d-Alanine: Distribution,origin, physiological relevance,and implications in disease

d-Alanine (d-Ala) is an unusual endogenous amino acid present in invertebrates and vertebrates. Compared to its l-isomer, the characterization of d-Ala is challenging because of the need for chiral resolution and the low amounts of the d-enantiomer present. With recent improvements in measurement capabilities, research on d-Ala, along with other d-amino acids, has been growing, especially as the functional significance of d-Ala in the mammalian nervous and endocrine systems is becoming known. Here we provide an overview of the distribution, origin, function, and disease implications of d-Ala.     

Complex genetic origin of Indian populations and its implications

Indian populations are classified into various caste, tribe and religious groups, which altogether makes them very unique compared to rest of the world. The long-term firm socio-religious boundaries and the strict endogamy practices along with the evolutionary forces have further supplemented the existing high-level diversity. As a result, drawing definite conclusions on its overall origin, affinity, health and disease conditions become even more sophisticated than was thought earlier. In spite of these challenges, researchers have undertaken tireless and extensive investigations using various genetic markers to estimate genetic variation and its implication in health and diseases. We have demonstrated that the Indian populations are the descendents of the very first modern humans, who ventured the journey of out-of-Africa about 65,000?years ago. The recent gene flow from east and west Eurasia is also evident. Thus, this review attempts to summarize the unique genetic variation among Indian populations as evident from our extensive study among approximately 20,000 samples across India.     

Alzheimer's disease: its origin at the membrane, evidence and questions

Numerous results on membrane lipid composition from different regions of autopsied Alzheimer's disease brains in comparison with corresponding fractions isolated from control brains revealed significant differences in serine- and ethanolamine-containing glycerophospholipid as well as in glycosphingolipid content. Changes in membrane lipid composition are frequently accompanied by alterations in membrane fluidity, hydrophobic mismatch, lipid signaling pathways, transient formation and disappearance of lipid microdomains, changes in membrane permeability to cations and variations of other membrane properties. In this review we focus on possible implications of altered membrane composition on beta-amyloid precursor protein (APP) and on proteolysis of APP leading eventually to the formation of neurotoxic beta-amyloid (A beta) peptides, the major proteinaceous component of extracellular senile plaques, directly involved in Alzheimer's disease pathogenesis.     

The monophyletic origin of delayed implantation in carnivores and its implications

Abstract. In several carnivores a newly fertilized egg enters diapause instead of being directly implanted into the uterus, a phenomenon called delayed implantation. Several hypotheses have been forwarded to explain the utility of this prolonged gestation period, but all of these depend on several independent origins of the character. Here, we conduct a phylogenetic reconstruction of the evolution of delayed implantation in the Carnivora that reveals one basal origin, with additional transitions all having occurred within the Mustelidae. Hence, previous hypotheses relating to its evolution become untestable. Further analyses revealed that the presence or absence of delayed implantation is unrelated to the timing of mating season and birth season. Instead, mustelids with direct implantation are smaller than those with delayed implantation. We therefore suggest that delayed implantation has been selected against in small species due to the relatively higher fecundity costs of a prolonged gestation period.     

The crustacean lacinia mobilis: a reconsideration of its origin, function and phylogenetic implications

The lacinia mobilis of the Crustacea Malacostraca is a more or less spine-like movable appendage of the medial mandibular edge, inserted near the base of the incisor process. It occurs in two or possibly three eumalacostracan superorders but is retained in the adult stage only in the Peracarida. The lacinia has been interpreted as the distal member of the spine-row found in many adult Malacostraca and/or their larvae, or alternatively as a derivative of a certain cusp ('cusp b') of the biting edge of the primitive lophogastrids. The distribution, ontogeny and function of the lacinia were studied in a variety of Eumalacostraca. There is great variability in the guiding and locking mechanisms involved in biting, within the subclass and even within single orders. A lacinia-based guiding and locking system is likely to function only in weak mandibles. New evidence is produced in favour of derivation of the lacinia from the spine-row, and the 'cusp b' derivation hypothesis is rejected, 'cusp b' being only a highly specialized lacinia. Doubt is cast upon the unity of the superorder Peracarida mainly because the place of the order Amphipoda within it is regarded as insecure.     

Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease

Gaucher disease, caused by pathological mutations GBA1, encodes the lysosome-resident enzyme glucocerebrosidase, which cleaves glucosylceramide into glucose and ceramide. In Gaucher disease, glucocerebrosidase deficiency leads to lysosomal accumulation of substrate, primarily in cells of the reticulo-endothelial system. Gaucher disease has broad clinical heterogeneity, and mutations in GBA1 are a risk factor for the development of different synucleinopathies. Insights into the cell biology and biochemistry of glucocerebrosidase have led to new therapeutic approaches for Gaucher disease including small chemical chaperones. Such chaperones facilitate proper enzyme folding and translocation to lysosomes, thereby preventing premature breakdown of the enzyme in the proteasome. This review discusses recent progress in developing chemical chaperones as a therapy for Gaucher disease, with implications for the treatment of synucleinopathies. It focuses on the development of non-inhibitory glucocerebrosidase chaperones and their therapeutic advantages over inhibitory chaperones, as well as the challenges involved in identifying and validating chemical chaperones.     

Sobo, a recently amplified satellite repeat of potato, and its implications for the origin of tandemly repeated sequences

Highly repetitive satellite DNA sequences are main components of heterochromatin in higher eukaryotic genomes. It is well known that satellite repeats can expand and contract dramatically, which may result in significant genome size variation among genetically related species. The origin of satellite repeats, however, is elusive. Here we report a satellite repeat, Sobo, from a diploid potato species, Solanum bulbocastanum. The Sobo repeat is mapped to a single location in the pericentromeric region of chromosome 7. This single Sobo locus spans approximately 360 kb of a 4.7-kb monomer. Sequence analysis revealed that the major part of the Sobo monomer shares significant sequence similarity with the long terminal repeats (LTRs) of a retrotransposon. The Sobo repeat was not detected in other Solanum species and is absent in some S. bulbocastanum accessions. Sobo monomers are highly homogenized and share >99% sequence identity. These results suggest that the Sobo repeat is a recently emerged satellite and possibly originated by a sudden amplification of a genomic region including the LTR of a retrotransposon and its flanking genomic sequences.     

DNA polymorphism in Allium cepa cytoplasms and its implications concerning the origin of onions

Summary Mitochondrial and chloroplast DNA was isolated from fertile and cytoplasmic male sterile cultivars of cultivated onions. Restriction fragment length polymorphism led to the distinction between cytoplasms S and M. Mitochondrial DNA patterns from S cytoplasms appeared dentical and characterized mostly male sterile lines. An open-pollinated variety was found to bear this cytoplasm and thought to be the origin of S types. Mitochondrial DNA patterns from M cytoplasms were subdivided into four types, M₁ and M₂ corresponding to normal N cytoplasm, M₃ and M₄ probably corresponding to T cytoplasms. S and M cytoplasms were also distinguished by chloroplast DNA restriction patterns. Our results confirm previous genetic distinction between S, N and T cytoplasms.     

Nuclear and chloroplast DNA reassessment of the origin of Indian potato varieties and its implications for the origin of the early European potato

The modern cultivated potato was first recorded in Europe in 1562, but its area(s) of exportation has long been in dispute. Two competing hypotheses have proposed an Andean area (somewhere from upland Venezuela to northern Argentina) or a lowland south central Chilean area. Potato landraces from these two areas can be distinguished, although sometimes with difficulty, by (1) cytoplasmic sterility factors, (2) morphological traits, (3) daylength adaptation, (4) microsatellite markers, and (5) co-evolved chloroplast (cp) and mitochondria (mt) DNA. The Chilean introduction hypothesis originally was proposed because of similarities among Chilean landraces and modern European cultivars with respect to traits 2 and 3. Alternatively, the Andean introduction hypothesis suggests that (1) traits 2 and 3 of European potato evolved rapidly, in parallel, from Andean landraces to a Chilean type through selection following import to Europe, and (2) the worldwide late blight epidemics beginning in 1845 in the United Kingdom displaced most existing European cultivars and the potato was subsequently improved by importations of Chilean landraces. We reassess these two competing hypotheses with nuclear microsatellite and cpDNA analyses of (1) 32 Indian cultivars, some of which are thought to preserve putatively remnant populations of Andean landraces, (2) 12 Andean landraces, and (3) five Chilean landraces. Our microsatellite results cluster all Indian cultivars, including putatively remnant Andean landrace populations, with the Chilean landraces, and none with the old Andigenum landraces. Some of these Indian landraces, however, lack the cpDNA typical of Chilean landraces and advanced cultivars, indicating they likely are hybrids of Andean landraces with Chilean clones or more advanced cultivars. These results lead us to reexamine the hypothesis that early introductions of potato to Europe were solely from the Andes.     

Cell competition and its implications for development and cancer

Cell competition is a struggle for existence between cells in heterogeneous tissues of multicellular organisms.Loser cells,which die during cell competition,are normally viable when grown only with other loser cells,but when mixed with winner cells,they are at a growth disadvantage and undergo apoptosis.Intriguingly,several recent studies have revealed that cells bearing mutant tumor-suppressor genes,which show overgrowth and tumorigenesis in a homotypic situation,are frequently eliminated,through cell competition,from tissues in which they are surrounded by wild-type cells.Here,we focus on the regulation of cellular competitiveness and the mechanism of cell competition as inferred from two different categories of mutant cells:(1) slower-growing cells and (2) structurally defective cells.We also discuss the possible role of cell competition as an intrinsic homeostasis system through which normal cells sense and remove aberrant cells,such as precancerous cells,to maintain the integrity and normal development of tissues and organs.     

Cell competition and its implications for development and cancer

Cell competition is a struggle for existence between cells in heterogeneous tissues of multicellular organisms.Loser cells,which die during cell competition,are normally viable when grown only with other loser cells,but when mixed with winner cells,they are at a growth disadvantage and undergo apoptosis.Intriguingly,several recent studies have revealed that cells bearing mutant tumor-suppressor genes,which show overgrowth and tumorigenesis in a homotypic situation,are frequently eliminated,through cell competition,from tissues in which they are surrounded by wild-type cells.Here,we focus on the regulation of cellular competitiveness and the mechanism of cell competition as inferred from two different categories of mutant cells:(1) slower-growing cells and (2) structurally defective cells.We also discuss the possible role of cell competition as an intrinsic homeostasis system through which normal cells sense and remove aberrant cells,such as precancerous cells,to maintain the integrity and normal development of tissues and organs.     

Rapid hydrogen sulfide consumption by Tetrahymena pyriformis and its implications for the origin of mitochondria

Although sulfide is typically regarded as toxic to eukaryotic cells, it is avidly consumed by Tetrahymena pyriformis. That was observed only when the sulfide concentration was kept below 1 microM. Previously concentrations that were too high had been tested. A new device (Sulfidostat) was used to measure sulfide consumption in steady-state concentrations as low as 10(-12)M. The technique was validated non-biologically by slowly injecting AgNO(3) into buffer and using Ag(2)S precipitation to mimic sulfide consumption, confirming that rates of sulfide consumption could be measured independently of sulfide concentrations. With T. pyriformis, sulfide consumption was 0.25 micromol (gprotein)(-1)s(-1) in 0.5 microM sulfide. Sulfide consumption required O(2) and was inhibited by HCN or by too much sulfide. When cells were separated into fractions, sulfide consumption occurred in the particulate (mitochondrial) fraction. Unexpectedly, the soluble cytosolic fraction slowly produced sulfide even when aerated. The observations are consistent with the conjecture that mitochondria evolved from sulfidotrophic symbionts in a sulfidogenic host cell.     

Translocation of H-Ras and its implications in the development of diabetic retinopathy

H-Ras, a small molecular weight G-protein, undergoes post-translational modifications enabling its translocation from cytosol to the membrane. Hyperglycemia increases apoptosis of retinal capillary cells via activation of H-Ras, which can be ameliorated by farnesylation inhibitors. Our aim is to investigate the mechanism of retinal H-Ras activation in diabetes. H-Ras and Raf-1 were quantified in the retinal membrane and cytosol fractions obtained from streptozotocin-induced diabetes rats, and the role of post-translation modification was determined by investigating the effect of simvastatin on diabetes-induced alterations. The effect of H-Ras-siRNA on membrane translocation and apoptosis was also determined in bovine retinal endothelial cells (BRECs). Diabetes increased expressions of H-Ras and Raf-1 in the retinal membranes, and simvastatin prevented such translocation. Glucose-exposure of BRECs increased membrane H-Ras expression and H-Ras-siRNA prevented this translocation, and also decreased their apoptosis. Thus, membrane translocation of H-Ras is a plausible mechanism responsible for accelerated apoptosis of retinal capillary cells in diabetes.     

The origin, development and regulation of osteoclasts

Osteoclasts, the multinucleated cells primarily responsible for dissolution of bone tissue, form by fusion of precursors that circulate in the bloodstream. A variety of factors have been shown to affect the mature osteoclast and its progenitor cell, such as calcium-regulating hormones, products of the immune system, and constituents of the arachidonic acid cascade. To date, however, the osteoclast precursor has not been identified. Furthermore, there is limited information on the factors that influence osteoclast development and regulation, reflecting in part the paucity of data on the osteoclast cell surface. Recent progress in understanding osteoclasts formation and function is discussed.     

Role of the extracellular matrix and its receptors in smooth muscle cell function: implications in vascular development and disease

PURPOSE OF REVIEW: Cardiovascular disease affects millions of people worldwide, while the sarcoglycan deficient cardiomyopathies are rare disorders. One important common feature, however, is the vascular smooth muscle. Here we focus on the roles of extracellular matrix components and their receptors in the functions of vascular smooth muscle cells. RECENT FINDINGS: Recent observations highlight the importance of integrins and the dystrophin-glycoprotein complex in development and cardiomyopathy. For example, integrin alpha4 and alpha7 subunits are important for distributing vascular smooth muscle cells during blood vessel development. Studies on delta-sarcoglycan deficient animals have revealed abnormal vascular smooth muscle proliferation and apoptosis. Furthermore, data suggest that perlecan, by affecting smooth muscle cell proliferation, participates in the atherosclerotic process. Overexpression of decorin leads to reduced progression of atherosclerosis and thrombospondin-1 has been implicated in regulation of smooth muscle cell contractility via inhibition of nitric oxide. Novel findings on versican suggest that the binding of versican to fibulin is of great importance for regulating smooth muscle cell function. SUMMARY: By regulating migration, proliferation and apoptosis as well as extracellular matrix synthesis and assembly, proteoglycans, integrins and the dystrophin-glycoprotein complex may be of great importance both during development and in vascular disease.     

Molecular mechanisms of RNAi: implications for development and disease

Research over the past few years has led to dramatic new discoveries on the role of double-stranded RNA (dsRNA) in the cell. RNA duplexes have been shown to orchestrate epigenetic changes, repress translation, and direct mRNA degradation in a sequence-specific manner. These diverse effects of dsRNA on gene expression have been termed RNA interference (RNAi). In addition to playing a role in viral defense and silencing transposons, RNAi also has a critical function in a number of developmental processes in the embryo. In this review, we explore these roles and discuss the molecular mechanisms behind dsRNA-mediated gene silencing. Further, we address the use of RNAi as a tool to study gene function in biology, and as a strategy for treating human disease.