NWChem: Past, present, and future.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

Effect of pericardial effusion on outcomes in children admitted with systemic lupus erythematosus: a multicenter retrospective cohort study from the United States.

OBJECTIVE: We sought to describe characteristics of children admitted with pericardial effusion (PCE) and systemic lupus erythematosus (SLE) and determine the association between PCE and outcomes of interest. METHODS: We performed a retrospective cohort study of the Pediatric Health Information System (PHIS). Patients were included if they were admitted to a PHIS participating hospital from 2004 to 2015 with a diagnosis of SLE and age ≤18 years. Children with congenital heart disease or who had undergone heart surgery were excluded. PCE was the primary predictor variable; multivariable analysis was used to evaluate the effect of PCE on the following outcomes: mortality, length of stay (LOS), and readmission within 30 days. RESULTS: There were 5679 admissions, of which 705 (12.4%) had PCE. Median age at admission was 15 years (interquartile range: 13-17). There were no significant differences for age or sex between patients admitted either with or without PCE. A significantly higher percentage of children in the PCE group were black compared with those without PCE (43% vs. 31%, p < 0.001). In multivariable analysis, the odds of a black patient having PCE were 1.7 higher than non-black patients ( p < 0.001). In-hospital mortality was 2.5 times higher in children with PCE compared with those without PCE ( p = 0.027). Those with PCE also had 1.5 greater odds of readmission within 30 days ( p < 0.001). PCE was not associated with increased LOS (0.99, p = 0.753). CONCLUSION: PCE is common in admissions of children with SLE. There are disproportionately more black patients with SLE affected by PCE than non-black. PCE is associated with significantly higher mortality and rates of readmission.

High genetic risk scores of SLIT3, PLEKHA5 and PPP2R2C variants increased insulin resistance and interacted with coffee and caffeine consumption in middle-aged adults.

BACKGROUNDS AND AIMS: Insulin resistance is a common feature of metabolic syndrome that may be influenced by genetic risk factors. We hypothesized that genetic risk scores (GRS) of SNPs that influence insulin resistance and signaling interact with lifestyles to modulate insulin resistance in Korean adults. METHODS AND RESULTS: Genome-wide association studies (GWAS) of subjects aged 40-65 years who participated in the Ansung/Ansan cohorts (8842 adults) in Korea revealed 52 genetic variants that influence insulin resistance. The best gene-gene interaction model was explored using the generalized multifactor dimensionality reduction (GMDR) method. GRS from the best model were calculated and the GRS were divided into low, medium and high groups. The best model for representing insulin resistance included SLIT3_rs2974430, PLEKHA5_rs1077044, and PPP2R2C_rs16838853. The odds ratios for insulin resistance were increased by 150% in the High-GRS group compared to the Low-GRS group. However, ORs for insulin secretion capacity, measured by HOMA-B, were not associated with GRS. Coffee and caffeine intake and GRS had an interaction with insulin resistance: In subjects with high coffee (≥10 cups/week) or caffeine intake (≥220 mg caffeine/day), insulin resistance was significantly elevated in the High-GRS group, but not in the Low-GRS. However, alcohol intake, smoking and physical activity did not have an interaction with GRS. Insulin secretion capacity was not significantly influenced by GRS when evaluating the adjusted odds ratios. CONCLUSIONS: Subjects with High-GRS may be susceptible to increased insulin resistance by 50% and its risk may be exacerbated by consuming more than 10 cups coffee/week or 220 mg caffeine/day.

Distinct physiological states of Plasmodium falciparum in malaria-infected patients.

Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in children, ranging from mild flu-like symptoms to coma and death. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown. Studies of in vitro gene expression have found few transcriptional differences between different parasite strains. Here we present a large study of in vivo expression profiles of parasites derived directly from blood samples from infected patients. The in vivo expression profiles define three distinct transcriptional states. The biological basis of these states can be interpreted by comparison with an extensive compendium of expression data in the yeast Saccharomyces cerevisiae. The three states in vivo closely resemble, first, active growth based on glycolytic metabolism, second, a starvation response accompanied by metabolism of alternative carbon sources, and third, an environmental stress response. The glycolytic state is highly similar to the known profile of the ring stage in vitro, but the other states have not been observed in vitro. The results reveal a previously unknown physiological diversity in the in vivo biology of the malaria parasite, in particular evidence for a functional mitochondrion in the asexual-stage parasite, and indicate in vivo and in vitro studies to determine how this variation may affect disease manifestations and treatment.

Anti-obesity effect of kimchi fermented with Weissella koreensis OK1-6 as starter in high-fat diet-induced obese C57BL/6J mice.

AIMS: In this study, we investigated the anti-obesity effects of kimchi (Korean traditional fermented vegetable) fermented either without starter culture or with a specific starter culture, Weissella koreensis OK1-6. METHODS AND RESULTS: C57BL/6J mice were divided into four groups (n = 7); normal diet, HF (high-fat diet), HF-KC (high-fat diet containing 3% kimchi manufactured without starter) and HF-KCO (high-fat diet containing 3% kimchi manufactured with the starter culture W. koreensis OK1-6). After 12 weeks of dietary intervention, the mice were killed, and serum and tissue samples were examined. Serum and hepatic lipid profile, insulin, leptin concentration and expression level of lipid anabolic genes like peroxisome proliferator-activated receptor γ, stearoyl-CoA desaturase-1, liver X receptor α and SREBP2 were significantly decreased (<0.05) along with body and epididymal fat pad weight in the HF-KCO group compared with the HF-KC and HF group. CONCLUSIONS: These results suggested that kimchi fermented with the starter W. koreensis OK1-6 has anti-obesity effects in HF-induced obese mice. SIGNIFICANCE AND IMPACT OF THE STUDY: These results may contribute to nutraceutical and food industries in developing functional food and probiotics based therapies for the treatment and prevention of obesity.

The critical care research networks experience.

Neurocritical care is a subspecialty of critical care medicine, dedicated to the care and the advancement of care of critically ill patients with neurosurgical or neurological diseases. Neurocritical care patients are heterogeneous, in both their disease process and the therapies they receive, however, several studies demonstrate that care of these patients in dedicated NeuroIntensive Care Units (neuroICUs) by neurointensivists, who coordinate their care is associated with reduced mortality and resource utilization. NeuroICUs foster innovation, and yet despite all the recent advances, much research needs to be undertaken in neurocritical care to better understand the disease pathophysiology and to demonstrate improved outcome with the use of goal-directed therapy based on evolving techniques and therapies.

People with the major alleles of ATP2B1 rs17249754 increases the risk of hypertension in high ratio of sodium and potassium, and low calcium intakes.

It is important to understand what genetic risk factors lead to hypertension and how genotype-specific dietary and lifestyle modification can mitigate the risk of developing hypertension. The ATP2B1 rs17249754 gene, which encodes a calcium pump expressed in vascular smooth muscle was identified as having variants that conferred higher or lower risk of hypertension-with the major allele carriers being increased at risk. However, the effects of dietary intakes on risk of hypertension among carriers of the different alleles have not been fully elucidated. Therefore, we evaluated ATP2B1 rs17249754 and its interaction with dietary intakes of sodium (Na), potassium (K) and calcium (Ca) on the risk of developing hypertension using the Ansan/Ansung (n=8842) and City-Rural (n=5512) cohorts from the Korean Genome and Epidemiology Study. Carriers of the major allele of ATP2B1 rs17249754 were at greater risk of developing hypertension and high Na intake and low Ca increased the risk more in major allele than among minor allele carriers. High potassium intake was more protective against hypertension in the subjects expressing minor alleles and a low Na/K intake ratio was the most consistently beneficial to the subjects expressing the minor allele. When controlling for Na and K, low Ca intake was associated with a substantially higher risk for high systolic blood pressure in the major allele carriers compared with minor allele, suggesting good calcium status is especially important for the major allele carriers. In conclusion, people with the major allele of ATP2B1 rs17249754 are susceptible to hypertension especially in low intake of Ca and high ratio of Na and K.

Defining the origin of Plasmodium falciparum resistant dhfr isolates in Senegal.

We previously reported a high baseline prevalence of mutations in the dhfr and dhps genes of Plasmodium falciparum throughout Senegal. The highest prevalence of the triple dhfr pyrimethamine associated mutations were found in isolates obtained in the western part of the country near the capital city of Dakar. In this study, we sought out to determine the relatedness of dhfr wild type and mutated strains by analyzing three microsatellite regions upstream of the dhfr locus. Twenty-six of the 31 wild type strains had a unique microsatellite pattern. In contrast, of the 17 isolates containing the triple mutation in dhfr, 11 had an identical microsatellite pattern. Diverse geographical isolates in Senegal containing the triple dhfr mutation have arisen from a limited number of ancestral strains. In addition, we demonstrate that these isolates have shared ancestry with the previously reported triple mutation haplotype found in Tanzania, South Africa, and southeast Asia. This common ancestry may have implications for the malaria control strategy for reducing the spread of sulfadoxine-pyrimethamine resistance in Senegal and elsewhere in Africa.

An optically accessible pyrolysis microreactor.

We report an optically accessible pyrolysis micro-reactor suitable for in situ laser spectroscopic measurements. A radiative heating design allows for completely unobstructed views of the micro-reactor along two axes. The maximum temperature demonstrated here is only 1300 K (as opposed to 1700 K for the usual SiC micro-reactor) because of the melting point of fused silica, but alternative transparent materials will allow for higher temperatures. Laser induced fluorescence measurements on nitric oxide are presented as a proof of principle for spectroscopic characterization of pyrolysis conditions.

Alprazolam-ritonavir interaction: implications for product labeling.

BACKGROUND: Pharmacokinetic interactions involving antiretroviral therapies may critically influence the efficacy and toxicity of these drugs, as well as pharmacologic treatments of coincident or complicating diseases. The viral protease inhibitor ritonavir is of particular concern since it both inhibits and induces the activity of cytochrome P450 3A (CYP3A) isoforms. METHODS: The inhibitory effect of ritonavir on the metabolism of alprazolam, a CYP3A-mediated reaction in humans, was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer subjects received 1.0 mg of alprazolam concurrent with low-dose ritonavir (four doses of 200 mg) or with placebo. RESULTS: Ritonavir was a potent in vitro inhibitor of alprazolam hydroxylation. The 50% inhibitory concentration was 0.11 micromol/L (0.08 microg/mL); this is below the usual therapeutic plasma concentration range (generally exceeding 2 microg/mL). In the clinical study, ritonavir reduced alprazolam clearance to 41% of control values (P < .001), prolonged elimination half-life (mean values, 30 versus 13 hours; P < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. CONCLUSION: Consistent with in vitro results, administration of low doses of ritonavir for a short duration of time resulted in large impairment of alprazolam clearance and enhancement of clinical effects. Removal from product labeling of a warning against coadministration of ritonavir and alprazolam was based on a previous study only of extended exposure to ritonavir, in which CYP3A induction offset inhibition. Kinetic interactions involving antiretroviral therapies may be complex and time dependent. Product labeling should reflect this complexity.

3' UTR elements enhance expression of Pgs28, an ookinete protein of Plasmodium gallinaceum.

In Plasmodium parasites the fusion of gametes to form a fertilized zygote and morphogenesis into the motile ookinete are critical developmental stages in the parasite's complex life cycle. In analogous developmental stages of metazoan organisms 3' gene flanking regions are critical in the regulation of gene expression. To determine whether these mechanisms are conserved in the protozoan parasite we studied the 3' gene flanking elements necessary for the expression of Pgs28, the major surface protein of mature zygotes and ookinetes of the chicken malaria Plasmodium gallinaceum. The DNA sequence of the pgs28 3' gene flanking region contains 7 eukaryotic polyadenylation consensus signals (AATAAA/ATTAAA). An unusual 82% T-rich region is located 55 nucleotides upstream of the fifth polyadenylation signal (ATTAAA). The pgs28 mRNA terminates approximately 20 nucleotides from the polyadenylation signal in a poly (A) tail. To determine whether the T-rich region and polyadenylation signals were necessary for Pgs28 protein expression, sexual stage parasites were transfected with plasmids containing deletions of these elements utilizing firefly luciferase (LUC) and beta-glucuronidase (GUS) as markers of transient gene transfection. The parasites were allowed to develop in vitro to the ookinete stage and assayed for enzymatic activity. Cells transfected with plasmids containing deletions of the T-rich region or fifth eukaryotic polyadenylation consensus signal expressed 89 and 92%, less enzymatic activity respectively than those transfected with the full length pgs28 3' gene flanking region. The U-rich element and fifth eukaryotic polyadenylation consensus sequence within the pgs28 3' UTR are therefore necessary for Pgs28 protein expression.

IGIV: a potential role for hepatitis B prophylaxis in the bone marrow peritransplant period.

Prevention of hepatitis B virus infection in transplant recipients can be difficult. Patients may be unresponsive to vaccination and intolerant of the intramuscular injections required to administer hepatitis B immune globulin (HBIG). A recipient of HBsAg-positive donor cells for a bone marrow transplant received multiple i.m. injections of HBIG. This mode of antibody delivery was limited by his thrombocytopenia and neutropenia and alternative forms of passive immunization were sought. Four lots of IGIV were investigated for anti-hepatitis B surface antibody (anti-HBs) content and all were found to contain significant antibody titer. Moreover, IGIV that was administered to four bone marrow transplant recipients for medical purposes unrelated to HBV transmission produced protective anti-HBs titers in all. These studies suggest IGIV may be useful for HBV prophylaxis in the appropriate setting or if HBIG is unavailable. The optimum regimen for HBV prevention in distinct transplant settings needs to be determined.

Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors.

The capacity of three clinically available nonnucleoside reverse transcriptase inhibitors (NNRTIs) to inhibit the activity of human cytochromes P450 (CYPs) was studied in vitro using human liver microsomes. Delavirdine, nevirapine, and efavirenz produced negligible inhibition of phenacetin O-deethylation (CYP1A2) or dextromethorphan O-demethylation (CYP2D6). Nevirapine did not inhibit hydroxylation of tolbutamide (CYP2C9) or S-mephenytoin (CYP2C19), but these CYP isoforms were importantly inhibited by delavirdine and efavirenz. This indicates the likelihood of significantly impaired clearance of CYP2C substrate drugs (such as phenytoin, tolbutamide, and warfarin) upon initial exposure to these two NNRTIs. Delavirdine and efavirenz (but not nevirapine) also were strong inhibitors of CYP3A, consistent with clinical hazards of initial cotreatment with either of these drugs and substrates of CYP3A. The in vitro microsomal model provides relevant predictive data on probable drug interactions with NNRTIs when the mechanism is inhibition of CYP-mediated drug biotransformation. However, the model does not incorporate interactions attributable to enzyme induction.

Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir.

Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir, saquinavir) were evaluated as in vitro inhibitors of the activity of six human cytochromes using an in vitro model based on human liver microsomes. Ritonavir was a highly potent inhibitor of P450-3A activity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir had high inhibition potency against cytochrome P450-2C9 (tolbutamide hydroxylation), -2C19 (S-mephenytoin hydroxylation), and -2D6 (dextromethorphan O-demethylation and desipramine hydroxylation), while the other protease inhibitors had one or more orders of magnitude lower inhibitory activity against these reactions. None of the protease inhibitors had important inhibitory potency against P450-1A2 (phenacetin O-deethylation) or -2E1 (chlorzoxazone hydroxylation). Thus, among available protease inhibitors, ritonavir carries the highest risk of incurring drug interactions due to inhibition of cytochrome P450 activity.

Inhibition of desipramine hydroxylation (Cytochrome P450-2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo.

Pharmacokinetic drug interactions with viral protease inhibitors are of potential clinical importance. An in vitro model was applied to the quantitative identification of possible interactions of protease inhibitors with substrates of cytochrome P450-2D6. Biotransformation of desipramine (DMI) to hydroxydesipramine (OH-DMI), an index reaction used to profile activity of human cytochrome P450-2D6, was studied in vitro using human liver microsomes. Quinidine and four viral protease inhibitors currently used to treat human immunodeficiency virus infection were tested as chemical inhibitors in this system. Formation of OH-DMI from DMI was consistent with Michaelis-Menten kinetics, having a mean Km value of 11.7 microM (range: 9.9-15.3 microM). Quinidine, a highly potent and relatively selective inhibitor of P450-2D6, strongly inhibited OH-DMI formation with an apparent competitive mechanism, having a mean inhibition constant of 0.16 microM (range: 0.13-0.18 microM). All four protease inhibitors impaired OH-DMI formation; the pattern was consistent with a mixed competitive-noncompetitive mechanism. Mean inhibition constants (small numbers indicating greater inhibiting potency) were as follows: ritonavir, 4.8 microM; indinavir, 15.6 microM; saquinavir, 24.0 microM; nelfinavir, 51.9 microM. In a clinical pharmacokinetic study, coadministration of ritonavir with DMI inhibited DMI clearance by an average of 59%. The in vitro findings, together with observed plasma ritonavir concentrations, provided a reasonable quantitative forecast of this interaction, whereas estimated unbound plasma or intrahepatic ritonavir concentrations yielded poor quantitative forecasts. Thus the in vitro model correctly identifies ritonavir as a potent and clinically important inhibitor of human P450-2D6. Other protease inhibitors may also inhibit 2D6 activity in humans, but with lower potency than ritonavir.

Characterization of biomass pyrolysis vapors with molecular beam, single photon ionization time-of-flight mass spectrometry.

A single photon ionization, molecular beam sampling, reflectron time-of-flight mass spectrometer (SPI/MBTOFMS) has been developed and used to study pyrolysis products from a selection of biomass materials. Spectra are characterized by high resolution and decreased fragmentation compared to electron-impact ionization mass spectra from related molecular beam mass spectrometer systems equipped with quadrupole mass analyzers.

Postexposure prophylaxis for HIV.

AIDS: Postexposure prophylaxis represents an advance in the management of percutaneous exposure to HIV in the workplace, but its efficacy in other settings needs further study. Three types of occupational exposure, percutaneous, mucous membrane, skin contact or loss of skin integrity, the postexposure prophylaxis to be used or offered, and the risk data and assessment for HIV acquisition are examined. Analysis of HIV transmission through percutaneous exposure reveals that occupational risk for health care workers is increased by deep injury to the exposed worker, visible blood on the injuring device, exposure of the device to source patients' vein or artery, and source patient's death from AIDS within 60 days of the accident. Prophylaxis for percutaneous exposure, if indicated, should be initiated within 1 to 2 hours to be effective. HIV antibody titers should be measured immediately and at 6 weeks, 12 weeks, and 6 months after exposure. AZT prophylaxis following percutaneous occupational exposure has dramatically decreased transmission in this setting and multiple drug regimens have become the standard of care to further increase efficacy. Sexual contact is the most frequent means of transmitting HIV infection and reducing exposure is the mainstay of public health efforts. Prophylaxis after non-occupational exposures such as sexual intercourse or sharing needles could potentially decrease transmission, although efficacy has not yet been demonstrated. Routine prophylaxis after sexual exposure may be an ineffective strategy.^ieng

Protease inhibitors and anticonvulsants.

AIDS: Due to adverse interactions, manufacturers of four licensed protease inhibitors are recommending that their products not be used with the three most frequently prescribed anticonvulsants: carbamazepine, phenobarbitol, and phenytoin. These adverse interactions and their causes are discussed, suggesting that concomitant administration of protease inhibitors may induce early viral resistance and possibly accelerate HIV progression. Further, ritonavir and nelfinavir use may raise serum levels of these anticonvulsants into toxic ranges. Although not approved for single-agent use in the United States, two anticonvulsants that are theoretically less prone to interact adversely with protease inhibitors are gabapentin and lamotrigine. Protocols to manage patients on protease inhibitors and anticonvulsants are suggested.^ieng

Ebselen pretreatment attenuates ischemia/reperfusion injury and prevents hyperglycemia by improving hepatic insulin signaling and ß-cell survival in gerbils.

Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic ß-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic ß-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and ß-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1ß and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased ß-cell mass due to increased ß-cell apoptosis. Ebselen prevented the increased ß-cell apoptosis, possibly by decreasing IL-1ß and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic ß-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease.