Cannabinoid receptor 1 positive allosteric modulator ZCZ011 shows differential effects on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice.

The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the therapeutic potential of CB1R by direct activation is limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating the CB1R by utilizing positive allosteric modulators (PAMs).

Effects of acute Δ-tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice.

Cannabis use is highly prevalent especially among people living with HIV (PLWH). Activation of the anti-inflammatory and neuroprotective endocannabinoid system by phytocannabinoids, i.e.

Migraine Treatment in the Emergency Department: Alternatives to Opioids and their Effectiveness in Relieving Migraines and Reducing Treatment Times.

The objective of this literature review is to evaluate the efficacy of opioids for the treatment of headaches, particularly migraines, in the emergency department (ED). Despite safer alternatives, opiates are routinely used as an abortive treatment for migraine headaches. The studies reviewed demonstrate that opiates are less effective in terminating acute headaches and result in prolonged ED visits.

HM⁺-RG complexes (M = group 2 metal; RG = rare gas): Physical vs. chemical interactions.

Previous work on the HM(+)-He complexes (M = Be-Ra) has been extended to the cases of the heavier rare gas atoms, HM(+)-RG (RG = Ne-Rn). Optimized geometries and harmonic vibrational frequencies have been calculated using MP2 theory and quadruple-ζ quality basis sets. Dissociation energies for the loss of the rare gas atom have been calculated at these optimized geometries using coupled cluster with single and double excitations and perturbative triples, CCSD(T)theory, extrapolating interaction energies to the basis set limit.

HM⁺ and HM⁺‑He (M = Group 2 metal): chemical or physical interactions?

We investigate the HM(+)‑He complexes (M = Group 2 metal) using quantum chemistry. Equilibrium geometries are linear for M = Be and Mg, and bent for M = Ca-Ra; the explanation for this lies in the differing nature of the highest occupied molecular orbitals in the two sets of complexes. The difference primarily occurs as a result of the formation of the H-M(+) bond, and so the HM(+) diatomics are also studied as part of the present work.

Exploring the mode of action of ebselen in Trypanosoma brucei hexokinase inhibition.

Glycolysis is essential to Trypanosoma brucei, the causative agent of African sleeping sickness, suggesting enzymes in the pathway could be targets for drug development. Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one, EbSe) was identified in a screen as a potent inhibitor of T. brucei hexokinase 1 (TbHK1), the first enzyme in the pathway.

Glycolysis in the african trypanosome: targeting enzymes and their subcellular compartments for therapeutic development.

Subspecies of the African trypanosome, Trypanosoma brucei, which cause human African trypanosomiasis, are transmitted by the tsetse fly, with transmission-essential lifecycle stages occurring in both the insect vector and human host. During infection of the human host, the parasite is limited to using glycolysis of host sugar for ATP production. This dependence on glucose breakdown presents a series of targets for potential therapeutic development, many of which have been explored and validated as therapeutic targets experimentally.

Glycerol 3-phosphate alters Trypanosoma brucei hexokinase activity in response to environmental change.

The African trypanosome, Trypanosoma brucei, compartmentalizes some metabolic enzymes within peroxisome-like organelles called glycosomes. The amounts, activities, and types of glycosomal enzymes are modulated coincident with developmental and environmental changes. Pexophagy (fusion of glycosomes with acidic lysosomes) has been proposed to facilitate this glycosome remodeling.

Roles of vertebrate Smc5 in sister chromatid cohesion and homologous recombinational repair.

The structural maintenance of chromosomes (Smc) family members Smc5 and Smc6 are both essential in budding and fission yeasts. Yeast smc5/6 mutants are hypersensitive to DNA damage, and Smc5/6 is recruited to HO-induced double-strand breaks (DSBs), facilitating intersister chromatid recombinational repair. To determine the role of the vertebrate Smc5/6 complex during the normal cell cycle, we generated an Smc5-deficient chicken DT40 cell line using gene targeting.

Quercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1.

Hexokinases from the African trypanosome, Trypanosoma brucei, are attractive targets for the development of anti-parasitic drugs, in part because the parasite utilizes glycolysis exclusively for ATP production during the mammalian infection. Here, we have demonstrated that the bioflavanoid quercetin (QCN), a known trypanocide, is a mixed inhibitor of Trypanosoma brucei hexokinase 1 (TbHK1) (IC(50) = 4.1 ± 0.

Blood glucose response to rate of consumption of digestible carbohydrate.

When the glycemic response to consuming digestible carbohydrate is measured, little or no attention appears to have been paid to the possible effect on this response of the rate at which the food is consumed. We compared glycemic responses when volunteers ate or drank foods containing digestible carbohydrate as rapidly as possible, or in five equal portions over 12 min. Expecting that the response would be greater when the food was consumed rapidly, we found that the responses were equally and randomly distributed between the two rates of eating.

A centrosome-autonomous signal that involves centriole disengagement permits centrosome duplication in G2 phase after DNA damage.

DNA damage can induce centrosome overduplication in a manner that requires G2-to-M checkpoint function, suggesting that genotoxic stress can decouple the centrosome and chromosome cycles. How this happens is unclear. Using live-cell imaging of cells that express fluorescently tagged NEDD1/GCP-WD and proliferating cell nuclear antigen, we found that ionizing radiation (IR)-induced centrosome amplification can occur outside S phase.

The glycemic response is a personal attribute.

The Glycemic Index (GI) is a measure of the extent of the change in blood glucose content (glycemic response) following consumption of digestible carbohydrate, relative to a standard such as glucose. We have explored whether the reported GIs of foods are a sufficient guide to a person wishing to avoid large glycemic responses and thereby avoid hyperglycemia. For this purpose, volunteers carried out multiple tests of four foods, following overnight fasting, measuring the glycemic response over 2 H.

A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity.

Background: The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the gamma-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T.

Increased sister chromatid cohesion and DNA damage response factor localization at an enzyme-induced DNA double-strand break in vertebrate cells.

The response to DNA damage in vertebrate cells involves successive recruitment of DNA signalling and repair factors. We used light microscopy to monitor the genetic dependencies of such localization to a single, induced DNA double strand break (DSB) in vertebrate cells. We used an inducible version of the rare-cutting I-SceI endonuclease to cut a chromosomally integrated I-SceI site beside a Tet operator array that was visualized by binding a Tet repressor-GFP fusion.

The cytoplasmic and transmembrane domains of secretor type alpha1,2fucosyltransferase confer atypical cellular localisation.

Carbohydrate structures influence many aspects of cell biology. Manipulating the glycosyltransferase enzymes, that sequentially add carbohydrate moieties to proteins and lipids as they pass through the Golgi and secretory pathway, can alter these carbohydrate epitopes. We previously demonstrated that the eight amino acid cytoplasmic tail of alpha1,2fucosyltransferase (FT) contained a sequence for Golgi localisation.

Selective biodegradation in hair shafts derived from archaeological, forensic and experimental contexts.

Background: Hair is degraded by the action of both dermatophytic and nondermatophytic microorganisms. The importance of understanding hair sample condition in archaeological and forensic investigation highlights the need for a detailed knowledge of the sequence of degradation in samples that have been either buried or left exposed at the ground surface.

Objectives: To investigate the sequence of biodegradative change to human terminal scalp hair from archaeological and forensic contexts.

DNA damage induces Chk1-dependent centrosome amplification.

Centrosomal abnormalities are frequently observed in cancers and in cells with defective DNA repair. Here, we used light and electron microscopy to show that DNA damage induces centrosome amplification, not fragmentation, in human cells. Caffeine abrogated this amplification in both ATM (ataxia telangiectasia, mutated)- and ATR (ATM and Rad3-related)-defective cells, indicating a complementary role for these DNA-damage-responsive kinases in promoting centrosome amplification.

Involvement of centrosome amplification in radiation-induced mitotic catastrophe.

Cells exposed to ionizing radiation die via different mechanisms, including apoptosis and mitotic catastrophe. To determine the frequency of mitotic catastrophe in tumor cells after irradiation, we used time-lapse imaging to track centrin-1 and histone H2B in U2OS osteosarcoma cells. We observed a dose-dependent increase in the frequency of mitotic catastrophe after irradiation, although a consistent 30% of cell death occurred through mitotic failure at doses from 2-10 Gy.

Synthesis of novel caspase inhibitors for characterization of the active caspase proteome in vitro and in vivo.

Caspases are cysteine proteases that are essential for cytokine maturation and apoptosis. To facilitate the dissection of caspase function in vitro and in vivo, we have synthesized irreversible caspase inhibitors with biotin attached via linker arms of various lengths (12a-d) and a 2,4-dinitrophenyl labeled inhibitor (13). Affinity labeling of apoptotic extracts followed by blotting reveals that these affinity probes detect active caspases.

Relationship of opioid receptors with GABAergic neurons in the rat inferior colliculus.

The inferior colliculus is a critical structure for processing auditory information and receives ascending and descending synaptic auditory projections. In addition to GABAergic and glutamatergic innervations, other neurotransmitter systems are also reported in the inferior colliculus, including opioid peptides. In the present study, the relative distribution of each type of opioid receptor, mu (MOR), delta (DOR) and kappa (KOR) within GABAergic neurons in the inferior colliculus was examined.