Bioscience hypotheses最新文献

Cerebral lateralization was once thought to be unique to humans, but is now known to be widespread among the vertebrates. Lateralization appears to confer cognitive advantages upon those that possess it. Despite the taxonomic ubiquity and described advantages of lateralization, substantial individual variation exists in all species. Individual variation in cerebral lateralization may be tied to individual variation in behaviour and the selective forces that act to maintain variation in behaviour may also act to maintain variation in lateralization. The mechanisms linking individual variation in the strength of cerebral lateralization to individual variation in behaviour remain obscure. We propose here a general hypothesis which may help to explain this link. We suggest that individuals with strong and weak lateralizations behave differently because of differences in the ability of one hemisphere to inhibit the functions of the other in each type of brain organization. We also suggest a specific mechanism involving the asymmetric epithalamic nucleus, the habenula. We conclude by discussing some predictions and potential tests of our hypothesis.

Clinical evidence from paediatric neurology supports the possibility that a protracted inflammatory state in the central nervous system (CNS) may enhance the predisposition of brain tissue to develop seizures. Consequently, non-steroidal anti-inflammatory drugs (NSAIDs) as well as selective cyclooxygenase-2 (COX-2) inhibitors were expected to positively modulate seizure susceptibility during a systemic inflammatory response. Nevertheless, experimental findings and clinical evidence provide controversial results. As a possible explanation for these apparent discrepancies, it is hypothesised that the amount of prostaglandin E₂ (PGE₂) induced in the immature brain parenchyma during systemic inflammatory response is crucial since PGE₂ plays a dual role. Indeed, on the one hand, this prostaglandin increases seizure susceptibility by stimulation of glutamate release from neurons and astrocytes. On the other hand, however, the same prostaglandin induces a massive release of corticosterone, being this hormone known to inhibit efficiently the seizure susceptibility of the immature brain. Hence, the dose–response curve of any given NSAID/COX-2 inhibitor on seizure susceptibility is expected to show different patterns, depending on the amount of PGE₂ levels produced in the brain parenchyma during the effect of drug. The proposed hypothesis also suggests that mild to moderate increase of PGE₂ levels in the immature brain parenchyma may act as a ‘preconditioning’ stimulus, i.e., it may confer a transient resistance to develop seizure-induced brain injury, besides to efficiently counteract seizure susceptibility.

Bone morphogenetic proteins (BMPs) are important for the development and functioning of a wide variety of tissues and organ systems. Their ability to induce bone formation has been harnessed for clinical application. Specifically, local application of BMPs into fractures and fusions has shown some efficacy in inducing bone formation. However, clinical success has not been as robust as might be expected from the results obtained using animal models. This difference may be due to a number of mechanisms regulating BMP activity in vivo. One class of major regulators is the extracellular antagonist (e.g. Noggin, Gremlin, DAN), the dysfunction of which has been shown to result in ectopic bone formation in animal models and human disease. We hypothesize that local application of BMPs at high concentrations induces increased production of BMP antagonists, thereby limiting BMP activity and clinical efficacy. Therapies blocking the function of BMP antagonists should therefore result in enhanced BMP activity and increased bone formation. Furthermore, titrated systemic regulation of BMP antagonist may potentially reverse osteoporosis. Our collective experience with the clinical use of BMP illustrates the importance of understanding mechanisms of endogenous antagonism and regulation in the exogenous application of a protein as a therapeutic.

Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) may results in severe vision loss. Upregulation of vascular endothelial growth factor (VEGF) in hypoxic retinal pigment epithelium (RPE), mediated by hypoxia-inducible factor 1 (HIF-1) is responsible for CNV. Hypoxia triggers ATP-deletion in RPE cells, which activates HIF-1 via the Rho GTPase. HIF-1 also activates the expression of other growth factors, which upregulate the expression of corresponding receptors on the membrane of choroidal endothelial cells (CECs). Activation of these growth factor receptors itself activates Rho GTPases, and hence HIF-1 and VEGF transcription. There is therefore an autocrine pathway of VEGF activation in these cells, as well as paracrine stimulation of the VEGF pathway from external VEGF. At present, the pivot of treating CNV is blocking VEGF, which however will only block the paracrine pathway. We suggest that the promising treatment target for CNV in AMD should be transferred to upstream of VEGF, such as HIF-1 or Rho family GTPases family.

Chronic liver disease (CLD) constitutes a major cause of morbidity and mortality worldwide. Follow-up studies have documented that the majority of patients with CLD never reach the cirrhotic stage, while others display a higher progression rate leading to liver failure at relatively short intervals. This phenomenon has never been adequately explained. Recent evidence suggests that the renin–angiotensin system (RAS) is a major coordinator of chronic liver inflammation and subsequent fibrosis development, a process often termed hepatic remodeling. Combining these data with the “natural neutralizing antibodies theory” led us to the assumption that there could be an intrinsic anti-remodeling mechanism consisted of natural antibodies against components of the RAS. Varying degrees of activation of this defense mechanism could account for the variability in disease progression rate among patients with CLD. Identifying the main components of this mechanism allowed us to develop a ratio, designated remodeling index, as a measure of an individual's predilection towards cirrhosis. We believe that this index could be used as a safe, non-invasive and cost effective tool for assessing progression rate in normotensive patients with early CLD, thus alleviating the need for repeated liver biopsies.

Occurrence of cell wall deficiency (L-form conversion) in hosts suggests one of the possible pathways by which tubercle bacilli can survive, replicate and persist within the body for a long period harboring latent tuberculosis. Non-acid fast and morphologically modified L-forms of Mycobacterium tuberculosis are difficult to identify and remain often unrecognized or are mistaken for contaminants.

Understanding the brain–adipose signaling axis sheds new lights on the mechanisms of electric therapy and caloric restriction for Parkinson's disease and obesity.

Lots of evidence showed that bone marrow stem cells can differentiate into cardiac myocytes so as to treat damaged hearts. However, the following studies revealed that bone marrow stem cells also produced protective effects on hearts by releasing some beneficial cytokines and suppressing inflammatory effects and so on. Therefore, we speculated that the cardiac differentiation of bone marrow stem cells did not play an important role in cardiac repair.

The treatment of neuropathic pain remains a major challenge to pain clinicians. Certain nociceptive and non-nociceptive dorsal root ganglion (DRG) neurons may develop abnormal spontaneous activities following peripheral nerve injury, which is believed to be a major contributor to chronic pain. Subthreshold membrane potential oscillation (SMPO) observed in injured DRG neurons was reported to be involved in the generation of abnormal spontaneous activity. Tetrodotoxin-sensitive sodium (Na⁺) channels were testified to be involved in the generation of SMPO, but their specific subunits have not been clarified. We hypothesize that the subunits of voltage-gated sodium channel, Na_v1.3 and Na_v1.6, are involved in the generation of SMPO. An attempt to test this hypothesis may lead to a new therapeutic strategy for neuropathic pain.