Nighttime Blood Pressure Abnormalities in Iranian CKD Patients: Necessity to Perform Ambulatory Blood Pressure Monitoring.

INTRODUCTION: Ambulatory blood pressure monitoring (ABPM) is a valuable tool for detecting abnormalities in nighttime blood pressure (BP), including non-dipping and nighttime hypertension. These abnormalities are independent predictors of a poor prognosis in patients with chronic kidney disease (CKD). The aim of our study  was to analyze ABPM data and evaluate nighttime BP abnormalities in an Iranian CKD population. METHODS: This cross-sectional study was conducted on sixty two patients at stages III and IV of CKD who were referred to a nephrology clinic in Tehran, Iran. The patients were classified as either dippers (19.4%) or non-dippers (80.6%), as well as nighttime normotensives (38.7%) or hypertensives (61.3%), based on ABPM  data and in accordance with 2023 ESC/ESH guidelines. We compared demographic data, estimated glomerular filtration rate (eGFR), and daytime BP levels among these groups. RESULTS: The mean age of patients was 56.34 years, with 61.1% of them being male. Daytime pulse pressure was significantly greater in non-dippers compared to dippers (52.67 vs. 44 mmHg, P = .02). We found a significant correlation between the extent of BP dipping and eGFR (R = 0.281, P = .02). Systolic and diastolic daytime BP levels were significantly higher in individuals with nighttime hypertension. Diabetic patients were more likely to be non-dippers and have nighttime hypertension. After adjusting for age, diabetes mellitus, and daytime pulse pressure in a multivariable model, we determined that eGFR independently predicted the  extent of BP dipping. CONCLUSION: Our results showed that both non-dipping and nighttime hypertension are highly prevalent in CKD patients, but they have distinct contributing factors. The eGFR was identified as an independent predictor of BP dipping, whereas nighttime BP levels were primarily determined by daytime BP levels. DOI: 10.52547/ijkd.7559.

Alteration in body water compartments following intermittent fasting in Ramadan.

Concerning the health outcomes of intermittent fasting in Ramadan, loss of fat-free mass (FFM) and changes in the content of body water are of paramount importance. In this study, we aimed to assess the concomitant alterations in body water compartment and composition following Ramadan fasting in healthy individuals. We conducted an open-label cohort with longitudinal follow-up, involving 73 healthy medical staff who planned to fast for at least 20 consecutive days during Ramadan. The primary outcomes of the cohort were changes in parameters related to body composition and water content, which were measured using bioelectrical impedance analysis by InBody S10 (InBody, Seoul, South Korea). Based on the results, the participants' weight decreased significantly by approximately 1,030 g after the fasting period (p < 0.001). There was a significant reduction in the fat mass of an average 828 g (p < 0.001), which accounted for more than 80% of the weight loss. The decline in FFM was not significant (190 g; p = 0.234). The amount of total body water (TBW) and extracellular water (ECW) did not change, while intracellular water (ICW) decreased significantly by about 160 mL (p = 0.027). A strong correlation was observed between the reduction of phase angle and the increase in ECW/TBW ratio (R = -0.71, p < 0.001). Overall, our findings revealed a minimal amount of weight loss after Ramadan fasting, which was mainly due to the loss of fat mass. The parallel decrease in ICW and phase angle indicated impaired cell membrane integrity, with subsequent movement of water from the intracellular to the extracellular compartment.

Gate-based quantum computing for protein design.

Protein design is a technique to engineer proteins by permuting amino acids in the sequence to obtain novel functionalities. However, exploring all possible combinations of amino acids is generally impossible due to the exponential growth of possibilities with the number of designable sites. The present work introduces circuits implementing a pure quantum approach, Grover's algorithm, to solve protein design problems. Our algorithms can adjust to implement any custom pair-wise energy tables and protein structure models. Moreover, the algorithm's oracle is designed to consist of only adder functions. Quantum computer simulators validate the practicality of our circuits, containing up to 234 qubits. However, a smaller circuit is implemented on real quantum devices. Our results show that using [Formula: see text] iterations, the circuits find the correct results among all N possibilities, providing the expected quadratic speed up of Grover's algorithm over classical methods (i.e., [Formula: see text]).

Transcriptomic analysis of human cytomegalovirus to survey the indirect effects on renal transplant recipients.

Post-transplant human cytomegalovirus (HCMV) viremia has been linked to adverse "indirect effects" among transplant patients. HCMV-created immunomodulatory mechanisms could be associated with the indirect effects. OBJECTIVE: In the present study, the RNA-Seq whole transcriptome of renal transplant (RT) patients was analyzed to seek the underlying pathobiologic pathways associated with the long-term indirect effects of HCMV. METHODS: To investigate the activated biological pathways in HCMV infection, total RNA was extracted from PBMCs of 2 RT patients with active HCMV and 2 RT patients without infection and then were sequenced using RNA-Seq. The resulted raw data were analyzed by conventional RNA-Seq software to determine the Differentially Expressed Genes (DEGs). Afterward, Gene Ontology (GO) and pathway enrichment analyses were conducted to determine the enriched pathways and biological processes by DEGs. Eventually, the relative expressions of some significant genes were validated in the twenty external RT patients. RESULT: The analysis of RNA-Seq data related to RT patients with HCMV active viremia led to the identification of 140 up-regulated and 100 down-regulated DEGs. KEGG pathway analysis revealed the enrichment of DEGs in IL18 signaling, AGE-RAGE signaling pathway in diabetic complications, signaling by GPCR, Platelet activation, signaling and aggregation, Estrogen signaling pathway and signaling by Wnt due to HCMV infection. The expression levels of six genes involved in enriched pathways including F3, PTX3, ADRA2B, GNG11, GP9, HBEGF were then verified using RT-qPCR. The results were in consistent with RNA-Seq resultsoutcomes. CONCLUSION: This study specifies some pathobiological pathways which are activated in HCMV active infection and could be linked to the adverse indirect effects caused by HCMV infection in transplant patients.

Frequency of CD39+, LAG3+, and CTLA4+ Regulatory T Cells in Two Different Immunosuppressive Protocols in Renal Allograft Recipients (Sirolimus vs Mycophenolate mofetil): A Cohort Report.

BACKGROUND: Impaired renal function is considered as a significant risk factor for cardiovascular events in chronic kidney disease patients. Several immunosuppressive drugs are used in these patients, which necessitates to minimize the drug-related side effects by employing alternative strategies. OBJECTIVE: This study aimed to evaluate prospectively the influence of low dose ATG induction therapy with two different protocols (Sirolimus versus Mycophenolate mofetil) on the expression of functional markers (LAG-3, CD39, and intracellular CTLA-4) on conventional Tregs in renal recipients. METHODS: Thirty-eight renal transplant recipients were enrolled in this study. The patients were randomly assigned into two groups, including TMP: Tacrolimus (Tac), Mycophenolate mofetil (MMF), and Prednisolone (n=23); and TSP: Tac, Sirolimus (SRL), and Prednisolone (n=15). The frequency of LAG-3, CD39, and intracellular CTLA-4 on circulating Tregs was analyzed by flow cytometry before and after transplantation. RESULTS: Analysis of the flow cytometry data showed that the frequency of CD4+CD25+FOXP3+ Tregs increased 4 months post-transplantation compared to pre-transplantation in both groups, although this increase was only significant in TMP group. In TMP treated patients, the frequency of LAG-3+ Tregs and CD39+ Tregs increased, whereas the frequency of intracellular CTLA-4+ Tregs decreased 4 months post-transplantation. In TSP group, while the frequency of CD39+ Tregs increased, the frequency of CTLA-4+ Tregs decreased in post-transplantation compared to pre-transplantation. CONCLUSIONS: it seems that both treatment regimen protocols with a low dose ATG induction therapy may be clinically applicable in kidney transplant recipients.

Characterization of adjacent charged residues near the agonist binding site of the nematode UNC-49 GABA receptor.

The UNC-49 receptor is a Cys-loop GABA receptor that is unique to the nematode phylum. The receptor differs from mammalian GABA receptors both in amino acid sequence and pharmacology which highlights its potential as a novel anthelmintic target. Sequence differences within and near the various ligand-binding loops of the nematode receptor suggest that there could be structural differences compared to mammalian receptors that result in different pharmacological and functional features. Here we investigated three residues in the UNC-49 receptor from the parasitic nematode Haemonchus contortus: K181, E183, and T230. Analysis of these residues was conducted via site-directed mutagenesis, electrophysiology, MD simulations, and mutant cycling analysis. In the UNC-49 receptor, E183 lies in close proximity to K181 where together they appear to play a role in GABA sensitivity and pharmacology, possibly interacting via an ionic bond. While the introduction of single alanine residues at each position separately had a negative impact on GABA EC50, the double alanine mutant (K181A/E183A) exhibited wildtype-level GABA EC50 and some differences in pharmacology. Overall, this study has revealed a potentially novel role for these two residues in nematode UNC-49 GABA receptors that could aid in understanding their function.

Parcellation-Free prediction of task fMRI activations from dMRI tractography.

The relationship between brain structure and function plays a crucial role in cognitive and clinical neuroscience. We present a supervised machine learning based approach that captures this relationship by predicting the spatial extent of activations that are observed with task based functional Magnetic Resonance Imaging (fMRI) from the local white matter connectivity, as reflected in diffusion MRI (dMRI) tractography. In particular, we explore three different feature representations of local connectivity patterns that do not require a pre-defined parcellation of cortical and subcortical structures. Instead, they employ cluster-based Bag of Features, Gaussian Mixture Models, and Fisher vectors. We demonstrate that our framework can be used to test the statistical significance of structure-function relationships, compare it to parcellation-based and group-average benchmarks, and propose an algorithm for visualizing our chosen feature representations that permits a neuroanatomical interpretation of our results.

Discordance Between Using Estimated and Measured Glomerular Filtration Rate for Drug Dosing in Kidney Transplant Recipients.

INTRODUCTION: Estimating glomerular filtration rate (eGFR) using different formulas is common clinical practice for evaluating kidney function and drug dosing. But, the performance of available eGFR equations is questionable during early days after kidney transplantation. METHODS: This study compared the performance of three common eGFR equations (Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) in relation with measured GFR (mGFR) using clearance of Tc-99m-diethylenetriaminepentaacetic acid, 7 to 10 days post kidney transplantation. Agreement of mGFR and different eGFR equations in the staging of kidney function and dosing of 8 common antimicrobials were assessed. RESULT: Thirty kidney and 5 simultaneous pancreas-kidney transplant recipients were included. CG applying total body weight (CGTBW) had the lowest bias (-12 mL/min/ 1.73 m2) and the highest percentage of estimation within 30% of mGFR (71.4%). MDRD showed the best precision (13.14 mL/min/ 1.73m2) and linear correlation with mGFR. CKD-EPI and MDRD acted better than CG for staging the level of kidney function. CGTBW had the lowest discordance rate with mGFR for antimicrobials dosing (33.6%). Discordance rates of drug dosing between mGFR and eGFR formulas were greater for drugs that have higher dosing levels such as (val)-ganciclovir (≥ 54.3%). CONCLUSION: Until developing more accurate methods for estimating kidney function during first 1 to 2 weeks after kidney transplantation, CGTBW method is suggested for drug dose adjustment and MDRD or CKD-EPI equation for the staging of kidney function in these patients, keeping in mind that these formulas underestimate the level of kidney function in new transplant recipients.

Using geometric criteria to study helix-like structures produced in molecular dynamics simulations of single amylose chains in water.

Amylose is a linear polymer chain of α-d-glucose units connected through α(1 → 4) glycosidic bonds. Experimental studies show that in non-polar solvents, single amylose chains form helical structures containing precise H-bond patterns. However, both experimental and computational studies indicate that these perfectly H-bonded helices are not stable in pure water. Nevertheless, amylose chains are observed to form helix-like structures in molecular dynamics (MD) simulations that exhibit imperfect H-bond patterns. In this paper, we study the structure of amylose chains in water using MD simulations to identify and characterize these "imperfect" helical structures. To this end we devise geometry-based criteria to define imperfect helical structures in amylose chains. Using this approach, the propensity of amylose chains to form these structures is quantified as a function of chain length and solvent temperature. This analysis also uncovers both short and long time helix-breaking mechanisms such as band-flips and kinks in the chain. This geometric approach to defining imperfect helices thus allows us to give new insight into the secondary structure of single amylose chains in spite of imperfect H-bond patterns.

Electronic transport properties of hydrogenated and fluorinated graphene: a computational study.

Hydrogenation and fluorination have been presented as two possible methods to open a bandgap in graphene, required for field-effect transistor applications. In this work, we present a detailed study of the phonon-limited mobility of electrons and holes in hydrogenated graphene (graphane) and fluorinated graphene (graphene fluoride). We pay special attention to the out-of-plane acoustic (ZA) phonons, responsible for the highest scattering rates in graphane and graphene fluoride. Considering the most adverse cut-off for long-wavelength ZA phonons, we have obtained electron (hole) mobilities of 28 (41) cm2 V-1 s-1 for graphane and 96 (30) cm2 V-1 s-1 for graphene fluoride. Nonetheless, for a more favorable cut-off wavelength of ∼2.6 nm, significantly higher electron (hole) mobilities of 233 (389) cm2 V-1 s-1 for graphane and 460 (105) cm2 V-1 s-1 for graphene fluoride are achieved. Moreover, while complete suppression of ZA phonons can increase the electron (hole) mobility in graphane up to 278 (391) cm2 V-1 s-1, it does not affect the carrier mobilities in graphene fluoride. Velocity-field characteristics reveal that the electron velocity in graphane saturates at an electric field of ∼4 × 105 V cm-1. Comparing the mobilities with other two-dimensional (2D) semiconductors, we find that hydrogenation and fluorination are two promising avenues to realize a 2D semiconductor while providing good carrier mobilities.

The effect of aerobic and resistance exercise training on the health related quality of life, physical function, and muscle strength among hemodialysis patients with Type 2 diabetes.

INTRODUCTION: Diabetic patients who undergo hemodialysis commonly suffer from reduction of both exercise capacity and muscle strength. These factors may have a negative effect on health related quality of life (HRQoL) and physical function. We investigated the effect of aerobic and resistance exercise training on the HRQoL, physical function, and muscle strength among hemodialysis patients with Type 2 diabetes. METHODS: Twenty-eight diabetic patients who were on hemodialysis in the Milad Hospital (Tehran, Iran) were recruited for the study. Subjects were randomized into control (n = 13) and exercise training groups (n = 15). The exercise training group performed combined aerobic and resistance exercise training at moderate intensity (11-15/20 on the Borg scale) during hemodialysis treatment, 3 times a week for 8 weeks. The primary outcomes consisted of physical function measured by a 6-min walk test (6MWT), HR-QoL measured by the Short Form Health Survey (SF-36), and lower limb muscle strength measured using a hand-held Digital Dynamometer. RESULTS: The 6MWT distance increased significantly in the exercise training group (36%). Bilateral hip flexor strength (right, 24.5%; left, 30.4%) and abductor strength (right, 27.6%; left, 25.2%) decreased significantly in the non-exercising control group but no significant change was found in the exercise group (P > 0.05). There were no significant changes in any of the 8 generic subscales of HR-QoL neither in the exercise training group nor controls following an 8- week study. CONCLUSIONS: 8 weeks of combined aerobic-resistance exercise training among diabetic hemodialysis patients seem to be effective in improvement of physical function and lower limb muscle strength.

Association Between Pre-Transplant Magnesemia and Post-Transplant Dysglycemia in Kidney Transplant Recipients.

BACKGROUND: Serum magnesium (Mg) status in kidney transplant recipients has been a center of attention in the past few years. Current evidence suggests an association between pre-transplant hypomagnesemia and post-transplant hyperglycemia. OBJECTIVE: The purpose of this study was to assess the associations of pre-transplant magnesemia with blood glucose disturbances within 6 months post-kidney transplantation. METHODS: In this retrospective cohort, 89 first-time kidney transplant recipients with 6 months of follow-up were included. None of the participants had a positive history of rejection, pre-transplant history of diabetes mellitus or fasting plasma glucose ≥ 100 mg/dL. RESULTS: Post-transplant diabetes mellitus (PTDM) and impaired fasting glucose (IFG) 6 months post-transplant was found in 7.9% and 41.6% of the study group, respectively. The mean pre-transplant serum Mg level was 1.92 ± 0.30 mg/dL in the study population (n = 89), and it was significantly lower in IFG (n = 37) and IFG/PTDM (n = 44) groups compared to normoglycemic (n = 45) recipients (1.83 ± 0.31 mg/dL vs. 2.00 ± 0.27 mg/dL, P = 0.008, and 1.84 ± 0.31 mg/dL vs. 2.00 ± 0.27 mg/dL, P = 0.012, respectively). Patients with serum Mg less than 1.9 mg/dL were nearly 2.6 times more likely to develop IFG or IFG/PTDM within 6 months post-transplant (P = 0.044 and P = 0.040, respectively). CONCLUSIONS: Pre-transplant hypomagnesemia may be considered a risk factor for developing post-transplant glycemic disturbances, and patients with lower pre-transplant Mg concentration could be at a higher risk for developing IFG.

Two-dimensional 67Zn HYSCORE spectroscopy reveals that a Zn-bacteriochlorophyll aP' dimer is the primary donor (P840) in the type-1 reaction centers of Chloracidobacterium thermophilum.

Chloracidobacterium (C.) thermophilum is a microaerophilic, chlorophototrophic species in the phylum Acidobacteria that uses homodimeric type-1 reaction centers (RC) to convert light energy into chemical energy using (bacterio)chlorophyll ((B)Chl) cofactors. Pigment analyses show that these RCs contain BChl aP, Chl aPD, and Zn2+-BChl aP' in the approximate ratio 7.1 : 5.4 : 1. However, the functional roles of these three different Chl species are not yet fully understood. It was recently demonstrated that Chl aPD is the primary electron acceptor. Because Zn2+-(B)Chl aP' is present at low abundance, it was suggested that the primary electron donor might be a dimer of Zn2+-BChl aP' molecules. In this study, we utilize isotopic enrichment and high-resolution two-dimensional (2D) 14N and 67Zn hyperfine sublevel correlation (HYSCORE) spectroscopy to demonstrate that the primary donor cation, P840+, in the C. thermophilum RC is indeed a Zn2+-BChl aP' dimer. Density functional theory (DFT) calculations and the measured electron-nuclear hyperfine parameters of P840+ indicate that the electron spin density on P840+ is distributed nearly symmetrically over two Zn2+-(B)Chl aP' molecules as expected in a homodimeric RC. To our knowledge this is the only example of a photochemical RC in which the Chl molecules of the primary donor are metallated differently than those of the antenna.

Comparison of Oral and Intravenous N-acetyl Cysteine in Preventing Contrast Nephropathy.

INTRODUCTION: Despite high rates of morbidity and mortality in patients with contrast-induced nephropathy (CIN), there is no consensus regarding prevention of this well-known complication of contrast media use. One agent that has been widely used in this regard is N-acetyl cysteine (NAC). Nevertheless, its efficacy is still controversial. The aim of this study was to assess the efficacy of NAC, both in the oral and intravenous forms, for the prevention of CIN. METHODS: This study is a double-blind randomized placebo controlled clinical trial. We randomized 434 adult patients with chronic kidney disease (constant serum creatinine ≥1.5 mg/dL) who were candidates for coronary angiography/plasty. The patients were categorized into three groups. One group received 1,200 mg NAC intravenously half an hour before the procedure and oral placebo starting 3 days before angiography. The second group received oral NAC 600 mg twice daily for 3 days, starting the day before the intervention and intravenous placebo half an hour before intervention. The third group received both oral and intravenous placebo. CIN was defined as a 25% relative increase in serum creatinine from baseline value, 48 h after use of contrast medium. RESULTS: Of the 434 patients, 149 received intravenous NAC, 145 received oral NAC, and the remaining 140 received placebo. The incidence of CIN in the three groups was 6.1%, 7.6%, and 10.8%, respectively (p = 0.34). CONCLUSION: In patients with chronic kidney disease, neither intravenous nor oral NAC is superior to placebo for preventing CIN.

Association Between CYP3A5 Genetic Polymorphisms with Tacrolimus Dose Requirement and Allograft Outcomes in Iranian Kidney Transplant Recipients.

INTRODUCTION: Tacrolimus is the cornerstone of immunosuppressive therapy in organ transplantation with variable inter-individual pharmacokinetics. This study assessed the relationship between CYP3A5/3A4 polymorphisms and tacrolimus dose requirement as well as 6-month transplant outcomes in Iranian kidney transplant recipients. METHODS: In this prospective study, 110 adult kidney transplant recipients treated with tacrolimus were genotyped for the presence of common SNPs: rs776746: A > G (CYP3A5*3). Patients who carried at least one CYP3A5*1 allele were known as CYP3A5 expressers while those who were CYP3A5*3/*3 homozygotes were classified as CYP3A5 non-expressers. RESULTS: The daily tacrolimus dose was significantly higher and tacrolimus dose adjusted trough levels (C/D ratio) was significantly lower in CYP3A5 expressers compared with non-expressers (P < .05). Although the incidence of clinically suggested acute allograft rejection was significantly higher (OR = 0.365 [95% CI: 0.14 - 0.93]; P < .05) and median time to first acute rejection was sooner among CYP3A5 expressers compared with non-expressers (12.17 vs. 26.83 days, P < .05); however, estimated glomerular filtration rate, incidence of biopsy proven acute rejection and delayed graft function and 6-month patients' and grafts' survival did not differ between the two groups. CONCLUSION: CYP3A5 genetic polymorphism is significantly associated with required tacrolimus dose. After achieving desired tacrolimus blood level, although some transplant outcomes such as the incidence of clinically suggested acute rejection and time to first rejection were different between CYP3A5 expressers and non-expressers, however, other clinical outcomes did not differ between groups. Therefore, it is not the time to routinely assess kidney transplant recipients for CYP3A5 genetic polymorphism before transplantation.

Electronic Transport Properties of Silicane Determined from First Principles.

Silicane, a hydrogenated monolayer of hexagonal silicon, is a candidate material for future complementary metal-oxide-semiconductor technology. We determined the phonon-limited mobility and the velocity-field characteristics for electrons and holes in silicane from first principles, relying on density functional theory. Transport calculations were performed using a full-band Monte Carlo scheme. Scattering rates were determined from interpolated electron-phonon matrix elements determined from density functional perturbation theory. We found that the main source of scattering for electrons and holes was the ZA phonons. Different cut-off wavelengths ranging from 0.58 nm to 16 nm were used to study the possible suppression of the out-of-plane acoustic (ZA) phonons. The low-field mobility of electrons (holes) was obtained as 5 (10) cm2/(Vs) with a long wavelength ZA phonon cut-off of 16 nm. We showed that higher electron (hole) mobilities of 24 (101) cm2/(Vs) can be achieved with a cut-off wavelength of 4 nm, while completely suppressing ZA phonons results in an even higher electron (hole) mobility of 53 (109) cm2/(Vs). Velocity-field characteristics showed velocity saturation at 3 × 105 V/cm, and negative differential mobility was observed at larger fields. The silicane mobility was competitive with other two-dimensional materials, such as transition-metal dichalcogenides or phosphorene, predicted using similar full-band Monte Carlo calculations. Therefore, silicon in its most extremely scaled form remains a competitive material for future nanoscale transistor technology, provided scattering with out-of-plane acoustic phonons could be suppressed.

All-Atom Molecular Dynamics Simulations of Dimeric Lung Surfactant Protein B in Lipid Multilayers.

Although lung surfactant protein B (SP-B) is an essential protein that plays a crucial role in breathing, the details of its structure and mechanism are not well understood. SP-B forms covalent homodimers, and in this work we use all-atom molecular dynamics simulations to study dimeric SP-B's structure and its behavior in promoting lipid structural transitions. Four initial system configurations were constructed based on current knowledge of SP-B's structure and mechanism, and the protein maintained a helicity consistent with experiment in all systems. Several SP-B-induced lipid reorganization behaviors were observed, and regions of the protein particularly important for these activities included SP-B's "central loop" and "hinge" regions. SP-B dimers with one subunit initially positioned in each of two adjacent bilayers appeared to promote close contact between two bilayers. When both subunits were initially positioned in the same bilayer, SP-B induced the formation of a defect in the bilayer, with water penetrating into the centre of the bilayer. Similarly, dimeric SP-B showed a propensity to interact with preformed interpores in the bilayer. SP-B dimers also promoted bilayer thinning and creasing. This work fleshes out the atomistic details of the dimeric SP-B structures and SP-B/lipid interactions that underlie SP-B's essential functions.

A mutational and molecular dynamics study of the cys-loop GABA receptor Hco-UNC-49 from Haemonchus contortus: Agonist recognition in the nematode GABA receptor family.

The UNC-49 receptor is a unique nematode γ-aminobutyric acid (GABA)-gated chloride channel that may prove to be a novel target for the development of nematocides. Here we have characterized various charged amino acid residues in and near the agonist binding site of the UNC-49 receptor from the parasitic nematode Haemonchus contorts. Utilizing the Caenorhabditis elegans GluCl crystal structure as a template, a model was generated and various charged residues [D83 (loop D), E131 (loop A), H137 (pre-loop E), R159 (Loop E), E185 (Loop B) and R241 (Loop C)] were investigated based on their location and conservation. These residues may contribute to structure, function, and molecular interactions with agonists. It was found that all residues chosen were important for receptor function to varying degrees. Results of the mutational analysis and molecular simulations suggest that R159 may be interacting with D83 by an ionic interaction that may be crucial for general GABA receptor function. We have used the results from this study as well as knowledge of residues involved in GABA receptor binding to identify sequence patterns that may assist in understanding the function of lesser known GABA receptor subunits from parasitic nematodes.

Development of a Simple Risk Score Model to Predict Renal Artery Stenosis.

BACKGROUND/AIMS: Renal artery stenosis (RAS) is a known cause of secondary hypertension and renal failure. Although renal artery angiography is the gold standard for diagnosing RAS, a simple method to estimate if patients will develop RAS is required. The aim of this retrospective study was to develop a simple risk score to predict significant RAS. METHODS: Four thousand one hundred seventy-seven patients who underwent renal angiography between 2002 and 2016 at Tehran Heart Center were included. Significant RAS was defined as narrowing of the renal artery by at least 70%. Multiple predictors of the RAS were determined using multivariable logistic regression with a backward elimination method. The scoring system obtained from the final model was presented as nomogram. The possible nonlinear effect of continuous variables was evaluated using restricted cubic splines. Overfitting of the final model was assessed applying the tenfold cross-validation method. Model performance was checked using calibration plot as well as Hosmer-Lemeshow goodness of fit test, and area under the receiver operating characteristics (ROC) curve. RESULTS: The prevalence of RAS was 14.1%. Female sex (OR [95% CI]: 1.53 [1.26-1.85]), hypertension (OR [95% CI]: 1.38 [1.08-1.77]), estimated glomerular filtration rate (OR [95% CI]: 0.98 [0.97-0.98]), body mass index (OR [95% CI]: 0.97 [0.95-0.99]), and age (OR [95% CI]: 1.01 [1.00-1.02]) were determined as the multiple predictors of RAS. The area under the ROC curve of the final predictive model was 0.702 (95% CI: 0.679-0.725). CONCLUSION: This model assesses the risk of RAS using available information. This model can be used for both clinical and research purposes.

Molecular Characterization of Binding Loop E in the Nematode Cys-Loop GABA Receptor.

Nematodes exhibit a vast array of cys-loop ligand-gated ion channels with unique pharmacologic characteristics. However, many of the structural components that govern the binding of various ligands are unknown. The nematode cys-loop GABA receptor uncoordinated 49 (UNC-49) is an important receptor found at neuromuscular junctions that plays an important role in the sinusoidal movement of worms. The unique pharmacologic features of this receptor suggest that there are structural differences in the agonist binding site when compared with mammalian receptors. In this study, we examined each amino acid in one of the main agonist binding loops (loop E) via the substituted cysteine accessibility method (SCAM) and analyzed the interaction of various residues by molecular dynamic simulations. We found that of the 18 loop E mutants analyzed, H142C, R147C, and S157C had significant changes in GABA EC50 and were accessible to modification by a methanethiosulfonate reagent (MTSET) resulting in a change in I GABA In addition, the residue H142, which is unique to nematode UNC-49 GABA receptors, appears to play a negative role in GABA sensitivity as its mutation to cysteine increased sensitivity to GABA and caused the UNC-49 receptor partial agonist 5-aminovaleric acid (DAVA) to behave as a full agonist. Overall, this study has revealed potential differences in the agonist binding pocket between nematode UNC-49 and mammalian GABA receptors that could be exploited in the design of novel anthelmintics.