Theoretical model of prion propagation: a misfolded protein induces misfolding

There is a hypothesis that dangerous diseases such as bovine spongiform encephalopathy, Creutzfeldt-Jakob, Alzheimer's, fatal familial insomnia, and several others are induced by propagation of wrong or misfolded conformations of some vital proteins. If for some reason the misfolded conformations were acquired by many such protein molecules it might lead to a "conformational" disease of the organism. Here, a theoretical model of the molecular mechanism of such a conformational disease is proposed, in which a metastable (or misfolded) form of a protein induces a similar misfolding of another protein molecule (conformational autocatalysis). First, a number of amino acid sequences composed of 32 aa have been designed that fold rapidly into a well defined native-like alpha-helical conformation. From a large number of such sequences a subset of 14 had a specific feature of their energy landscape, a well defined local energy minimum (higher than the global minimum for the alpha-helical fold) corresponding to beta-type structure. Only one of these 14 sequences exhibited a strong autocatalytic tendency to form a beta-sheet dimer capable of further propagation of protofibril-like structure. Simulations were done by using a reduced, although of high resolution, protein model and the replica exchange Monte Carlo sampling procedure.     

Influence of Li2O Incrementation on Mechanical and Gamma-Ray Shielding Characteristics of a TeO2-As2O3-B2O3 Glass System

According to the Makishema–Mackenzie model assumption, the dissociation energy and packing density for a quaternary TeO₂-As₂O₃-B₂O₃-Li₂O glass system were evaluated. The dissociation energy rose from 67.07 to 71.85 kJ/cm³, whereas the packing factor decreased from 16.55 to 15.21 cm³/mol associated with the replacement of TeO₂ by LiO₂ compounds. Thus, as a result, the elastic moduli (longitudinal, shear, Young, and bulk) were enhanced by increasing the LiO₂ insertion. Based on the estimated elastic moduli, mechanical properties such as the Poisson ratio, microhardness, longitudinal velocity, shear velocity, and softening temperature were evaluated for the investigated glass samples. In order to evaluate the studied glasses’ gamma-ray shield capacity, the MCNP-5 code, as well as a theoretical Phy-X/PSD program, were applied. The best shielding capacity was achieved for the glass system containing 25 mol% of TeO_2, while the lowest ability was obtained for the glass sample with a TeO₂ concentration of 5 mol%. Furthermore, a correlation between the studied glasses’ microhardness and linear attenuation coefficient was performed versus the LiO₂ concentration to select the glass sample which possesses a suitable mechanical and shielding capacity.     

Quantitative determination of ion distributions in bacterial lipopolysaccharide membranes by grazing-incidence X-ray fluorescence

A model of the outer membrane of Gram-negative bacteria was created by the deposition of a monolayer of purified rough mutant lipopolysaccharides at an air/water interface. The density profiles of monovalent (K⁺) and divalent (Ca²⁺) cations normal to the lipopolysaccharides (LPS) monolayers were investigated using grazing-incidence X-ray fluorescence. In the absence of Ca²⁺, a K⁺ concentration peak was found in the negatively charged LPS headgroup region. With the addition of CaCl₂, Ca²⁺ ions almost completely displaced K⁺ ions from the headgroup region. By integrating the experimentally reconstructed excess ion density profiles, we obtained an accurate measurement of the effective charge density of LPS monolayers. The experimental findings were compared to the results of Monte Carlo simulations based on a coarse-grained minimal model of LPS molecules and showed excellent agreement.     

美罗培南优化两步点滴法中不同点滴模型药代动力学／药效动力学参数比较

目的通过测定美罗培南优化两步点滴法两种点滴模型的药代动力学参数／药效动力学（PK／PD）参数,比较不同点滴方法的优劣。方法收集中、重度细菌性下呼吸道感染患者20例,随机分为实验组和对照组各10例。实验组和对照组分别按0．5h／250mg＋2．5h／750mg和0．5h／500mg＋2．5h／500mg的点滴模型给药;使用高效液相色谱内标法测定患者的药物浓度,使用Winnonlin求出实验组和对照组的美罗培南的血浆清除率（CL）,表观分布容积（Vd）,清除半衰期（t1/2）,峰浓度（Cmax）,达峰时间（Tmax）,曲线下面积（AUC）等药代动力学参数;使用CrystalBall软件按PK／PD模型进行蒙特卡罗模拟（MCS）计算Cmax／MIC、％T〉MIC的比值及达标概率（PTAs）,比较两种点滴方法的差异和优劣。结果实验组的Vd为35．51±3．33,t1/2为1．59±0．26,CL为14．80±1．11,Tmax为1．48±0．12,Cmax为11．86±0．54,AUC为64．40±4．62,对照组的Vd为29．13±4．21,t1／2为1．32±0．34,CL为14．41±1．76,Tmax为1．95±0．11,Cmax为15．25±0．93,AUC为64．56±7．38;在MIC分别为1、2、4μg／ml时,实验组的Cmax／MIC为6．40±0．55,3．20±0．27,1．60±0．14,％T〉MIC为118．94±9．71,97．13±7．20,74．28±4．77,PTAs都为100％,而对照组的Cmax／MIC为15．46±1．97,7．71±0．98,3．87±0．49,％T〉MIC为105．70±13．92,87．29±10．60,68．58±7．29,PTAs都为100％。结论实验组比对照组的Cmax／MIC小,但实验组的％T〉MIC大于对照组,两组的达标概率都为100％,结果显示可能实验组要优于对照组,在临床上可以采用0．5h／250mg＋2．5h／750mg的点滴方法抗感染。     

Prediction of Magnetocaloric Effect Induced by Continuous Modulation of Exchange Interaction: A Monte Carlo Study

A magnetic-to-thermal energy conversion, derived from the continuous modulation of intrinsic exchange energy, is conceived and studied by performing Monte Carlo simulations. On the basis of thermodynamics and Weiss’s molecular field theories, we modified the Maxwell formula, where the magnetic entropy change (∆S_M) is calculated by integrating the temperature derivative of magnetization under a continuously increasing exchange interaction, rather than an external magnetic field, from zero to a given value. For the conventional ∆S_M induced through increasing magnetic field, the ∆S_M maximum value is enhanced with increasing magnetic field, while the ∆S_M peak temperature is weakly influenced by the magnetic field. On the contrary, the ∆S_M induced by changing the exchange interaction is proportional to the exchange interaction while suppressed by a magnetic field. Another feature is that the relative cooling power calculated from the ∆S_M induced by changing the exchange interaction is fully independent of the magnetic field perspective for obtaining the magnetically stabilized self-converted refrigerants. The controlled variation of exchange interaction could be realized by partial substitution or the application of hydrostatic pressure to lower the cost of magnetic energy at no expense of magnetocaloric response, which opens an avenue to develop the practical and energy-saving devices of conversion from magnetic energy to thermal energy, highly extending the material species of the magnetocaloric effect.     

Monte Carlo simulation of an ethanol pharmacokinetic model

BACKGROUND: One challenge of using even relatively simple pharmacokinetic models is valuation of model parameters. Unknown model parameter values can be determined by fitting the model to measured data. Goals of the present study were to (1) obtain ethanol pharmacokinetic data from a cohort of dogs, (2) propose a physiologic ethanol pharmacokinetic model, (3) and perform Monte Carlo simulation to determine model parameter values. The rationale for the particular model proposed here was to account for the interrelationship between blood ethanol concentration and gastrointestinal physiology. METHODS: To each of five fasted dogs, 1 g of ethanol/kg body weight was administered as a gavage of 20% w/v ethanol solution. Developed was an ethanol pharmacokinetic model that comprised a gastric emptying mechanism, a body water compartment, ethanol diffusion through the stomach mucosa, gastric alcohol dehydrogenase (GADH) oxidation of ethanol, diffusion through the small intestine epithelia to the villi, a countercurrent exchanger model of the villi, and liver alcohol dehydrogenase oxidation of ethanol. Monte Carlo simulation was used to estimate model parameter values and standard deviations by minimization of the chi function. RESULTS: Fitting the experimental data to the model using Monte Carlo simulation yielded reasonable values for model parameters. The model predicted that the capacity for ethanol absorption in the intestine was 6.79-fold greater than the ethanol absorption capacity in the stomach. The model indicated that 23.8 +/- 8.3% of the ethanol dose was actually absorbed in the stomach, and an insignificant amount of ethanol was metabolized by GADH. CONCLUSIONS: Ethanol metabolism by GADH is insignificant in the present case. The blood ethanol profile was strongly determined by gastric emptying. Differences between experimental data and simulation results largely result from the gastric emptying model selected. Therefore, accuracy of the complete pharmacokinetic model can be improved significantly by improving the gastric emptying model.     

A lamin B receptor in the nuclear envelope.

Using a solution binding assay, we show that purified 125I-labeled lamin B binds in a saturable and specific fashion to lamin-depleted avian erythrocyte nuclear membranes with a Kd of approximately 0.2 microM. This binding is significantly greater than the binding of 125I-labeled lamin A and is competitively inhibited by unlabeled ligand. We demonstrate that a 58-kDa integral membrane protein (p58) is a lamin B receptor by virtue of its abundance in the nuclear envelope and association with 125I-labeled lamin B in ligand blotting assays. Specific antibodies raised against p58 recognize one protein in isolated nuclei and partially block 125I-labeled lamin B binding to lamin-depleted nuclear membranes. Cell fractionation and indirect immunofluorescence microscopy show that p58 is located in the periphery of the nucleus. This protein may serve as a membrane attachment site for the nuclear lamina by acting as a specific receptor for lamin B.     

Optimizing antibiotic pharmacodynamics in hospital-acquired and ventilator-acquired bacterial pneumonia

Nosocomial pneumonia carries a high morbidity and mortality and creates a large burden on health care use. As resistance to currently available antibiotics continues to increase, the role of pharmacodynamics in drug regimen optimization becomes pivotal to the clinical success of patient therapy. This article reviews the evidence behind pharmacodynamic optimization including the use of Monte Carlo simulations, changes in pharmacokinetic parameters of critically ill patients, and differing strategies to optimize drug regimens. Emphasis is placed on drugs used to treat hospital-acquired and ventilator-acquired pneumonia, and programs implementing pharmacodynamic optimization are highlighted.     

Economic evaluation of Chagas disease screening of pregnant Latin American women and of their infants in a non endemic area

Migration is a channel through which Chagas disease is imported, and vertical transmission is a channel through which the disease is spread in non-endemic countries. This study presents the economic evaluation of Chagas disease screening in pregnant women from Latin America and in their newborns in a non endemic area such as Spain. The economic impact of Chagas disease screening is tested through two decision models, one for the newborn and one for the mother, against the alternative hypothesis of no screening for either the newborn or the mother. Results show that the option “no test” is dominated by the option “test”. The cost effectiveness ratio in the “newborn model” was 22 €/QALYs gained in the case of screening and 125 €/QALYs gained in the case of no screening. The cost effectiveness ratio in the “mother model” was 96 €/QALYs gained in the case of screening and 1675 €/QALYs gained in the case of no screening. Probabilistic sensitivity analysis highlighted the reduction of uncertainty in the screening option. Threshold analysis assessed that even with a drop in Chagas prevalence from 3.4% to 0.9%, a drop in the probability of vertical transmission from 7.3% to 2.24% and with an increase of screening costs up to €37.5, “test” option would still be preferred to “no test”. The current study proved Chagas screening of all Latin American women giving birth in Spain and of their infants to be the best strategy compared to the non-screening option and provides useful information for health policy makers in their decision making process.     

Decreased and aberrant nuclear lamin expression in gastrointestinal tract neoplasms

BACKGROUND: Altered expression of lamins A/C and B1, constituent proteins of the nuclear lamina, may occur during differentiation and has also been reported in primary lung cancer. AIMS: To examine the expression of these proteins in gastrointestinal neoplasms. PATIENTS: Archival human paraffin wax blocks and frozen tissue from patients undergoing surgical resection or endoscopic biopsy. METHODS: Immunohistochemistry and western blotting using polyclonal antisera against A type lamins and lamin B1. RESULTS: The expression of lamin A/C was reduced and was frequently undetectable by immunohistochemistry in all primary colon carcinomas and adenomas, and in 7/8 primary gastric cancers. Lamin B1 expression was reduced in all colon cancers, 16/18 colonic adenomas, and 6/8 gastric cancers. Aberrant, cytoplasmic labelling with both antibodies occurred in some colonic cancers and around one third of colonic adenomas. Cytoplasmic lamin A/C expression was detected in 3/8 gastric cancers. Lamin expression was reduced in gastric dysplasia, but not intestinal metaplasia, atrophy, or chronic gastritis. Lamin expression was low in carcinomas of oesophagus, prostate, breast, and uterus, but not pancreas. CONCLUSIONS: Reduced expression of nuclear lamins, sometimes together with aberrant, cytoplasmic immunoreactivity is common in gastrointestinal neoplasms. Altered lamin expression may be a biomarker of malignancy in the gastrointestinal tract.     

Quantification of Chlorides and Sulphates on Concrete Surfaces Using Portable X-ray Fluorescence. Optimization of the Measurement Method Using Monte Carlo Simulation

A correct assessment of the pathologies that can affect a reinforced concrete structure is required in order to define the repair procedure. This work addresses the challenge of quantifying chlorides and sulphates directly on the surface of concrete. The quantification was carried out by means of X-ray fluorescence analysis on the surface of concrete specimens at different points with portable equipment. Concrete prisms were made with different amounts of NaCl and Na₂SO₄. To avoid the influence of coarse aggregate, a qualitative estimate of the amount of coarse aggregate analyzed has been made, although the results show that there is no significant influence. Monte Carlo simulations were carried out in order to establish the necessary number of random analyses of the mean value to be within an acceptable range of error. In the case of quantifying sulphates, it is necessary to carry out six random analyses on the surface, and eight measurements in the case of quantifying chlorides; in this way, it is ensured that errors are below 10% in 95% of the cases. The results of the study highlight that a portable XRF device can be used in situ to obtain concentrations of chlorides and sulphates of a concrete surface with good accuracy. There is no need to take samples and bring them to a laboratory, allowing lower overall costs in inspection and reparation works.     

Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy

We previously identified a novel mutation, namely LMNA R482Q, that was found to underlie Dunnigan-type partial lipodystrophy (FPLD) and diabetes in an extended Canadian kindred. We have since sequenced LMNA in five additional Canadian FPLD probands and herein report three new rare missense mutations in LMNA: V440M, R482W, and R584H. One severely affected subject was a compound heterozygote for both V440M and R482Q. The findings indicated that 1) a spectrum of LMNA mutations underlies FPLD; 2) aberrant lamin A, and not lamin C, is likely to underlie FPLD, as R584H occurs within LMNA sequence that is specific for lamin A; 3) the V440M mutation may not cause lipodystrophy on its own; 4) compound heterozygosity for V440M and R482Q is associated with a relatively more severe FPLD phenotype, but not with complete lipodystrophy; and 5) variation in the severity of the phenotype might be related to environmental factors.     

Granulocytic nuclear differentiation of lamin B receptor-deficient mouse EPRO cells

OBJECTIVE: Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane. Recent studies have demonstrated that genetic deficiency of LBR during granulopoiesis results in hypolobulation of the mature neutrophil nucleus, as observed in human Pelger-Hu?t anomaly and mouse ichthyosis (ic). In this study, we utilized differentiated early promyelocytes (EPRO cells) that were derived from the bone marrow of homozygous and heterozygous ichthyosis mice to examine changes to the expression of nuclear envelope proteins and heterochromatin structure that result from deficient LBR expression. MATERIALS AND METHODS: Wild-type (+/+), heterozygous (+/ic), and homozygous (ic/ic) granulocytic forms of EPRO cells were analyzed for the expression of multiple lamins and inner nuclear envelope proteins by immunostaining and immunoblotting techniques. The heterochromatin architecture was also examined by immunostaining for histone lysine methylation. RESULTS: Wild-type (+/+) and heterozygous (+/ic) granulocytic forms revealed ring-shaped nuclei and contained LBR within the nuclear envelope; ic/ic granulocytes exhibited smaller ovoid nuclei devoid of LBR. The pericentric heterochromatin of undifferentiated and granulocytic ic/ic cells was condensed into larger spots and shifted away from the nuclear envelope, compared to +/+ and +/ic cell forms. Lamin A/C, which is normally not present in mature granulocytes, was significantly elevated in LBR-deficient EPRO cells. CONCLUSIONS: Our observations suggest roles for LBR during granulopoiesis, which can involve augmenting nuclear membrane growth, facilitating compartmentalization of heterochromatin, and promoting downregulation of lamin A/C expression.     

From the Cover: Thermodynamic feasibility of shipboard conversion of marine plastics to blue diesel for self-powered ocean cleanup

Collecting and removing ocean plastics can mitigate their environmental impacts; however, ocean cleanup will be a complex and energy-intensive operation that has not been fully evaluated. This work examines the thermodynamic feasibility and subsequent implications of hydrothermally converting this waste into a fuel to enable self-powered cleanup. A comprehensive probabilistic exergy analysis demonstrates that hydrothermal liquefaction has potential to generate sufficient energy to power both the process and the ship performing the cleanup. Self-powered cleanup reduces the number of roundtrips to port of a waste-laden ship, eliminating the need for fossil fuel use for most plastic concentrations. Several cleanup scenarios are modeled for the Great Pacific Garbage Patch (GPGP), corresponding to 230 t to 11,500 t of plastic removed yearly; the range corresponds to uncertainty in the surface concentration of plastics in the GPGP. Estimated cleanup times depends mainly on the number of booms that can be deployed in the GPGP without sacrificing collection efficiency. Self-powered cleanup may be a viable approach for removal of plastics from the ocean, and gaps in our understanding of GPGP characteristics should be addressed to reduce uncertainty.

An estimated 4.8 million to 12.7 million tons of plastic enter the ocean each year, distributing widely across the ocean’s surface and water column, settling into sediments, and accumulating in marine life (1–3). Numerous studies have shown that plastics contribute to significant damages to marine life and birds, therefore motivating introduction of effective mitigation and removal measures (4). Reducing or eliminating the amount of plastic waste generated is critically important, especially when the current loading may persist for years to even decades (1, 5, 6).As a highly visible part of an integrated approach for removing plastics from the environment (1, 5, 6), efforts are underway to collect oceanic plastic from accumulation zones in gyres formed by ocean currents (3, 7). Present approaches to remove plastic from the open ocean utilize a ship that must store plastic on board until it returns to port, often thousands of kilometers away, to unload the plastic, refuel, and resupply.Optimistic evaluation of cleanup time using the harvest–return approach indicates that at least 50 y will be required for full plastic removal (7), with an annual cost of $36.2 million (8); more conservative estimates suggest that partial removal will require more than 130 y (7, 9). Cleanup times of decades mean that environmental degradation may have already reduced the existing plastics to microscopic and smaller forms that can no longer be harvested before cleanup is completed (1, 4, 9). These considerations underscore the massive challenge of removing plastics from the ocean and naturally raise the following question: Can any approach remove plastics from the ocean faster than they degrade?Some current plastic removal strategies involve accumulation via a system of booms, consisting of semicircular buoys fit with a fine mesh extending below the ocean surface (7, 10). These booms are positioned so that prevailing currents bring plastic to the boom, where it then accumulates. The currently envisioned approach is for a ship to steam to the boom system, collect plastic, and then return to port to offload and refuel before resuming collection activities.The time required for recovering plastics could be reduced if return trips to refuel and unload plastic were eliminated. Indeed, the harvested plastic has an energy density similar to hydrocarbon fuels; harnessing this energy to power the ship could thereby eliminate the need to refuel or unload plastic from the ship, reducing fossil fuel usage and potentially cleanup times.Self-powered harvesting may provide a way to accomplish cleanup using the passive boom collection approach at timescales less than environmental degradation. Unfortunately, cleanup itself is a moving target, as technology improves (7) and especially as plastic continues to accumulate. What is required, therefore, is a framework to evaluate the impact of self-powered harvesting on cleanup time and fuel usage. The framework can then be updated as more data becomes available.To be valuable, the cleanup framework must be reducible to practice using actual technology. A viable technology for converting plastics into a usable fuel is hydrothermal liquefaction (HTL), which utilizes high temperature (300 °C to 550 °C) and high pressure (250 bar to 300 bar) to transform plastics into monomers and other small molecules suitable as fuels (11–13). Oil yields from HTL are typically >90% even in the absence of catalysts and, unlike pyrolysis, yields of solid byproducts—which would need to be stored or burned in a special combustor—are less than 5% (11–13), thus conferring certain comparative advantages to HTL. Ideally, a vessel equipped with an HTL-based plastic conversion system could fuel itself, creating its fuel from recovered materials. The result could be termed “blue diesel,” to reference its marine origin and in contrast with both traditional marine diesel and “green diesel,” derived from land-based renewable resources (14).To make the HTL approach feasible, the work produced from the plastic must exceed that required by the process and, ideally, the ship’s engines so that fuel can be stockpiled during collection for later use. Exergy analysis provides a framework to determine the maximum amount of work that a complex process is capable of producing without violating the fundamental laws of thermodynamics (15). The reliability of an exergy analysis depends on the reliability of the data it uses as inputs, and key parameters describing HTL performance and ocean surface plastic concentration are currently not known with certainty. A rigorous and statistically meaningful analysis of shipboard plastic processing must therefore integrate uncertainty (16). Here, the Monte Carlo (MC) simulation method, which has proven its usefulness for similar types of analyses, is an appropriate tool for handling the uncertainties inherent in the current application (17) and allows for the integration of new information and data as further study of oceanic surface plastic is completed.Accordingly, the thermodynamic performance of a shipboard HTL process was evaluated to determine whether (and when) the process could provide sufficient energy to power itself plus the ship. A framework was then developed to evaluate the implications of shipboard plastic conversion on fuel use and cleanup times. The results provide valuable insight into the potential use of shipboard conversion technologies for accelerating removal of plastics from the ocean, and the framework should prove useful for guiding future work in this area.     

Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is characterized by dramatic premature aging and accelerated cardiovascular disease. HGPS is almost always caused by a de novo point mutation in the lamin A gene (LMNA) that activates a cryptic splice donor site, producing a truncated mutant protein termed "progerin." WT prelamin A is anchored to the nuclear envelope by a farnesyl isoprenoid lipid. Cleavage of the terminal 15 aa and the farnesyl group releases mature lamin A from this tether. In contrast, this cleavage site is deleted in progerin. We hypothesized that retention of the farnesyl group causes progerin to become permanently anchored in the nuclear membrane, disrupting proper nuclear scaffolding and causing the characteristic nuclear blebbing seen in HGPS cells. Also, we hypothesized that blocking farnesylation would decrease progerin toxicity. To test this hypothesis, the terminal CSIM sequence in progerin was mutated to SSIM, a sequence that cannot be farnesylated. SSIM progerin relocalized from the nuclear periphery into nucleoplasmic aggregates and produced no nuclear blebbing. Also, blocking farnesylation of authentic progerin in transiently transfected HeLa, HEK 293, and NIH 3T3 cells with farnesyltransferase inhibitors (FTIs) restored normal nuclear architecture. Last, treatment of both early- and late-passage human HGPS fibroblasts with FTIs resulted in significant reductions in nuclear blebbing. Our results suggest that treatment with FTIs represents a potential therapy for patients with HGPS.     

Pharmacodynamic profiling of antimicrobials against Gram-negative respiratory isolates from Canadian hospitals

BACKGROUND:

With diminishing antimicrobial potency, the choice of effective empirical therapy has become more challenging. Thus, the pharmacodynamic evaluation of potential therapies is essential to identify optimal agents, doses and administration strategies.

METHODS:

Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. Minimum inhibitory concentrations were obtained for Escherichia coli (n=64 respiratory isolates), Enterobacter cloacae (n=53), Klebsiella pneumoniae (n=75) and Pseudomonas aeruginosa (n=273) throughout Canada. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. A CFR ≥90% was defined as optimal.

RESULTS:

All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. Prolonged infusion doripenem and meropenem 1 g and 2 g every 8 h, along with standard infusion doripenem and meropenem 2 g every 8 h, were the only regimens to attain optimal exposures against P aeruginosa. Ciprofloxacin had the lowest CFR against P aeruginosa, followed by cefepime. Among the P aeruginosa isolates collected in the intensive care unit (ICU) compared with the wards, differences of 0.5% to 10% were noted in favour of non-ICU isolates for all agents; however, marked differences (10% to 15%) in CFR were observed for ciprofloxacin in favour of ICU isolates.

CONCLUSION:

Standard dosing of cefepime, doripenem, ertapenem and meropenem has a high likelihood of obtaining optimal pharmacodynamic indexes against these Enterobacteriaceae. For P aeruginosa, aggressive treatment with high-dose and/or prolonged infusion regimens are likely required to address the elevated resistance rates of respiratory isolates from Canada.     

Antibodies to nuclear lamin C in chronic hepatitis delta virus infection

Sera of patients with chronic hepatitis delta virus infection stained the nuclear periphery in indirect immunofluorescence. Using proteins of isolated nuclei, isolated nuclear matrices, the nuclear pore complex-lamina fraction and purified lamins A and C as antigen source in immunoblotting experiments, nuclear lamin C was identified as the reactive antigen. Most sera tested (8 of 10) recognized nuclear lamin C exclusively, but not the nuclear lamins A and B. Antibodies reacting with both nuclear lamins A and C, which share extensive sequence homologies, have been reported to occur in autoimmune hepatitis and primary biliary cirrhosis. The present findings suggest that the novel autoantibody associated with chronic hepatitis delta virus infection recognizes an epitope localized in the short carboxyterminal region of nuclear lamin C.     

Modeling and design by hierarchical natural moves

We develop a unique algorithm implemented in the program MOSAICS (Methodologies for Optimization and Sampling in Computational Studies) that is capable of nanoscale modeling without compromising the resolution of interest. This is achieved by modeling with customizable hierarchical degrees of freedom, thereby circumventing major limitations of conventional molecular modeling. With the emergence of RNA-based nanotechnology, large RNAs in all-atom representation are used here to benchmark our algorithm. Our method locates all favorable structural states of a model RNA of significant complexity while improving sampling accuracy and increasing speed many fold over existing all-atom RNA modeling methods. We also modeled the effects of sequence mutations on the structural building blocks of tRNA-based nanotechnology. With its flexibility in choosing arbitrary degrees of freedom as well as in allowing different all-atom energy functions, MOSAICS is an ideal tool to model and design biomolecules of the nanoscale.