Illicit drugs, such as cocaine, are known to increase the likelihood and severity of HIV-1 associated neurocognitive disorders (HAND). In the current studies synaptic integrity was assessed following exposure to low concentrations of the HIV-1 viral protein Tat 1-86B, with or without cocaine, by quantifying filamentous actin (F-actin) rich structures (i.e., puncta and dendritic spines) on neuronal dendrites in vitro. In addition, the synapse-protective effects of either R-Equol (RE) or S-Equol (SE; derivatives of the soy isoflavone, daidzein) were determined. Individually, neither low concentrations of HIV-1 Tat (10 nM) nor low concentrations of cocaine (1.6 μM) had any significant effect on F-actin puncta number; however, the same low concentrations of HIV-1 Tat + cocaine in combination significantly reduced dendritic synapses. This synaptic reduction was prevented by pre-treatment with either RE or SE, in an estrogen receptor beta dependent manner. In sum, targeted therapeutic intervention with SE may prevent HIV-1 + drug abuse synaptopathy, and thereby potentially influence the development of HAND.
The bacterial histidine permease, an ABC transporter, from Salmonella typhimurium is composed of a membrane-bound complex, HisQMP2, comprising two hydrophobic subunits (HisQ and HisM), two copies of an ATP-hydrolyzing subunit, HisP, and a soluble receptor, HisJ. We describe the purification and characterization of HisQMP2 using a 6-histidines extension at the carboxy terminus of HisP [HisQMP2(his6)]. The purification is rapid and effective, giving a seven-fold purification with a yield of 85 and 98% purity. Two procedures are described differing in the detergent used (decanoylsucrose and octylglucoside, respectively) and in the presence of phospholipid. HisQMP2(his6) has ATPase and transport activities upon reconstitution into proteoliposomes (PLS). HisQMP2(his6) has a low level ATPase activity (intrinsic activity), which is stimulated to a different extent by the receptor--liganded and unliganded. Its pH optimum is 7.8-8.0, it requires a cation for activity and it displays cooperativity for ATP. The effect of various ATP analogs was analyzed. Determination of the molecular size of HisQMP2(his6) indicates that it is a monomer. The permeability properties of two kinds of reconstituted PLS preparations are described.
Infection plays a complex role in cerebrovascular disease and is believed to have both direct and indirect mechanisms on stroke pathogenesis. if not diagnosed and treated promptly, this may have devastating consequences. Management of infection-related strokes focuses on the treatment of the underlying infection with appropriate antimicrobial drugs and the prevention of medical complications. This can lead to devastating neurological deficits. We present two cases of cryptococcal meningoencephalitis that presented with an atypical cerebral infarction. A 55-year-old male with a history of unknown autoimmune disease presented with acute onset cognitive changes and no stroke-like symptoms. A 35-year-old male with no history of autoimmune disease or other existing immunodeficiency presented with breakthrough seizure a long with stroke-like symptoms. Both patients developed multiple cerebral infarcts in multiple vascular territories, with histologic and radiologic findings consistent with a central nervous system cryptococcosis. They were subsequently diagnosed with cryptococcal meningoencephalitis and started on the appropriate anti-fungal regimen with amphotericin B and flucytosine. Prior to discharge to an inpatient rehabilitation facility, both patients were notably improved and near their neurologic baseline. It is important to understand the pathogenesis of cryptococcal infection in the central nervous system because it produces a wide variety of clinico-radiographic features that can be overlooked. Clinicians should keep infection-mediated cerebral infarcts in mind, regardless of risk factors, in order to expedite antimicrobial therapy and minimize adverse events.
The use of 2-mm tibial resection osteotomy with 2-mm distraction provides a predictable model for fracture nonunion in mice with the oligotrophic phenotype closely resembling the clinical correlate. This model offers a promising means for characterization of the molecular events that occur during the development of fracture nonunion and for evaluation of noninvasive methods of nonunion rescue.
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