genes. The subsequent cloning of genes for rodent vomeronasal receptors, which are important in pheromone detection, has revealed an unexpected diversity of around 250 receptors belonging to two structurally different classes. This review will focus on the chemical nature of mammalian pheromones and the complementary roles of the main olfactory system and vomeronasal system in mediating pheromonal responses. Recent studies using genetically modified mice and electrophysiological recordings have highlighted the complexities of chemosensory communication via the vomeronasal system and the role of this system in handling information about sex and genetic identity. Although the vomeronasal organ is often regarded as only a pheromone detector, evidence is emerging that suggests it might respond to a much broader variety of chemosignals.     

How are the Non-classically Secreted Bacterial Proteins Released into the Extracellular Milieu?

Most bacterial proteins that are destined to leave the cytoplasm are exported across the cell membrane to their sites of function. These proteins are generally exported via the classical secretion pathway, in which the signal peptide plays a central role. However, some bacterial proteins have been found in the extracellular milieu without any apparent signal peptide. As none of the classical secretion systems is involved in their secretion, this occurrence is termed non-classical protein secretion. The mechanism or mechanisms responsible for non-classical secretion are contentious. This review compiles evidence from the debate over whether the release of the non-classically secreted proteins is the result of cell lysis and discusses how these proteins are exported to the exterior of the cell.     

Conversion of the BASE prion strain into the BSE strain: the origin of BSE?

Atypical neuropathological and molecular phenotypes of bovine spongiform encephalopathy (BSE) have recently been identified in different countries. One of these phenotypes, named bovine "amyloidotic" spongiform encephalopathy (BASE), differs from classical BSE for the occurrence of a distinct type of the disease-associated prion protein (PrP), termed PrP(Sc), and the presence of PrP amyloid plaques. Here, we show that the agents responsible for BSE and BASE possess different biological properties upon transmission to transgenic mice expressing bovine PrP and inbred lines of nontransgenic mice. Strikingly, serial passages of the BASE strain to nontransgenic mice induced a neuropathological and molecular disease phenotype indistinguishable from that of BSE-infected mice. The existence of more than one agent associated with prion disease in cattle and the ability of the BASE strain to convert into the BSE strain may have important implications with respect to the origin of BSE and spongiform encephalopathies in other species, including humans.     

Dinosaur protofeathers: pushing back the origin of feathers into the Middle Triassic?

Reports of primordial feathers (protofeathers) in dinosaurs have received widespread interest. Recently, it was proposed that a novel protofeather in the theropod dinosaur Beipiaosaurus completes the transitional series in the evolution of the feather and provides the first evidence of filamentous feathers as display in nonavian theropods. A more far-reaching evolutionary ramification is the claim that these structures push the origin of monofilamentous integumentary structures into the Middle Triassic or earlier. I discuss problems with the analyses within the broader context of studies concerning the hypothesis of protofeathers, and show that affinity between the integumentary structures in Beipiaosaurus and feathers is improbable. The scientific methodology is questioned by its failure to make phenomena perceivable by objective means, by questionable rationalizations in critical issues, and by lack of consideration of exceptions to the postulated thesis. The notion that primordial feathers occurred in a clade more inclusive than the Coelurosauria and that it is supported by the presence of integumental structures in Psittacosaurus is analyzed and rejected.     

Immune privilege or inflammation? Insights into the Fas ligand enigma

Fas ligand (FasL) has become an enigmatic molecule: some evidence indicates that it contributes to immune privilege in tissues and tumors, whereas other data demonstrates that FasL can elicit inflammation. New findings may begin to reconcile the paradoxical effects of FasL.     

Does the correlation between schmorl's nodes and vertebral morphology extend into the lumbar spine?

Schmorl's nodes are depressions on vertebrae due to herniation of the nucleus pulposus of the intervertebral disc into the vertebral body. This study provides an extension of our previous study which analyzed the shape of the lower thoracic spine and found that vertebral morphology was associated with the presence of Schmorl's nodes. Ninety adult individuals from the late Medieval site of Fishergate House, York, and the Post‐Medieval site of Coach Lane, North Shields, Tyne and Wear, England, were analysed using 2D geometric morphometrics to identify possible relationships between vertebral morphology and Schmorl's nodes at the thoraco‐lumbar junction and in the lumbar spine. A significant correlation was found between vertebral shape and the presence of Schmorl's nodes in the twelfth thoracic vertebrae and the first to third lumbar vertebrae. The findings corroborate previous studies and suggest that vertebral shape may be an important factor in spinal health. It is hypothesized that the pedicle shape of affected vertebrae may not provide adequate structural support for the vertebral bodies, resulting in vertical disc herniation. Am J Phys Anthropol 157:526–534, 2015. © 2015 Wiley Periodicals, Inc.     

Is the cholesterol bilayer domain a barrier to oxygen transport into the eye lens?

In the eye lens, the oxygen partial pressure is very low and the cholesterol (Chol) content in cell membranes is very high. Disturbance of these quantities results in cataract development. In human lens membranes, both bulk phospholipid-Chol domains and the pure Chol bilayer domains (CBDs) were experimentally detected. It is hypothesized that the CBD constitutes a significant barrier to oxygen transport into the lens. Transmembrane profiles of the oxygen diffusion-concentration product, obtained with electron paramagnetic resonance spin-labeling methods, allow evaluation of the oxygen permeability (P_M) of phospholipid membranes but not the CBD. Molecular dynamics simulation can independently provide components of the product across any bilayer domain, thus allowing evaluation of the P_M across the CBD. Therefore, to test the hypothesis, MD simulation was used. Three bilayers containing palmitoyl-oleoyl-phosphorylcholine (POPC) and Chol were built. The pure Chol bilayer modeled the CBD, the 1:1 POPC-Chol bilayer modeled the bulk membrane in which the CBD is embedded, and the POPC bilayer was a reference. To each model, 200 oxygen molecules were added. After equilibration, the oxygen concentration and diffusion profiles were calculated for each model and multiplied by each other. From the respective product profiles, the P_M of each bilayer was calculated. Favorable comparison with experimental data available only for the POPC and POPC-Chol bilayers validated these bilayer models and allowed the conclusion that oxygen permeation across the CBD is ~ 10 smaller than across the bulk membrane, supporting the hypothesis that the CBD is a barrier to oxygen transport into the eye lens.     

Plant natural products: Back to the future or into extinction?

Natural product substances have historically served as the most significant source of new leads for pharmaceutical development. However, with the advent of robotics, bioinformatics, high throughput screening (HTS), molecular biology-biotechnology, combinatorial chemistry, in silico (molecular modeling) and other methodologies, the pharmaceutical industry has largely moved away from plant derived natural products as a source for leads and prospective drug candidates. Can, or will, natural products ever recapture the preeminent position they once held as a foundation for drug discovery and development? The challenges associated with development of natural products as pharmaceuticals are illustrated by the Taxol^® story. Several misconceptions, which constrain utilization of plant natural products, for discovery and development of pharmaceuticals, are addressed to return natural products to the forefront.     

Neutrophil migration into the placenta: Good,bad or deadly?

ABSTRACT

Almost 2 decades have passed since the discovery that pregnancy is associated with a basal inflammatory state involving neutrophil activation, and that this is more overt in cases with preeclampsia, than in instances with sepsis. This pivotal observation paved the way for our report, made almost a decade ago, describing the first involvement of neutrophil extracellular traps (NETs) in a non-infectious human pathology, namely preeclampsia, where an abundance of these structures were detected directly in the placental intervillous space.

Despite these remarkable findings, there remains a paucity of interest among reproductive biologists in further exploring the role or involvement of neutrophils in pregnancy and related pathologies. In this review we attempt to redress this deficit by highlighting novel recent findings including the discovery of a novel neutrophil subset in the decidua, the interaction of placental protein 13 (PP13) and neutrophils in modulating spiral artery modification, as well as the use of animal model systems to elucidate neutrophil function in implantation, gestation and parturition. These model systems have been particularly useful in identifying key components implicated in recurrent fetal loss, preeclampsia or new signaling molecules such as sphingolipids. Finally, the recent discovery that anti-phospolipid antibodies can trigger NETosis, supports our hypothesis that these structures may contribute to placental dysfunction in pertinent cases with recurrent fetal loss.     

What drives proteins into the major or minor grooves of DNA?

The energetic profiles of a significant number of protein-DNA systems at 20 °C reveal that, despite comparable Gibbs free energies, association with the major groove is primarily an enthalpy-driven process, whereas binding to the minor groove is characterized by an unfavorable enthalpy that is compensated by favorable entropic contributions. These distinct energetic signatures for major versus minor groove binding are irrespective of the magnitude of DNA bending and/or the extent of binding-induced protein refolding. The primary determinants of their different energetic profiles appear to be the distinct hydration properties of the major and minor grooves; namely, that the water in the A+T-rich minor groove is in a highly ordered state and its removal results in a substantial positive contribution to the binding entropy. Since the entropic forces driving protein binding into the minor groove are a consequence of displacing water ordered by the regular arrangement of polar contacts, they cannot be regarded as hydrophobic.     

Do neural crest cells in the pancreas differentiate into somatostatin-containing cells?

Summary The possibility that the somatostatin cells are derived from the neurectoderm has been questioned in avian embryos. Isotopic and isochronic transplantations of the neural primordium from quail into chick embryos were made at the vagal level (somites 1 to 7). Quail and chick cells can be distinguished by the structure of their nucleus. The somatostatin cells were characterized immunocytochemically. In no case did quail cells showing the immunological reaction originate from the neural crest.     

Lack of new antiinfective agents: Passing into the pre-antibiotic age?

The lack of newly developed antibiotics, together with the increase in multi-resistance of relevant pathogenic bacteria in the last decades, represents an alarming signal for human health care worldwide. The number of severely infected persons increases not only in developing but also in highly industrialized countries. This relates in first line to the most severe form of a bacterial infection, sepsis and the septic shock syndrome, with high mortality on critical care units. No particular anti-sepsis drug is available, and the therapy with conventional antibiotics more and more fails to provide a survival benefit. Due to the fact that the pharmaceutical industry has withdrawn to a high degree from the development of anti-infectious agents, a huge challenge for health care is approaching in the 21 st century. In this article, these problems are outlined and possible alternatives are presented which may be helpful to solve the problem.     

Der1-mediated preprotein import into the periplastid compartment of chromalveolates?

Phototrophic chromalveolates possess plastids surrounded by either 3 or 4 membranes, revealing their secondary endosymbiotic origin from an engulfed eukaryotic alga. In cryptophytes, a member of the chromalveolates, the organelle is embedded within a designated region of the host's rough endoplasmic reticulum (RER). Its eukaryotic compartments other than the plastid were reduced to the mere remains of its former cytosol, the periplastid compartment (PPC, PP space), and its nucleus, the nucleomorph, separated from the RER by its former plasma membrane, the periplast membrane (PPM). In the nucleomorph genome of the cryptophyte Guillardia theta, we identified several genes sharing homology with components of the ER-associated degradation (ERAD) machinery of yeast and higher eukaryotes, namely ORF201 and ORF477, homologs of membrane-bound proteins, Der1p (Degradation in the ER protein 1) and the RING-finger ubiquitin ligase Hrd1, and a truncated version of Udf1, a cofactor of Cdc48, a lumenal ATPase. Exemplarily, studies on the Der1-homolog ORF201 showed that this protein partially rescued a yeast deletion mutant, indicating the existence of a functional PPC-specific ERAD-like system in cryptophytes. With the noninvestigated exception of haptophytes a phylogenetically and mechanistically related system is apparently present in all chromalveolates with 4 membrane-bound plastids because amongst others, PPC-specific Derlins (Der1-like proteins), CDC48 and its cofactor Ufd1 were identified in the nuclear genomes of diatoms and apicomplexa. These proteins are equipped with the required topogenic signals to direct them into the periplastid compartment of their secondary symbionts. Based on our findings, we suggest that all chromalveolates with 4 membrane-bound plastids express an ERAD-derived machinery in the PPM of their secondary plastid, coexisting physically and systematically adjacent to the host's own ERAD system. We propose herewith that this system was functionally adapted to mediate transport of nucleus-encoded PPC/plastid preproteins from the RER into the periplastid space.     

How does the TOM complex mediate insertion of precursor proteins into the mitochondrial outer membrane?

A multisubunit translocase of the outer mitochondrial membrane (TOM complex) mediates both the import of mitochondrial precursor proteins into the internal compartments of the organelle and the insertion of proteins residing in the mitochondrial outer membrane. The proposed beta-barrel structure of Tom40, the pore-forming component of the translocase, raises the question of how the apparent uninterrupted beta-barrel topology can be compatible with a role of Tom40 in releasing membrane proteins into the lipid core of the bilayer. In this review, I discuss insertion mechanisms of proteins into the outer membrane and present alternative models based on the opening of a multisubunit beta-barrel TOM structure or on the interaction of outer membrane precursors with the outer face of the Tom40 beta-barrel structure.