Astrocyte–neuron interactions in neurological disorders

Astrocytes have long been considered as just providing trophic support for neurons in the central nervous system, but recently several studies have highlighted their importance in many functions such as neurotransmission, metabolite and electrolyte homeostasis, cell signaling, inflammation, and synapse modulation. Astrocytes are, in fact, part of a bidirectional crosstalk with neurons. Moreover, increasing evidence is stressing the emerging role of astrocyte dysfunction in the pathophysiology of neurological disorders, including neurodegenerative disease, stroke, epilepsy, migraine, and neuroinflammatory diseases.     

On some formulas in a partnership model from the perspective of a semi-Markov process

Many deterministic models of sexually transmitted diseases, as well as population models in general, contain elements of stochastic or statistical reasoning. An example of such a model is that of Dietz and Hadeler (1988) concerning sexually transmitted diseases in which there is partnership formation and dissolution. Among the interesting formulas in this paper, which enter into the analysis of the model, are those for the expected number of partners a male or female has during a lifetime. To a probabilist such formulas suggest the possibility that some stochastic process may be constructed so as to yield these formulas as well as others that may be of interest. The principal purpose of this paper is to demonstrate that such a stochastic process does indeed exist in the form of a three state semi-Markov process in continuous time with stationary laws of evolution and with a one-step density matrix determined by four parameters which were interpreted as constant latent risk functions in the classical theory of competing risks. This construction of a semi-Markov process not only provides a framework for the systematic derivation of the formulas of Dietz and Hadeler but also suggests pathways,for extensions to the age-dependent case.This research was partially supported by NATO Grant D.890350     

Ultrastructure of human dermal mast cells in 29 different lysosomal storage diseases

The effect of lysosomal storage diseases on the ultrastructure of human mast cells has not previously been reported. Indeed, there has been little published evidence indicating that mast cells contain typical lysosomes. However, mast cell cytoplasmic granules contain hydrolases similar to those found in lysosomes, but which differ from lysosomal hydrolases in exhibiting optimal activity at higher pH. We therefore examined by transmission electron microscopy the dermal mast cells in 58 biopsies of patients exhibiting 1 of 29 different lysosomal storage diseases. We found mast cells containing abnormal lysosomes in 16 of these disorders. In 6 of these 16 diseases, the mast cells' cytoplasmic granules appeared normal. These observations indicate that human mast cells can contain lysosomes, and provide evidence that the enzymes affected by lysosomal storage diseases are active in mast cells.     

Inborn errors of cobalamin metabolism: Effect of cobalamin supplementation in culture on methylmalonyl CoA mutase activity in normal and mutant human fibroblasts

We have examined the effect of addition of hydroxocobalamin to growth medium on the activity of the adenosylcobalamin-requiring enzyme methylmalonyl CoA mutase in normal human fibroblasts and in mutant human fibroblasts derived from patients with inherited methylmalonicacidemia. The mutant cell lines were assigned to four distinct genetic complementation groups (cbl A, cbl B, cbl C, and cbl D), each deficient in some step in the synthesis of adenosylcobalamin from hydroxocobalamin. After control cells were grown in cobalamin-supplemented medium, mutase holoenzyme activity increased markedly in a time- and concentration-dependent fashion. Growth in cobalamin-supplemented medium had no effect on mutase activity in some mutant lines belonging to the cbl B group, while activity increased severalfold in other cbl B mutants and in all cbl A, cbl C, and cbl D mutants examined, although mutase activity was still <10% of control. Comparison of mutase holoenzyme activity and total propionate pathway activity suggests that enhancement of mutase activity in mutant cells after cobalamin supplementation to values 5–10% of control may be sufficient to overcome the inherited metabolic block and to restore total pathway activity to normal.This work was supported in part by a research grant from the National Institutes of Health (AM 12579). H. F. W. is a recipient of a traineeship from the National Institutes of Health (T01-GM02299).     

4-(3-Alkyl/benzyl-guanidino)benzenesulfonamides as selective carbonic anhydrase VII inhibitors

The treatment of chronic neuropathic pain remains one of the most challenging of all neurological diseases and very much an art. There exists no consensus for the optimal management of this condition at the moment. Gaining inspiration from recent studies which pointed out the involvement of brain-associated carbonic anhydrase (CA, EC 4.2.1.1) isoform VII in the pathology of various neurodegenerative diseases, which highlighted the relationship between selective inhibition of this isozyme and relieve of neuropathic pain, herein we report the synthesis and CA VII inhibitory activity of novel 4-(3-alkyl/benzyl-guanidino)benzenesulfonamides. Ten benzyl-substituted and five alkyl-substituted 4-guanidinobenzenesulfonamide derivatives were obtained, some of which (7c, 7h, 7m and 7o) exhibited satisfactory selectivity towards CA VII over CA I and II, with K_I-s in the subnanomolar range and good selectivity indexes for inhibiting the target versus the off-target isoforms.     

Modifying mosquitoes to suppress disease transmission: Is the long wait over?

For more than 50 years it has been a dream of medical entomologists and public health workers to control diseases like malaria and dengue fever by modifying, through genetics and other methods, the arthropods that transmit them to humans. A brief synopsis of the history of these efforts as applied to mosquitoes is presented; none proved to be effective in reducing disease prevalence. Only in the last few years have novel approaches been developed or proposed that indicate the long wait may be over. Three recent developments are particularly promising: CRISPR-Cas9 driven genetic modification, shifting naturally occurring allele frequencies, and microbe-based modifications. The last is the furthest along in implementation. Dengue fever incidence has been reduced between 40% and 96% in 4 different regions of the world where Wolbachia-infected Aedes aegypti have been established in the field. It is not yet clear how sustainable such control programs will prove to be, but there is good reason for optimism. In light of this, the time is ripe for reinvigorated research on vectors, especially genetics. Vector-borne diseases primarily affect under-developed countries and thus have not received the attention they deserve from wealthier countries with well-developed and funded biomedical research establishments.     

MYH9: structure,functions and role of non-muscle myosin ⅡA in human disease

MYH9-related diseases (MYH9-RD) are a group of autosomal dominant diseases caused by mutations in the MYH9 gene, which are featured by thrombocytopenia, giant platelets and granulocyte cytoplasmic inclusion bodies. MYH9-RD patients generally suffer from bleeding syndromes, progressive kidney disease, deafness, or cataracts. Here, we reported on a case of MYH9-RD. A novel heterozygous mutation of MYH9 (c.2344-2345delGTinsTA, p.T782Y) was discovered by targeted sequencing technology. Immunofluorescence analysis of neutrophils confirmed abnormal aggregation of MYH9 protein. The results of this study should expand the MYH9 gene mutation spectrum and provide reference for subsequent researchers and genetic counseling.