Mutations in KPTN Cause Macrocephaly,Neurodevelopmental Delay,and Seizures

The proper development of neuronal circuits during neuromorphogenesis and neuronal-network formation is critically dependent on a coordinated and intricate series of molecular and cellular cues and responses. Although the cortical actin cytoskeleton is known to play a key role in neuromorphogenesis, relatively little is known about the specific molecules important for this process. Using linkage analysis and whole-exome sequencing on samples from families from the Amish community of Ohio, we have demonstrated that mutations in KPTN, encoding kaptin, cause a syndrome typified by macrocephaly, neurodevelopmental delay, and seizures. Our immunofluorescence analyses in primary neuronal cell cultures showed that endogenous and GFP-tagged kaptin associates with dynamic actin cytoskeletal structures and that this association is lost upon introduction of the identified mutations. Taken together, our studies have identified kaptin alterations responsible for macrocephaly and neurodevelopmental delay and define kaptin as a molecule crucial for normal human neuromorphogenesis.     

Essential‐Oil Composition of the Fruits of Six Heracleum L. Species from Iran: Chemotaxonomic Significance

The fruit essential oils of Heracleum persicum, H. rechingeri, H. gorganicum, H. rawianum, H. pastinacifolium, and H. anisactis from Iran were obtained by hydrodistillation and characterized by GC‐FID and GC/MS analyses. The oils of the six species were compared to determine the similarities and differences among their compositions. Overall, 36 compounds were identified in the fruit oils, accounting for 92.40–96.74% of the total oil compositions. Aliphatic esters constituted the main fraction of the oils (86.61–94.31%), with octyl acetate and hexyl butyrate as the major components. The oil compositions of species belonging to section Pubescentia (H. persicum, H. gorganicum, and H. rechingeri) were discriminated by equally high contents of both octyl acetate (13.84–20.48%) and hexyl butyrate (17.73–38.36%). On the other hand, the oils of H. rawianum, H. pastinacifolium and H. anisactis, belonging to section Wendia, showed lower hexyl butyrate contents (3.62–6.6%) and higher octyl acetate contents (48.71–75.36%) than the former. Moreover, isoelemicin was identified at low amounts (0.10–2.51%) only in the oils of the latter species. The differences in the oil composition among the six species were investigated by hierarchical cluster and principal component analyses, which indicated that the oil composition confirmed well the taxonomical classification based on the morphological and botanical data, and, thus, may provide a reliable marker to discriminate Heracleum species at the intersectional level.     

Butyrylcholinesterase K variant and the APOE-ε4 allele work in synergy to increase the risk of coronary artery disease especially in diabetic patients

We have previously shown that butyrylcholinesterase-K (BCHE-K, G1615A/Ala539Thr) variant increases the risk of coronary artery disease (CAD). In addition, we have found that the presence of APOE-ε4 allele augments the risk of CAD in patients with type II diabetes mellitus (T2DM/CAD). Here we explored the concomitant presences of two alleles of the BCHE-K and APOE-ε4 in increasing the risk of CAD or diabetes in T2DM patients with or without CAD and CAD patients without T2DM. This case–control study comprised 631 subjects undergoing their first coronary angiography. They were matched and randomly assigned into four groups: type II diabetic patients with no sign of CAD (T2DM), type II diabetic patients with CAD/ND (T2DM/CAD), CAD patients with no sign of diabetes (CAD/ND), and healthy individuals (NCAD/ND). BCHE-K variant and APOE genotypes were detected by PCR-RFLP and serum lipid level was measured enzymatically. We found that BCHE-K and APOE-ε4 allele act synergistically to increase the risk of CAD in both T2DM, non-diabetic and total CAD (TCAD = T2DM/CAD + CAD/ND) individuals. The level of synergy 1.5 and 1.2 fold are higher in CAD patients (OR = 4.5; P = 0.011) with T2DM than the non-diabetic CAD patients (OR = 3.07; P = 0.024) and TCAD patients (OR = 3.74; P = 0.018), respectively. The CAD subjects with and without T2DM and TCAD patients carrying both APOE-ε4 allele and BCHE-K had significantly lower plasma HDL-C (P values = 0.008, 0.047, and 0.036, respectively) and higher plasma LDL-C (P values = 0.025, 0.048, and 0.04, respectively), than that of the control carriers both APOE-ε4 and BCHE-K. We have found that BCHE-K and APOE-ε4 allele not only act synergistically to increase the risk of CAD, particularly in T2DM subjects in population from western Iran, who have high levels of LDL-C and low levels of HDL-C, suggesting that a specific therapeutic intervention should be considered for these particular groups of patients.     

HIV Capsid and Protease,New Targets of Melittin

International Journal of Peptide Research and Therapeutics - Melittin is a 26 amino acid amphipathic peptide, the main part of a bee venom. It has been confirmed that melittin can act against a...     

Antibody–receptor interactions mediate antibody-dependent cellular cytotoxicity

Binding of antibodies to their receptors is a core component of the innate immune system. Understanding the precise interactions between antibodies and their Fc receptors has led to the engineering of novel mAb biotherapeutics with tailored biological activities. One of the most significant findings is that afucosylated monoclonal antibodies demonstrate increased affinity toward the receptor FcγRIIIa, with a commensurate increase in antibody-dependent cellular cytotoxicity. Crystal structure analysis has led to the hypothesis that afucosylation in the Fc region results in reduced steric hindrance between antibody–receptor intermolecular glycan interactions, enhancing receptor affinity; however, solution-phase data have yet to corroborate this hypothesis. In addition, recent work has shown that the fragment antigen-binding (Fab) region may directly interact with Fc receptors; however, the biological consequences of these interactions remain unclear. By probing differences in solvent accessibility between native and afucosylated immunoglobulin G1 (IgG1) using hydroxyl radical footprinting–MS, we provide the first solution-phase evidence that an IgG1 bearing an afucosylated Fc region appears to require fewer conformational changes for FcγRIIIa binding. In addition, we performed extensive molecular dynamics (MD) simulations to understand the molecular mechanism behind the effects of afucosylation. The combination of these techniques provides molecular insight into the steric hindrance from the core Fc fucose in IgG1 and corroborates previously proposed Fab–receptor interactions. Furthermore, MD-guided rational mutagenesis enabled us to demonstrate that Fab–receptor interactions directly contribute to the modulation of antibody-dependent cellular cytotoxicity activity. This work demonstrates that in addition to Fc–polypeptide and glycan-mediated interactions, the Fab provides a third component that influences IgG–Fc receptor biology.     

Prevalence,molecular characteristics and risk factors for cryptosporidiosis among Iranian immunocompromised patients

Cryptosporidium spp. is a major cause of diarrhea in developing countries, mainly affecting people with compromised immune systems in general and HIV‐infected individuals with low CD4 + T‐cell counts in particular. This infection is self‐limiting in healthy persons; however, it can be severe, progressive and persistent in those who are immunocompromised. There are few published studies concerning cryptosporidiosis and Cryptosporidium genotypes in Iranian immunocompromised patients and none of them describe risk factors. This study was undertaken to identify prevalence, genotypes and risk factors for cryptosporidiosis in immunocompromised patients. Three fecal samples were obtained at two day intervals from each of the 183 patients and processed with modified Ziehl–Neelsen staining methods and 18S rRNA gene amplification and sequencing. The overall infection prevalence was 6%. Cryptosporidium parvum was identified in isolates from five HIV‐infected patients, one patient who had undergone bone marrow transplantation and one with chronic lymphocytic leukemia. Cryptosporidium hominis was identified in isolates from two HIV‐infected patients and two patients with acute lymphocytic leukemia. According to univariate analysis, the statistically significant factors were diarrhea (OR = 21.7, CI = 2.83–78.4, P= 0.003), CD4 + lymphocytes less than 100 cells/mm³ (OR = 41.3, CI = 13.45–114.8, P < 0.0001), other microbial infections (OR = 7.1321.7, CI = 1.97–25.73, P = 0.006), weight loss (OR = 73.78, CI = 15.5–350, P < 0.0001), abdominal pain (OR = 10.29, CI = 2.81–37.74.4, P= 0.001), dehydration (OR = 72.1, CI = 17.6–341.5, P < 0.0001), vomiting (OR = 4.87, CI = 1.4–16.9, P= 0.015), nausea (OR = 9.4, CI = 2.38–37.2, P < 0.001), highly active antiretroviral therapy (OR = 0.089, CI = 0.01–0.8, P= 0.015) and diarrhea in household members (OR = 7.37, CI = 2.04–26.66, P= 0.001). After multivariate analysis and a backward deletion process, only < 100 CD4 + T‐lymphocytes/mm³ maintained a significant association with infection. The authors recommend that this infection should be suspected in patients with diarrhea, weight loss and dehydration in general and in diarrheal individuals with < 100 CD4 + T‐lymphocytes/mm³.     

Study on the physiology of diapause, cold hardiness and supercooling point of overwintering pupae of the pistachio fruit hull borer, Arimania comaroffi

The pistachio fruit hull borer, Arimania comaroffi (Ragonot) (Lepidoptera: Pyralidae), is a key pest of pistachio orchards in Iran. This pest passes the winter as diapausing pupae. In this study, some physiological changes in relation to environmental temperature were investigated in field collected pupae. The relationship between supercooling point, cold hardiness and physiological changes of a wild population of this pest was also investigated. The glycogen content decreased with decrease in environmental temperature. Decrease in glycogen content was proportional to increase in total body sugar, trehalose, myo-inositol and sorbitol contents. In January with mean ambient temperature of 5.4°C, glycogen (5 mg/g fresh body weight) content was at the lowest level whereas total body sugar (10.3 mg/g fresh body weight), trehalose (8.6 mg/g fresh body weight), myo-inositol (5.3 mg/g fresh body weight) and sorbitol (2.6 mg/g fresh body weight) were at the highest levels. Total body sugar, trehalose, myo-inositol and sorbitol contents increased as mean temperature decreased from 22.7°C in October to 5.4°C in January. Total body lipid decreased during overwintering and reached to the lowest level at the end of March. Supercooling points were decreased from October to January and reached to the lowest level (-16°C) in January with minimum ambient temperature of -10°C. Survival at low temperature after 24 h was also greatest in January with 72% survival at -10°C, 39% survival at -15°C and 0% survival at -20°C. Increase in temperature from February onward, was proportional with increase in supercooling points and decrease in survival rate. Regardless of sampling date, all pupae died after 24 h at -20°C, whereas none pupae died after 24 h at -5°C. This indicates that this insect is freeze-intolerant.