Distribution of polymorphic variants of CYP2A6 and their involvement in nicotine addiction

Tobacco consumption has become a major public health issue, which has motivated studies to identify and understand the biological processes involved in the smoking behavior for prevention and smoking cessation treatments. CYP2A6 has been identified as the main gene that codifies the enzyme that metabolizes nicotine. Many alleles have been identified after the discovery of CYP2A6, suggesting a wide interethnic variability and a diverse smoking behavior of the allele carrying individuals. The main purpose of this review is to update and highlight the effects of the CYP2A6 gene variability related to tobacco consumption reported from diverse human populations. The review further aims to consider CYP2A6 in future studies as a possible genetic marker for the prevention and treatment of nicotine addiction. Therefore, we analyzed several population studies and their importance at addressing and characterizing a population using specific parameters. Our efforts may contribute to a personalized system for detecting, preventing and treating populations at a higher risk of smoking to avoid diseases related to tobacco consumption

The Giardial Arginine Deiminase Participates in Giardia-Host Immunomodulation in a Structure-Dependent Fashion via Toll-like Receptors

Beyond the problem in public health that protist-generated diseases represent, understanding the variety of mechanisms used by these parasites to interact with the human immune system is of biological and medical relevance. Giardia lamblia is an early divergent eukaryotic microorganism showing remarkable pathogenic strategies for evading the immune system of vertebrates. Among various multifunctional proteins in Giardia, arginine deiminase is considered an enzyme that plays multiple regulatory roles during the life cycle of this parasite. One of its most important roles is the crosstalk between the parasite and host. Such a molecular “chat” is mediated in human cells by membrane receptors called Toll-like receptors (TLRs). Here, we studied the importance of the 3D structure of giardial arginine deiminase (GlADI) to immunomodulate the human immune response through TLRs. We demonstrated the direct effect of GlADI on human TLR signaling. We predicted its mode of interaction with TLRs two and four by using the AlphaFold-predicted structure of GlADI and molecular docking. Furthermore, we showed that the immunomodulatory capacity of this virulent factor of Giardia depends on the maintenance of its 3D structure. Finally, we also showed the influence of this enzyme to exert specific responses on infant-like dendritic cells

Evaluación de viabilidad social en modelos de negocio preexistentes

ITESO, A.C

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase

Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme’s structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman’s method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis

Drainage of the hepatic cyst by laparoscopy - clinical case

Liver cysts are formations of serous content surrounded by normal liver parenchyma, without communication with the bile duct. The cyst wall is generally lined with cuboidal epithelium surrounded by layers of connective tissue. They are rare entities in adult patients, generally, they are asymptomatic in 3%, and between 10-15% of all patients will generate symptoms that lead them to consult. A 38-year-old man with an external abdominal tomography study that reported a giant hepatic cyst. Laboratory blood tests: hemoglobin 7.9 g/dl; leukocytosis 11,000/ul; serum electrolytes, liver transaminases, and bilirubin were normal, alkaline phosphatase, and gamma glutamyl-transpeptidase 94 U/l and 241 U/l, respectively. Non-reactive anti-human immuno-deficiency virus (HIV 1) and two antibodies, venereal disease research laboratory (VDRL), cancer antigen (CA) 19-9 antigen, hepatitis B-C surface antigen, and carcinoembryonic antigen were negative. He underwent surgery by laparoscopic drainage of the liver cyst, through a median infraumbilical incision with the Hasson technique and placement of three 12 mm trocars, hepatomegaly was observed without finding an exit site for purulent material, it was punctured through liver segment V, and 2000 ml of citrine fluid was extracted. The hepatic wound is addressed with a 1-0 caliber chromic catgut thread, placing a Penrose-type drain. At 48 hours postoperatively, it evolves favorably, so it is decided to discharge. Hepatic cysts are fluid-filled cavities lined by a single-layered cuboidal or columnar biliary epithelium in the liver. A majority of hepatic cysts are found incidentally on liver imaging, such as abdominal ultrasonography, computed tomography, or magnetic resonance imaging

Phosphogypsum waste lime as a promising substitute of commercial limes : a rheological approach

This paper presents the rheological properties of three types of lime putty, specifying the influence of their origin. The study aims to compare a special lime putty prepared from phosphogypsum with a commercial lime powder and an aged lime putty. The results obtained in terms of chemical composition, crystalline structure, grain size and rheological characterization, (linear viscoelasticity, shear rate and time-dependent flow behaviour) are presented in the study. Putties studied present a similar rheological response, which mainly depends on the particle size and water content. Lower values of the linear viscoelastic functions and viscosity were found for the phosphogypsum lime putty, in agreement with the higher particle size. Transient flow tests reveal a predominant elastic response with no significant shear-induced structural perturbations. However, either a thickening phenomenon over time, i.e. rheopexy, favoured at low shear rates, or a viscosity decrease, i.e. thixotropy, favoured at high shear rates, was observed.The authors would like to thank the aid of CITIUS at the University of Seville for the use of their laboratories for the characterization analyses. A.M.B.-L. has received a Ph.D. Research Grant from the Ministerio de Education, Cultura y Deporte (FPU16/03697)

Phosphogypsum waste lime as a promising substitute of commercial limes: A rheological approach

This paper presents the rheological properties of three types of lime putty, specifying the influence of their origin. The study aims to compare a special lime putty prepared from phosphogypsum with a commercial lime powder and an aged lime putty. The results obtained in terms of chemical composition, crystalline structure, grain size and rheological characterization, (linear viscoelasticity, shear rate and time-dependent flow behaviour) are presented in the study. Putties studied present a similar rheological response, which mainly depends on the particle size and water content. Lower values of the linear viscoelastic functions and viscosity were found for the phosphogypsum lime putty, in agreement with the higher particle size. Transient flow tests reveal a predominant elastic response with no significant shear-induced structural perturbations. However, either a thickening phenomenon over time, i.e. rheopexy, favoured at low shear rates, or a viscosity decrease, i.e. thixotropy, favoured at high shear rates, was observed

Naturally occurring deamidated triosephosphate isomerase is a promising target for cell-selective therapy in cancer

Human triosephosphate isomerase (HsTIM) is a central glycolytic enzyme and is overexpressed in cancer cells with accelerated glycolysis. Triple-negative breast cancer is highly dependent on glycolysis and is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Deamidated HsTIM was recently proposed as a druggable target. Although thiol-reactive drugs affect cell growth in deamidated HsTIM-complemented cells, the role of this protein as a selective target has not been demonstrated. To delve into the usefulness of deamidated HsTIM as a selective target, we assessed its natural accumulation in breast cancer cells. We found that deamidated HsTIM accumulates in breast cancer cells but not in noncancerous cells. The cancer cells are selectively programmed to undergo cell death with thiol-reactive drugs that induced the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs). In vivo, a thiol-reactive drug effectively inhibits the growth of xenograft tumors with an underlying mechanism involving deamidated HsTIM. Our findings demonstrate the usefulness of deamidated HsTIM as target to develop new therapeutic strategies for the treatment of cancers and other pathologies in which this post translationally modified protein accumulates

Dynamic equivalence between atomic and colloidal liquids

We show that the kinetic-theoretical self-diffusion coefficient of an atomic fluid plays the same role as the short-time self-diffusion coefficient D_S in a colloidal liquid, in the sense that the dynamic properties of the former, at times much longer than the mean free time, and properly scaled with D_S, will indistinguishable from those of a colloidal liquid with the same interaction potential. One important consequence of such dynamic equivalence is that the ratio D_L/ D_S of the long-time to the short-time self-diffusion coefficients must then be the same for both, an atomic and a colloidal system characterized by the same inter-particle interactions. This naturally extends to atomic fluids a well-known dynamic criterion for freezing of colloidal liquids[Phys. Rev. Lett. 70, 1557 (1993)]. We corroborate these predictions by comparing molecular and Brownian dynamics simulations on (soft- and hard-sphere) model systems, representative of what we may refer to as the "hard-sphere" dynamic universality class

Gene discovery for facioscapulohumeral muscular dystrophy by machine learning techniques

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder that shows a preference for the facial, shoulder and upper arm muscles. FSHD affects about one in 20-400,000 people, and no effective therapeutic strategies are known to halt disease progression or reverse muscle weakness or atrophy. Many genes may be incorrectly regulated in affected muscle tissue, but the mechanisms responsible for the progressive muscle weakness remain largely unknown. Although machine learning (ML) has made significant inroads in biomedical disciplines such as cancer research, no reports have yet addressed FSHD analysis using ML techniques. This study explores a specific FSHD data set from a ML perspective. We report results showing a very promising small group of genes that clearly separates FSHD samples from healthy samples. In addition to numerical prediction figures, we show data visualizations and biological evidence illustrating the potential usefulness of these results.Peer ReviewedPostprint (published version