Do patients return to sports and work after total shoulder replacement surgery?
Studies evaluating the return to sports and work after shoulder arthroplasty are rare, and there are no studies evaluating return to work after total shoulder arthroplasty (TSA). Patients undergoing TSA will be able to return to their preoperative sports levels and occupations. Case series; Level of evidence, 4. A total of 154 patients with 170 TSAs for primary glenohumeral arthritis were included. Two subgroups were formed: patients who had participated in sports during the 5 years before surgery (group 1; n = 105 [68%]) and patients who had never participated in sports (group 2; n = 49 [32%]). The return-to-work rate in patients who had not retired after surgery were also analyzed, as were responses to a survey. The mean age at the time of surgery was 71 years (range, 33-88 years) in group 1 and 76 years (range, 54-88 years) in group 2. Mean follow-up time was 6.2 years (range, 2.5-12.6 years). Fifty-seven patients (54%) in group 1 participated in sports right up to the time of surgery. All 57 (100%) returned to sports after surgery. A further 3 patients (3%) from group 1 resumed sporting activity after surgery; swimming was the most popular sport. No patient in group 2 started sports activity after shoulder replacement surgery. Many of the patients, 14% of the entire group, had retired by final follow-up because of TSA. Fourteen percent of patients in group 1 and group 2 were pursuing their work at the time of most recent follow-up. Thirty patients of the entire cohort (19.5%) had to change their occupations because of surgery. Patients who participated in sports before TSA were successfully able to return to sports activities after surgery. Patients who did not participate in sports just before surgery were unlikely to start sports after surgery. Fourteen percent of the entire cohort was able to return to work after surgery.


[Intraperitoneal chemotherapy of CDDP and etoposide in patients with advanced ovarian cancer].
Intraperitoneal disseminated ovarian cancer has a poor prognosis and its treatment is difficult. Recently, we undertook intraperitoneal chemotherapy (IP) of CDDP (Pt) and etoposide (Et) using an implantable reservoir. The subjects were 14 patients with advanced ovarian cancer. One hundred mg of Pt and 200 mg of Et were administered intraperitoneally through the reservoir, and the therapeutic results were evaluated. In 6 patients, levels of total platinum (t-Pt), free platinum (f-Pt) and Et were determined in the blood and intraperitoneal fluid by flameless atomic absorption spectrophotometry. 1. The 14 patients received 82 courses of IP. In 10 cases of IIIrd stage, no recurrence was detected in 5 radical operable cases, and 4 of 5 inoperable cases were able to undergo radical operation after IP. One case was inoperable even after IP. Recurrences were detected in 2 of 4 cases which subsequently became operable. In a case of IVth stage, remission was achieved, but the tumor markers began rising again 18 months after operation. No further recurrence was detected in a treated recurrence case. In 2 cases of metastatic cancer, recurrences were detected 3 and 7 months after operation, respectively. As a side effect, the incidence of gastrointestinal toxicities, anemia, leukocytopenia and alopecia was high, but the grade was almost 1 or 2. Intraperitoneal mean maximum concentrations were t-Pt: 21.98 +/- 5.78; f-Pt: 17.72 +/- 4.97; Et: 62.98 +/- 23.94 micrograms/ml. Blood mean maximum concentrations were t-Pt: 2.84 +/- 0.41; f-Pt: 0.84 +/- 0.22; Et: 11.38 +/- 2.12 micrograms/ml. Mean AUC of the blood were t-Pt: 57.76 +/- 6.62; f-Pt: 2.96 +/- 0.47; Et: 108.76 +/- 18.94 micrograms.h/ml. 2. IP is considered to be effective for advanced ovarian cancer not only as a local therapy but as a general therapy, and is feasible as maintenance therapy with the implantable reservoir and tolerable side effects.


Effect of propranolol on hypertonic saline-evoked masseter muscle pain and autonomic response in healthy women during rest and mental arithmetic task.
To investigate in a randomized, double-blinded, placebo controlled, crossover study the effect of a single dose of the nonselective β-adrenergic receptor antagonist propranolol (40 mg) on hypertonic saline (HS)-evoked masseter muscle pain and autonomic activity during rest and during a mental arithmetic task (Paced Auditory Serial Addition Task, PASAT). Sixteen healthy women participated in two sessions in which propranolol or placebo was administered orally prior to two 5-minute infusions (30 minutes apart) of HS in the masseter muscle. The second HS infusion was combined with PASAT. HS-evoked pain intensity was scored on a numeric rating scale (NRS, 0 to 10). Heart rate variability and hemodynamic measures were recorded noninvasively (Task Force Monitor). Data were analyzed with repeated measurements analysis of variance (ANOVA). Propranolol did not reduce NRS pain scores compared with placebo but did induce significant autonomic changes with reduced heart rate and increased heart rate variability (standard deviations of all normal RR intervals; root mean square successive differences; low-frequency power; high-frequency power; and total power) independent of the mental task. A single dose of propranolol had no effect on acute HS-evoked pain levels during rest or during mental arousal. However, it influenced the tone of the autonomic nervous system, possibly reflecting an anxiolytic effect.


Quantification of dissolved natural organic matter (DOM) mediated phototransformation of phenylurea herbicides in lakes.
For many important classes of pesticides including phenylurea herbicides (PUHs) and triazines, photosensitized transformation may be the only relevant elimination process in surface waters. In this study, the dissolved organic matter (DOM) mediated phototransformation of PUHs has been investigated in laboratory and field experiments. The results indicate that, in surface waters, the photosensitized transformation of PUHs may be significant and occurs primarily by an initial one-electron oxidation most likely involving excited triplet states of DOM (3DOM*) constituents. Using isoproturon and diuron as model compounds, it is shown that for a given DOM, quantum yield factors determined in the laboratory at a few selected wavelengths can be used to quantify the overall DOM- mediated phototransformation of a given PUH under sunlight irradiation. Furthermore, it is demonstrated that this process can be modeled for a given surface water, by applying the program GCSOLAR and a simple algorithm for cloud cover for quantification of average daily light intensities. Finally, the model has been successfully applied to predict vertical concentration profiles of isoproturon and diuron in a small lake in Switzerland. To our knowledge, this is the first study in which DOM-mediated phototransformation of organic pollutants has been quantitatively validated in the field.


Metastasis and neuroendocrine system in stressed mice.
The effects of experimental stressors have been examined for their differential effects on primary tumor growth and spontaneous lung metastasis in syngeneic mice bearing the weakly immunogenic tumor Lewis lung carcinoma. The effects caused by the early weaning, physical restraint and foot-shock are in general small, and affected by a high variability. On the contrary, spatial disorientation reproducibly causes a specific increase in tumor metastases. The effects of spatial disorientation are sensitive to the inhibition by treatment with bromocryptine and guanethidine, and particularly by a central and peripheral adrenergic neuron blocking agent reserpine. The use of different lighting conditions and assay of urinary melatonin excretion reveal an association between pineal gland function and effects of spatial disorientation on metastasis.


Photoswitchable Layer-by-Layer Coatings Based on Photochromic Polynorbornenes Bearing Spiropyran Side Groups.
Herein, we present the synthesis of linear photochromic norbornene polymers bearing spiropyran side groups (poly(SP-R)) and their assembly into layer-by-layer (LbL) films on glass substrates when converted to poly(MC-R) under UV irradiation. The LbL films were composed of bilayers of poly(allylamine hydrochloride) (PAH) and poly(MC-R), forming (PAH/poly(MC-R)) n coatings. The merocyanine (MC) form presents a significant absorption band in the visible spectral region, which allowed tracking of the LbL deposition process by UV-vis spectroscopy, which showed a linear increase of the characteristic MC absorbance band with increasing number of bilayers. The thickness and morphology of the (PAH/poly(MC-R)) n films were characterized by ellipsometry and scanning electron microscopy, respectively, with a height of ∼27.5 nm for the first bilayer and an overall height of ∼165 nm for the (PAH/poly(MC-R))5 multilayer film. Prolonged white light irradiation (22 h) resulted in a gradual decrease of the MC band by 90.4 ± 2.9% relative to the baseline, indicating the potential application of these films as coatings for photocontrolled delivery systems.


HR-MALDI-MS imaging assisted screening of β-carboline alkaloids discovered from Mycena metata.
Fruiting bodies of Mycena metata were screened for the presence of new secondary metabolites by means of HPLC-UV, LC-HR-ESIMS, and high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (HR-MALDI-MS imaging). Thus, a new β-carboline alkaloid, 6-hydroxymetatacarboline D (1d), was isolated from fruiting bodies of M. metata. 6-Hydroxymetatacarboline D consists of a highly substituted β-carboline skeleton, which is likely to be derived biosynthetically from l-tryptophan, 2-oxoglutaric acid, l-threonine, and l-proline. The structure of the alkaloid was established by 2D NMR spectroscopic methods and HR-ESIMS. Moreover, by extensive application of LC-HR-ESIMS, LC-HR-ESIMS/MS, and LC-HR-ESIMS(3) techniques we were able to elucidate the structures of a number of accompanying β-carboline alkaloids, 1a-1c, 1e-1i, and 2a-2g, structurally closely related to 6-hydroxymetatacarboline D, which are present in M. metata in minor amounts. The absolute configuration of the stereogenic centers of the β-carboline alkaloids was determined by GC-MS comparison with authentic synthetic samples after hydrolytic cleavage and derivatization of the resulting amino acids.


Korean atomic bomb survivors' report on the present status and health of their children: a mail questionnaire survey.
A mail questionnaire survey on the present status and health of children of Korean survivors of the 1945 atomic bombing of Japan was conducted in 2004. In total, 1,115 Korean A-bomb survivors' reports on demographic factors and the health of their children (n = 4,079) were analysed. In 2004, 293 of their children were reported to have died and 3,786 children still living. Among the deceased children, the cause of death was unidentified in 64 per cent of cases. The most frequently reported cause of death was infectious disease (9.6%). Most of the deaths (51%) were reported to have occurred in children less than ten years old. The most frequently reported congenital disorders among living children were mental retardation (0.18%) and congenital bone disorders (0.18%). Further study and administrative support are needed to more accurately determine the status of Korean A-bomb survivors and their children.


Excited Precursor Reactivity, Fast 1,2-H Shifts, and Diffusion-Controlled Methanol Insertion in 1,2-Diphenylalkylidenes.
The photochemistry of several arylalkyldiazo compounds has been investigated by steady-state direct and triplet sensitized irradiations and by nanosecond laser flash photolysis. Steady-state photolyses in methanol yielded methyl ethers and alkenes as the only significant products. Ethers were formed by denitrogenation of the diazo compound followed by carbene insertion into the MeO-H bond, and alkenes were obtained by 1,2-R (R = H,Ph) migrations both in the free carbene and in the singlet excited state of the diazo precursor. Evidence for the exited-state precursor reaction came from differences in product yields as a function of excitation wavelength and excited-state multiplicity. The yields of methyl ethers increased with increasing excitation wavelengths and were greatest upon triplet-state sensitization but were never the sole products formed despite expected diffusion-controlled insertion rates. Accordingly, the formation of pyridine ylides analyzed by laser flash photolysis in the presence of high concentrations of the base yielded relatively modest transient absorptions. The kinetics of the 1,2-H reaction, analyzed by time-resolved detection of stilbene in the case of 1,2-diphenylethylidenes, displayed fast and slow components. The fast component was attributed to stilbene that formed from the excited-state precursor and from the originally formed singlet carbene within the 20 ns pulse. The long-lived component was attributed to a spin-state equilibrated carbene with a lifetime of 70-80 ns in fluorocarbon solvents. Analysis of the long-lived component by a Stern-Volmer treatment upon addition of MeOH gave a lower limit for the reaction rate constant with a value of k1,2-H > 5 × 109 s-1 in a mixed Freon-methanol solvent. It is concluded that the combined effect of phenyl substituents at the carbon bearing the migrating group and high solvent polarity can lead to intramolecular 1,2-H shifts and 1,2-Ph migrations that are fast enough to compete with diffusion-controlled intermolecular MeO-H insertion in concentrated MeOH solutions.


Modeling spatial variation of brominates trihalomethane in a water distribution system of Ontario, Canada.
Conventional approaches to characterize and model the formation of trihalomethanes (THM) species in the distribution system use either residence time or water temperature. A significant deviation of THM levels were observed at the beginning and the end of a selected distribution system in Ontario, which may be because the consumption rate of residual chlorine is not constant in the distribution system. The approach developed in this study incorporates water temperature and proceeds with a trend and decomposition modeling method to incorporate the traveled distance and to explain the seasonal THM variation in the distribution system. The model has been tested and verified using a database from the Bettravia distribution system in Ontario, Canada. The deviations at the extremes of the distribution system were minimized due to the modeling technique used to develop the model and by including more factors that affect THM formation in the distribution system. The agreement between predicted and measured THM values at the beginning and the end of the distribution system is pronounced. The model presented in this paper is a robust tool that may be used by SDWAA to evaluate regulatory options and justify potential regulations regarding THM levels of the drinking water distribution system.


Brain-specific transcript variants of 5' and 3' ends of mouse VPS13A and VPS13C.
Mutations in vacuolar protein sorting 13A (VPS13A) gene are responsible for chorea-acanthocytosis (ChAc). We previously determined the full-length sequence and exon-intron structure of mouse VPS13A and generated a ChAc model mouse by using the gene targeting technique. In the process, we found diverse 5' and 3' transcript variants. Since ChAc is a rare neurodegenerative disorder, the mouse model should be useful for investigation of ChAc molecular pathogenesis, and the model's brain specific variants of VPS13A will be indispensable in these investigations. In the present study, we investigated mouse VPS13A transcript variants. We found brain-specific variants of mouse VPS13A, which may be involved in the brain-specific pathology of ChAc. In addition, we identified for the first time mouse VPS13C cDNA sequences and brain-specific variants of VPS13C.


Bovine spongiform encephalopathy surveillance in Argentina.
Bovine spongiform encephalopathy (BSE) is a new disease of cattle first described in the United Kingdom in November 1986. BSE belongs to the scrapie-related group of diseases. The epidemiological studies performed in the United Kingdom demonstrate that the BSE epidemic was caused by feeding cattle with ruminant-derived protein contaminated by a scrapie-like agent. Until June 1994, the disease had been detected in indigenous cattle in Ireland, Switzerland and France. Three cases reported in Germany, two in the Sultanate of Oman, and single cases in the Falkland Islands (Islas Malvinas), Denmark, Portugal and Canada occurred in animals imported from the United Kingdom. Several countries have implemented surveillance programmes analysing the risk factors involved in the epidemic. An analysis of risk factors conducted in Argentina shows that it is highly unlikely that BSE or scrapie exist in the country, or will arise via feed in the future. As a continuation of the analysis of risk factors, a surveillance programme was implemented in the field and in abattoirs. Specialised personnel were trained in the clinical, histopathological and biochemical detection of the disease through a network of laboratories which covered 85% of the total cattle population and 100% of the high-risk group (dairy cows over five years of age). By using a statistical procedure with reference to the bovine population in nine provinces, 1,019 brains from animals belonging to the high-risk group were selected and studied by histopathological and biochemical analyses for BSE detection. The results were negative in all cases. It can be concluded from this analysis (with a sensitivity of detection of 2.95 per 1,000, and 95% statistical confidence) that Argentina may be regarded as BSE-free, and that the importation of infected animals or by-products may represent the sole potential source of introduction of BSE infection into the country in the future.


[Electrical characteristics of the sensory neurons of the medical leech].
The electrical characteristics of three types of sensory neurons (N, T and P) were determined in the leech Hirudo medicinalis. Statistically significant differences were found between the values of tau, Cs and Rs in the neurons of N- and T-types. The same parameters show the least variation coefficients. The value of time constant (tau) is 17.000-46 ms, the resistivity of the soma membrane TRs) is 19.50 kphi-cm2 in T-neurons and 35 kphi-cm2 in N-neurons. The surface of the neurons estimated by their capacitance (Cs) can be 4-10 times larger than the surface of a sphere of the same size. The possible influence of electrical characteristics of the neurons on the peculiarities of their electrical reactions is discussed.


Clustering-neural network models for freeway work zone capacity estimation.
Two neural network models, called clustering-RBFNN and clustering-BPNN models, are created for estimating the work zone capacity in a freeway work zone as a function of seventeen different factors through judicious integration of the subtractive clustering approach with the radial basis function (RBF) and the backpropagation (BP) neural network models. The clustering-RBFNN model has the attractive characteristics of training stability, accuracy, and quick convergence. The results of validation indicate that the work zone capacity can be estimated by clustering-neural network models in general with an error of less than 10%, even with limited data available to train the models. The clustering-RBFNN model is used to study several main factors affecting work zone capacity. The results of such parametric studies can assist work zone engineers and highway agencies to create effective traffic management plans (TMP) for work zones quantitatively and objectively.


[Comparison of Atherosclerotic Lesions in Patients With Acute Myocardial Infarction and Stable Angina Pectoris Using Intravascular Ultrasound].
to compare noninfarct-related lesions in patients with acute myocardial infarction (MI) with culprit and non-culprit lesions in patients with stable angina pectoris (SAP) using intravascular ultrasound virtual histology (VH-IVUS). Overall 70 patients were enrolled: 38 with ST elevation (STE) MI and 32 with stable angina pectoris (SAP). All patients underwent three-vessel coronary angiography and gray-scale and VH-IVUS after percutaneous coronary intervention (PCI) of infarct-related lesion in STEMI or culprit lesion in SAP.


Randomized double blind trial comparing sotalol and propranolol in chronic ventricular arrhythmia.
Sotalol is a beta-blocker which also prolongs repolarization. Its relative efficacy towards suppressing chronic ventricular arrhythmia was tested by comparison with propranolol. This double blind parallel comparison study involved 30 patients with or without coronary artery disease who had chronic symptomatic ventricular arrhythmia and more than an average of 30 premature ventricular complexes (PVCs) per hour. After the placebo baseline period patients received four weeks of active treatment with sotalol or propranolol. Responders were patients who had 75% or more reduction of PVCs during 24 h Holter monitoring. One patient in each treatment group had intolerable side effects on a low dose of the drug and were withdrawn. Side effects were present more frequently in the propranolol group compared with sotalol. Proarrhythmic effects were present in one patient on sotalol. There was no significant difference in suppression of ventricular extrasystoles (sotalol 65%, propranolol 44%), with reduction in ventricular couplets being 99% for sotalol and 49% for propranolol. There was a significant increase in QTc in patients on sotalol. Therefore, sotalol is a well tolerated drug and may be preferable to propranolol for control of chronic ventricular arrhythmia.


Modeling subtype-selective agonists binding with alpha4beta2 and alpha7 nicotinic acetylcholine receptors: effects of local binding and long-range electrostatic interactions.
The subtype-selective binding of 14 representative agonists with alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs) has been studied by performing homology modeling, molecular docking, geometry optimizations, and microscopic and phenomenological binding free energy calculations. All of the computational results demonstrate that the subtype selectivity of the agonists binding with alpha4beta2 and alpha7 7 nAChRs is affected by both local binding and long-range electrostatic interactions between the receptors and the protonated structures of the agonists. The effects of the long-range electrostatic interactions are mainly due to the distinct difference in the net charge of the ligand-binding domain between the two nAChR subtypes. For the alpha4beta2-selective agonists examined, the microscopic binding modes with the alpha4beta2 nAChR are very similar to the corresponding modes with the alpha7 nAChR, and therefore, the subtype selectivity of these agonists binding with alpha4beta2 and alpha7 nAChRs is dominated by the long-range electrostatic interactions. For the alpha7-selective agonists, their microscopic binding modes with the alpha7 nAChR are remarkably different from those with the alpha4beta2 nAChR so that the local binding (including the hydrogen bonding and cation-pi interactions) with the alpha7 nAChR is much stronger than that with the alpha4beta2 nAChR. The calculated phenomenological binding free energies are in good agreement with available experimental data for the relative binding free energies concerning the subtype selectivity of agonists binding with the two different nAChR subtypes. The fundamental insights obtained in the present study should be valuable for future rational design of potential therapeutic agents targeted to specific nAChR subtypes.


Behavior change, environmental hazards and respiratory protection among a southern farm community.
The agricultural industry ranks as one of the most dangerous in terms of occupational deaths and injuries. A wide variety of respiratory illnesses can result from the exposure to grain and organic dusts and working in animal confinement facilities and barns. This article analyzes the Transtheoretical Model of Change for implications relevant to health promotion and education. This study explored differences of perception of occupational health, environmental exposures, and stages of change consistent with the readiness to take action and the confidence to act toward respiratory health among farmers who report respiratory symptoms with physical activity and those who do not. A convenience sample of 123 farm owners and agricultural employees recruited from community-based agricultural events in southeast and central Louisiana completed three surveys: (a) Health Risk and Environmental Assessment; (b) Identification of Respiratory Mask Use; (c) Stage of Awareness and Preventive Respiratory Health; and demographic information. Subjects performed pulmonary function tests including three Forced Vital Capacity (FVC) maneuvers while connected to a Renaissance spirometer. Even though the majority of subjects rated themselves in action stage of change, subjects reported using respiratory protective devices less than 10% of the time. No significant differences were found in environmental exposures. Using chi-square analysis, those farmers who reported breathlessness were significantly more likely to report fatigue, chest pain, and dizziness. Those farmers who report breathlessness are significantly less likely to perceive respiratory health as important compared to other occupational illnesses/conditions. There is a need for additional studies to further examine the relationship between respiratory symptoms, exposure risks, and behavior change theory.


Implicit memory: effects of network size and interconnectivity on cued recall.
Previous findings have indicated that the recall of a recently studied word is affected by how many associates it has in long-term memory (set size). The purpose of these experiments was to determine whether recall is also affected by the connectivity of these associates. Studied words were preselected to represent combinations of set size and connectivity and, in different experiments, recall was cued with extralist or intralist cues and with cues sharing few or many associates with the studied words. Effects of study time, encoding context, and levels of processing were also investigated. The results indicated that recall was more likely for words with smaller associative sets and for words with more interconnected sets of associates. These findings demonstrate that the recall of a recently presented word in the presence of a retrieval cue is affected by both the size and organization of its implicitly activated associative structure.


Anti-inflammatory effects of myristic acid mediated by the NF-κB pathway in lipopolysaccharide-induced BV-2 microglial cells.
Parkinson's disease (PD) is a serious neurodegenerative disorder wherein changes in metabolites related to lipids, glutathione, and energy metabolism occur. Currently, metabolite changes in PD have been reported, yet their role in the prognosis of disease remains poorly understood. Functional metabolites can be used to diagnose diseases, especially PD, and can exert neuroprotective effects. This study used a PD animal model and a lipopolysaccharide (LPS)-mediated inflammatory response model (using the BV-2 mouse microglial cell line) to identify functional metabolites that can identify important metabolic disorders during PD, and comprehensively evaluated their profiles using a metabolomics-based approach. Our results showed that co-treatment with myristic acid and heptadecanoic acid downregulated the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in BV-2 cells. Additionally, myristic acid and 10 μM heptadecanoic acid significantly inhibited the LPS-induced inflammatory response through the nuclear factor-κB pathway in BV-2 microglial cells, which provides a potential approach for PD treatment. Myristic acid and heptadecanoic acid were the active metabolites found by active metabolomics technology, but at present, there is no research report about their function for PD treatment, and our findings offer a novel research strategy for PD diagnosis and treatment.


A new mode of swimming in singly flagellated Pseudomonas aeruginosa.
SignificanceThe monotrichous Pseudomonas aeruginosa was usually thought to swim in a pattern of "run and reverse" (possibly with pauses in between), where straight runs alternated with reverses with angular changes of swimming direction near 180°. Here, by simultaneously tracking the cell swimming and the morphology of its flagellum, we discovered a swimming mode in P. aeruginosa-the wrap mode, during which the flagellar filament wrapped around the cell body and induced large fluctuation of the body orientation. The wrap mode randomized swimming direction, resulting in a broad distribution of angular changes over 0 to 180° with a peak near 90°. This allowed the bacterium to explore the environment more efficiently, which we confirmed by stochastic simulations of P. aeruginosa chemotaxis.


Diverse effects of RacV12 on cell transformation by Raf: partial inhibition of morphological transformation versus deregulation of cell cycle control.
Activated Raf kinases and Rac GTPases were shown to cooperate in the oncogenic transformation of fibroblasts, which is characterised by the disassembly of the cellular actin cytoskeleton, a nearly complete loss of focal adhesion complexes and deregulated cell proliferation. This is surprising since the Rac GTPase induces actin structures and the adhesion of suspended cells to extracellular matrix proteins. NIH 3T3 cells expressing a hydroxytamoxifen-inducible oncogenic c-Raf-1-oestrogen receptor fusion protein (c-Raf-1-BxB-ER, N-BxB-ER cells) undergo morphological transformation upon stimulation of the Raf kinase. We show that treatment with the Rac, Rho and Cdc42 activating Escherichia coli toxin CNF1 or coexpression of an activated RacV12 mutant partially inhibits and reverses the disassembly of cellular actin structures and focal adhesion complexes by oncogenic Raf. Activation of the Rac GTPase restores actin structures and focal adhesion complexes at the cellular boundary, leading to spreading of the otherwise spindle-shaped Raf-transformed cells. Actin stress fibres, however, which are regulated by the function of the Rho GTPase, are disassembled by oncogenic Raf even in the presence of activated Rac and Rho. With respect to the RacV12-mediated spreading of Raf-transformed cells, we postulate an anti-oncogenic function of the activated Rac. Another feature of cell transformation is the deregulation of cell cycle control. NIH 3T3 cells expressing high levels of the c-Raf-1-BxB-ER protein undergo a cell cycle arrest upon stimulation of the oncogenic Raf kinase. Our results show that in N-BxB-ER-RacV12 cells the expression of the activated RacV12 mediates cell proliferation in the presence of high-intensity Raf signals and high levels of the Cdk inhibitor p21(Cip1). These results indicate a pro-oncogenic function of the Rac GTPase with respect to the deregulation of cell cycle control.


Solvent-induced structural dynamics in noninterpenetrating porous coordination polymeric networks.
Three novel soft porous coordination polymer (PCP) or metal-organic framework (MOF) compounds have been synthesized with a new rigid ligand N-(4-pyridyl)-1,4,5,8-naphathalenetetracarboxymonoimide (PNMI) by partial hydrolysis of N,N'-di-(4-pyridyl)-1,4,5,8-naphthalenete-tracarboxydiimide (DPNI) during solvothermal reactions with Zn(II), Cd(II), and Mn(II) salts, and they are [Zn(PNMI)]·2DMA (1·2DMA, 1a), [Cd(PNMI)]·0.5DMA·5H2O (2·0.5DMA·5H2O), and [Mn(PNMI)]·0.75DMF (3·0.75DMF). The structure of 1 is based on paddle-wheel secondary building unit (SBU) with a 3,6-connected rtl net topology, whereas 2 and 3 are isotypical but the M(O2C-C)2 fragments aggregate in one-dimension and the overall connectivity is the same rtl net topology. All these three MOFs have one-dimensional rhombic channels filled with guest molecules. The guest molecules in 1a can be exchanged with EtOH in a single-crystal to single-crystal (SCSC) manner to 1·1.25EtOH·0.375H2O (1b). Further, the guest molecules in 1b can be replaced with ethylene glycol, triethylene glycol and allyl alcohol without destroying its single crystal nature. These guest exchanges are accompanied by reduction in volume of the unit cell up to 16%, as well as the void volume up to 33.1%. Similarly, triethylene glycol (TEGly) selectively exchanges EtOH in a mixture of the above solvents, which might be the result of correct fit of the hydrogen-bonded TEGly dimer in the channel of 1. While activated 1 and 3 exhibit no uptake of N2 and H2 at 1 bar and 77 K and very low uptake of CO2 gas at 1 bar and 196 K, activated 2 shows selective CO2 uptake, 278 cm(2)·g(-1), over N2 and H2 at 1 bar and 196 K, which corresponds to 5.87 molecules of CO2 per formula unit of 2.


Cep169, a Novel Microtubule Plus-End-Tracking Centrosomal Protein, Binds to CDK5RAP2 and Regulates Microtubule Stability.
The centrosomal protein, CDK5RAP2, is a microcephaly protein that regulates centrosomal maturation by recruitment of a γ-tubulin ring complex (γ-TuRC) onto centrosomes. In this report, we identified a novel human centrosomal protein, Cep169, as a binding partner of CDK5RAP2, a member of microtubule plus-end-tracking proteins (+TIPs). Cep169 interacts directly with CDK5RAP2 through CM1, an evolutionarily conserved domain, and colocalizes at the pericentriolar matrix (PCM) around centrioles with CDK5RAP2. In addition, Cep169 interacts with EB1 through SxIP-motif responsible for EB1 binding, and colocalizes with CDK5RAP2 at the microtubule plus-end. EB1-binding-deficient Cep169 abolishes EB1 interaction and microtubule plus-end attachment, indicating Cep169 as a novel member of +TIPs. We further show that ectopic expression of either Cep169 or CDK5RAP2 induces microtubule bundling and acetylation in U2OS cells, and depletion of Cep169 induces microtubule depolymerization in HeLa cells, although Cep169 is not required for assembly of γ-tubulin onto centrosome by CDK5RAP2. These results show that Cep169 targets microtubule tips and regulates stability of microtubules with CDK5RAP2.


Undergraduate education in primary care: the Rockford experience.
Four years of experience with an undergraduate program in primary care in a new community-based medical school are described. Students are intimately involved over a two-and-a-half-year period in the delivery of primary care in rural and semi-rural community health centers. Despite problems of financing and, especially, faculty recruitment and development, the program has been enthusiastically endorsed by students and patients and appears to represent a viable new model for medical education.


The role of dietary factors in prevention and progression of breast cancer.
Breast cancer (BC) is the leading global cause of cancer-related death in women. There is growing evidence for a role for dietary factors in BC pathophysiology. The aim of the present review was to evaluate the impact of dietary factors in BC risk. Bibliographical searches were performed in PubMed, using the following terms: "nutrition and breast cancer", "nutrition and breast carcinoma", "dietary factors and breast cancer", "risk factors and breast cancer", "diet and breast cancer, "breast cancer epidemiology", "breast cancer and prevention". Consumption of well-done red meat appears to be associated with increased risk of BC, whereas fish may be protective. Total cholesterol, triglyceride levels and glycaemic load should be monitored and controlled in at risk populations because they may be associated with increased risk of BC, although the exact mechanisms involved are not clear. Alcohol intake should be minimized since it is a risk factor for BC. High intake of polyphenol/phyto-oestrogen -rich food (i.e. flavonoids, soya products), as well as fibres, fruits and vegetables, may have potential protective effects against BC occurrence but the results might vary according to hormonal status. Vitamin D supplements appear protective against BC development and similarly other vitamins and oligo-elements might decrease BC risk, although further large prospective studies are required. There exist increasing evidence that dietary factors can play an important role in both the development and prevention of BC. Large randomized clinical and epidemiological studies are required but are difficult to design due to the number of variable factors.


Fast estimation of crystal densities.
A simple, efficient and accurate method for the estimation of crystal densities is of interest for different applications. By analysis of the Cambridge Structural Database (CSD) we derived an average atom volume method to estimate the cell volume for a given formula and Z value. This method extends the work of Mighell et al. (1987) by inclusion of the thermal expansion and error estimation.


Evidence and mapping of extinction debts for global forest-dwelling reptiles, amphibians and mammals.
Evidence of extinction debts for the global distributions of forest-dwelling reptiles, mammals and amphibians was tested and the debt magnitude was estimated and mapped. By using different correlation tests and variable importance analysis, the results showed that spatial richness patterns for the three forest-dwelling terrestrial vertebrate groups had significant and stronger correlations with past forest cover area and other variables in the 1500 s, implying the evidence for extinction debts. Moreover, it was likely that the extinction debts have been partially paid, given that their global richness patterns were also significantly correlated with contemporary forest variables in the 2000 s (but the absolute magnitudes of the correlation coefficients were usually smaller than those calculated for historical forest variables). By utilizing species-area relationships, spatial extinction-debt magnitudes for the three vertebrate groups at the global scale were estimated and the hotspots of extinction debts were identified. These high-debt hotspots were generally situated in areas that did not spatially overlap with hotspots of species richness or high extinction-risk areas based on IUCN threatened status to a large extent. This spatial mismatch pattern suggested that necessary conservation efforts should be directed toward high-debt areas that are still overlooked.


Multiple Patterns of Regulation and Overexpression of a Ribonuclease-Like Pathogenesis-Related Protein Gene, OsPR10a, Conferring Disease Resistance in Rice and Arabidopsis.
An abundant 17 kDa RNase, encoded by OsPR10a (also known as PBZ1), was purified from Pi-starved rice suspension-cultured cells. Biochemical analysis showed that the range of optimal temperature for its RNase activity was 40-70°C and the optimum pH was 5.0. Disulfide bond formation and divalent metal ion Mg2+ were required for the RNase activity. The expression of OsPR10a::GUS in transgenic rice was induced upon phosphate (Pi) starvation, wounding, infection by the pathogen Xanthomonas oryzae pv. oryzae (Xoo), leaf senescence, anther, style, the style-ovary junction, germinating embryo and shoot. We also provide first evidence in whole-plant system, demonstrated that OsPR10a-overexpressing in rice and Arabidopsis conferred significant level of enhanced resistance to infection by the pathogen Xoo and Xanthomona campestris pv. campestris (Xcc), respectively. Transgenic rice and Arabidopsis overexpressing OsPR10a significantly increased the length of primary root under phosphate deficiency (-Pi) condition. These results showed that OsPR10a might play multiple roles in phosphate recycling in phosphate-starved cells and senescing leaves, and could improve resistance to pathogen infection and/or against chewing insect pests. It is possible that Pi acquisition or homeostasis is associated with plant disease resistance. Our findings suggest that gene regulation of OsPR10a could act as a good model system to unravel the mechanisms behind the correlation between Pi starvation and plant-pathogen interactions, and also provides a potential application in crops disease resistance.


Expert Opinion on the Management of Acute and Chronic Cough: An Indian Perspective in Primary Care Setting.
Cough is the body's reflex when the throat or airway is irritated by a foreign body, such as irritants, microbes, and fluids. Cough caused due to a disorder or infection can last for a few days to a couple of weeks and is usually self-limiting and self-resolving. However, in certain cases, cough can persist for months, disrupting everyday activities, affecting the patient's mental health, and causing pain and fatigue. There are a number of different therapeutic strategies to manage acute and chronic cough, depending on the cause. Dry cough can be treated using opioids, nonopioids, antitussives, and antihistamines. Expectorants and mucolytics are widely used in the management of productive cough. The underlying cause of cough should be appropriately managed with specific therapy. The choice of treatment regimen is dependent on the patient's medical history, symptoms, and preexisting conditions. Based on the literature review and clinical practice, a comprehensive approach to the management of cough as a symptom has been proposed.


Molecular analysis of multi-drug resistant Salmonella typhi from urban paediatric population of Bangladesh.
The prevalence and genetic basis of resistance of multi-drug resistant (MDR) S typhi strains from an urban paediatric population was determined. Blood cultures performed on 109 cases of suspected typhoid fever yielded 30(27.5%) S typhi isolates. Of these, 20(67%) S typhi isolates were resistant to the common antimicrobials used in Bangladesh, eg, chloramphenicol, ampicillin, cotrimoxazole, streptomycin and tetracycline, while 6(20%) isolates were resistant only to streptomycin. However, all the isolates were sensitive to fluquinolones and cephalosporins. Molecular analysis demonstrated that all MDR strains possessed a single large transferable 98 MDal plasmid. On conjugation, chloramphenicol, ampicillin and cotrimoxazole resistance was transferred from MDR strains to E coli K-12. Restriction endonuclease analysis of plasmid DNA showed similar digest profiles of all 5 selected donors and their transconjugants. This trend of increasing resistant strains of S typhi, especially by the transferable plasmid is of major public health concern.


Should we treat severe vasovagal syncope with a pacemaker?
Cardiac pacing for vasovagal syncope (VVS) addresses the cardioinhibitory component of the reflex but cannot directly affect vasodepression, which occurs in every reflex even when hidden by dominant cardioinhibition. The randomized controlled trials of pacing in VVS have, after almost 2 decades, determined that a small number of patients can benefit because their vasodepressor component is not severe. Early studies compared pacing with no therapy yielding highly significant benefits. Subsequently, all study patients had implanted devices with half being switched off. No benefit was seen. The ISSUE-3 study found significant benefit (P < 0.039) in prevention of syncope recurrence in older patients. A sub-study later showed those with negative tilt tests, otherwise indistinguishable from tilt-positives, had 5% recurrence in 21 months (P < 0.004). There is acceptance that pacing must be dual chamber, but the question of how pacing is delivered remains open. Relying on falling heart rate is insufficient, probably because it occurs too late. Other algorithms which indirectly detect neuroendocrine changes earlier than heart rate fall may have useful application. In clinical terms, the patient to be considered for pacing should not be young and have severe symptoms. Ideally, tilt testing should be negative implying vasodepression of lesser severity and, therefore, yielding fewer syncope recurrences. When selecting pacing, additional concern must be given to regression to the mean of symptoms, severe to less severe. Patients seek help when they are at their worst. Moreover, many years of pacing are unlikely to be free of complications related to implanted hardware.


Testicular changes during infantile 'quiescence' in the marmoset and their gonadotrophin dependence: a model for investigating susceptibility of the prepubertal human testis to cancer therapy?
Inexplicably, boys treated with some therapies for cancer at age 2-10 years, a time of supposed 'testicular quiescence', are at risk of low sperm counts/infertility in adulthood. Our aims were to use the marmoset as a surrogate for man to establish testicular cell function/activity during 'quiescence' between the neonatal period and puberty, and to test if any cell activity could be suppressed by prior treatment with a GnRH antagonist. Based on immunoexpression studies, functional development of Sertoli cells (SGP-2, androgen receptor) and Leydig cells (3 beta-hydroxysteroid dehydrogenase) was detectable at an age (35 weeks) when the testis is considered to be quiescent, and in advance of the pubertal rise in blood testosterone levels (50-60 weeks). Other changes at 35 weeks were the appearance of focal seminiferous tubule lumens and proliferating germ cells [indicated by immunoexpression of proliferating cell nuclear antigen (PCNA)]. Treatment from 25 to 35 weeks with GnRH antagonist largely (>85%) prevented these changes. However, the PCNA-labelling index of spermatogonia in GnRH antagonist-treated animals did not differ from controls (41.3 versus 43.6%) though total spermatogonia volume per testis was reduced by 41%. Some protein markers (inhibin-alpha, estrogen receptor-beta) showed little change with age or treatment. Beyond 35 weeks, GnRH antagonist-treated animals showed a delay in the pubertal rise in plasma testosterone levels. These findings reinforce the view that the 'childhood' testis is not quiescent. This may explain the damaging effects of some cancer therapies on subsequent fertility of boys and raises the issue of protective intervention. The present studies suggest that GnRH antagonist-based intervention might be only partially successful. Identification of the factors regulating spermatogonial development in the infant marmoset may aid in the design of such strategies.


Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N.
Vacuolar protein sorting 35 (VPS35) is a core component of the retromer complex, crucial to endosomal protein sorting and intracellular trafficking. We recently linked a mutation in VPS35 (p.D620N) to familial parkinsonism. Here, we characterize human VPS35 and retromer function in mature murine neuronal cultures and investigate neuron-specific consequences of the p.D620N mutation. We find VPS35 localizes to dendritic spines and is involved in the trafficking of excitatory AMPA-type glutamate receptors (AMPARs). Fundamental neuronal processes, including excitatory synaptic transmission, AMPAR surface expression and synaptic recycling are altered by VPS35 overexpression. VPS35 p.D620N acts as a loss-of-function mutation with respect to VPS35 activity regulating synaptic transmission and AMPAR recycling in mouse cortical neurons and dopamine neuron-like cells produced from induced pluripotent stem cells of human p.D620N carriers. Such perturbations to synaptic function likely produce chronic pathophysiological stress upon neuronal circuits that may contribute to neurodegeneration in this, and other, forms of parkinsonism.


Definers and drivers of functional high-risk multiple myeloma: insights from genomic, transcriptomic, and immune profiling.
Traditional prognostic models for newly diagnosed patients with multiple myeloma (MM), including International Staging System criteria and number of high-risk chromosomal abnormalities, are based on disease characteristics at diagnosis. However, the identification of patients at risk of more rapidly progressive MM is inherently a dynamic assessment. In a subset of patients with MM, adverse disease biology only becomes evident after the failure of first-line therapy. We define this entity as functional high-risk MM (FHRMM), encompassing relapse within 18 months of treatment initiation and/or within 12 months of frontline autologous stem cell transplantation. FHRMM is not adequately captured by traditional prognostic models, and there is a need for better understanding of mechanisms or risk factors for early relapse or progression. In this review, we explore potential definitions of FHRMM before delving into its underlying drivers based on genetic, transcriptomic, and immune cell profiling studies. Emerging data suggest that specific features of both myeloma cells and immune cells can enable the FHRMM phenotype. We conclude our review by discussing ongoing and future studies that seek to identify and intervene upon patients with FHRMM preemptively.


The value of laparoscopy in the management of ampullary, duodenal, and distal bile duct tumors.
Laparoscopy identifies radiologically occult advanced disease in patients with pancreatic adenocarcinoma. The value of laparoscopy in the management of peri-ampullary tumors was determined. One hundred forty-four patients with radiologically resectable nonpancreatic adenocarcinoma, periampullary tumors were identified from a prospective database between August 1993 and December 2000. Criteria for laparoscopic unresectability included histologically proved peritoneal or hepatic metastases, distant nodal involvement, arterial involvement, and local extension outside the resection field. Median age at operation was 70 years (range 31 to 87 years) and 56% of the patients were men. An adequate laparoscopy was performed in 134 cases (93%). Laparoscopy identified 13 patients (10%) with unresectable disease. Of 121 patients with laparoscopic resectable disease, 111 (92%) went on to subsequent resection; CT correctly predicted resectability in 82%. Laparoscopy spared 36% of unresectable patients a nontherapeutic laparotomy. Patients with resectable disease were treated by pancreaticoduodenectomy (n = 91, 76%), ampullectomy (n = 12, 10%), duodenal resection (n = 10, 9%), or bile duct excision (n = 6, 5%). The addition of diagnostic laparoscopy to dynamic CT scanning in this selected patient population identifies an additional 10% of patients with unresectable disease. We believe that laparoscopy should be used in a selective manner for preoperative staging of patients suspected of having nonpancreatic periampullary tumors.


An analysis of the stimulus requirements for setting the molecular switch reveals a lower threshold for metaplasticity than synaptic plasticity.
The requirements for the synaptic activation of metabotropic glutamate (mGlu) receptors and for the induction of metaplasticity in the hippocampus are not known. In the present study, we have investigated the synaptic activation of mGlu5 receptors and the setting of the molecular switch, a form of metaplasticity, at CA1 synapses in the mouse hippocampus. We find that as few as eight stimuli (delivered at 100Hz) are sufficient to set the molecular switch, since a subsequent tetanus delivered to the same input is able to induce long-term potentiation (LTP) in the presence of the mGlu receptor antagonist MCPG ((S)-alpha-methyl-4-carboxyphenylglycine). In addition, we find that the molecular switch can be activated over a wide frequency range. When 10 shocks were delivered the threshold frequency was 4Hz. The ability of 10 shocks (delivered at 100Hz) to set the molecular switch was lost in the mGlu5 knockout. These data show that mGlu5 receptors can be activated synaptically and metaplasticity can be induced by relatively few stimuli. Indeed, metaplasticity was induced by stimuli that were subthreshold for the induction of LTP per se. Thus, metaplasticity has a lower threshold than the synaptic plasticity that it regulates.


Prognostic potential of body composition indices in detecting risk of musculoskeletal injury in army officer cadet profiles.
High values in most of the body composition indices have been related to musculoskeletal injuries, but limited data exists on the accuracy of these diagnoses when detecting musculoskeletal injuries in military populations. The suitability of body fat percentage, body mass index, fat mass index and fat free mass index to identify injury risk was examined in a group of army officer recruits. All body composition diagnoses were measured in 268 male army officer recruits prior to the commencement of basic combat training. Musculoskeletal injury was identified using codes from the International Classification of Diseases. The area under the curve, in the receiver operating characteristic curve, was used to quantify the overall ability to discriminate between those who were injured and those who were not. The statistics indicated that all indices, apart from body mass index, had a significant possibility to detect musculoskeletal injury potential (p < 0.05; 61%-63%). The respective cut-off points used to classify individuals as injured were for body fat percentage >22, for fat mass index >6.5 and for fat free mass index <16.5. Body mass index values can not similarly detect the possibility of occurrence of musculoskeletal injuries in army officer recruits, just as other body composition diagnoses related to fat mass or/and free fat mass. However, the cut off-points related to the overall diagnostic performance of each body composition index should be used with caution and in accordance with the aims of each experimental setting.


The WRKY transcription factor, WRKY13, activates PDR8 expression to positively regulate cadmium tolerance in Arabidopsis.
Cadmium (Cd) extrusion is an important mechanism conferring Cd tolerance by decreasing its accumulation in plants. Previous studies have identified an Arabidopsis ABC transporter, PDR8, as a Cd extrusion pump conferring Cd tolerance. However, the regulation of PDR8 in response to Cd stress is still largely unknown. In this study, we identified an Arabidopsis cadmium-tolerant dominant mutant, designated xcd3-D, from the XVE-tagging T-DNA insertion lines by a gain-of-function genetic screen. The corresponding gene was cloned and shown to encode a nuclear WRKY transcription factor WRKY13. Expression of WRKY13 was induced by Cd stress. Overexpression of WRKY13 resulted in decreased Cd accumulation and enhanced Cd tolerance, whereas loss-of-function of WRKY13 led to increased Cd accumulation and sensitivity. Further analysis showed that WRKY13 activates the transcription of PDR8 by directly binding to its promoter. Genetic analysis indicated that WRKY13 acts upstream of PDR8 to positively regulate Cd tolerance. Our results provide evidence that WRKY13 directly targets PDR8 to positively regulate Cd tolerance in Arabidopsis.


Transcranial sonography in patients with Parkinson's disease with glucocerebrosidase mutations.
The aim of this study was to search for possible differences in the findings of transcranial sonography (TCS) between groups of patients with glucocerebrosidase (GBA)-associated Parkinson's disease (PD) (4 patients with Gaucher disease type 1 and parkinsonism [GD+PD+] and 18 PD patients with heterozygous GBA mutations; [GBA+PD+]) and groups of 12 patients with Gaucher disease type 1 and no signs of parkinsonism (GD+PD-), 9 asymptomatic carriers of heterozygous GBA mutations (GBA+PD-), 32 sporadic PD patients (sPD), and 43 healthy controls. In all groups of patients, except asymptomatic carriers of heterozygous GBA mutations (mean ± SD: 0.16 ± 0.03 cm(2)), the maximal areas of substantia nigra hyperechogenicity (aSN-max) was higher (GD+PD+: 0.28 ± 0.15 cm(2); GD+PD-: 0.18 ± 0.06 cm(2); GBA+PD+: 0.27 ± 0.06 cm(2); sPD: 0.28 ± 0.10 cm(2)) when compared to controls (0.12 ± 0.08 cm(2)) (p = 0.001). In GBA-associated PD (GD+PD+ and GBA+PD+) and sPD, aSNmax values were very similar. Moderate or marked SN hyperechogenicity was present in 87.5% of sPD patients and in 83% of PD patients with heterozygous GBA mutations, but in only 11.6% of controls, and in 22.2% and 33.3% of patients from GBA+PD- and GD+PD- groups, respectively (p < 0.001). The prevalence of interrupted or missing echogenicity of the brainstem raphe differed between the groups (p = 0.046), while no difference was observed in the diameter of the third ventricle. TCS findings in GBA-associated PD were consistent to those of patients with sporadic PD.


Acute pancreatitis and cytokines: "second attack" by septic complication leads to organ failure.
Acute pancreatitis is accompanied by destruction and digestion of tissues, causing hypercytokinemia and hyperreactivity of leukocytes (macrophages and neutrophils) and vascular endothelial cells. As one of the biological defense mechanisms in this condition, neutrophils infiltrate vital organs such as the lung, liver, and digestive organs. When acute pancreatitis is complicated by infection, hyperreactive macrophages release a large amount of proinflammatory cytokines that activate primed neutrophils, as a "second attack." Utilizing proteolytic enzymes and oxidant, neutrophils injure the infiltrated vital organs, causing cellular damage and dysfunction of vital organs distant from the pancreas. Multiple organ failure in acute pancreatitis with septic complications can develop, at least in part, by proinflammatory cytokine release and neutrophil activation.


Free-Energy-Driven Lock/Open Assembly-Based Optical DNA Sensor for Cancer-Related microRNA Detection with a Shortened Time-to-Result.
Quantification of cancer biomarker microRNAs (miRs) by exquisitely designed biosensors with a short time-to-result is of great clinical significance. With immobilized capture probes (CPs) and fluorescent-labeled signal probes (SPs), surface-involved sandwich-type (SST) biosensors serve as powerful tools for rapid, highly sensitive, and selective detection of miR in complex matrices as opposed to the conventional techniques. One key challenge for such SST biosensors is the existence of false-negative signals when the amount of miRs exceeds SPs in solution phase for a surface with a limited number of CP. To meet this challenge, a dynamic lock/open DNA assembly was designed to rationally program the pathway for miR/SP hybrids. Based on secondary structure analysis and free-energy assessment, a "locker" strand that partially hybridizes with target miR by two separated short arms was designed to stabilize target miR, preventing possible false-negative signals. The strategy was demonstrated on a fiber-based fluorescent DNA-sensing platform. CP/miR/SP sandwiches formed on the fiber surface would generate fluorescent signals for quantitative analysis. The developed SST biosensor was able to detect miR Hsa let-7a with a detection limit of 24 pM. The applicability of this free-energy-driven lock/open assembly-based optical DNA sensor was further confirmed with spiked human urine and serum samples.


Importance of comparison of current and prior mammograms in breast cancer screening.
To retrospectively determine the influence of comparing current mammograms with prior mammograms on breast cancer detection in screening and to investigate a protocol in which prior mammograms are viewed only when necessary. Institutional review board approval was not required. Participants gave written informed consent. Twelve experienced screening radiologists read 160 soft-copy screening mammograms twice, once with and once without prior mammograms. Eighty mammograms were obtained in women in whom breast cancer was diagnosed later; the other 80 mammograms had been reported as normal or benign. All cancers were visible in retrospect. Readers located potential abnormalities, estimated likelihood of malignancy for each finding, and indicated whether prior mammograms were considered necessary. The effect of prior mammograms on detection was determined by computing the mean lesion localized fraction in a range of low fractions of nonlesion locations corresponding to operating points in screening. Scores for both reading sessions were combined to assess the effect of making prior mammograms available only when requested. Data were analyzed by comparing the number of localized lesions between the two reading conditions with a paired two-tailed Student t test and applying a linear mixed model to test differences in average mean lesion localized fraction between reading conditions. P values less than .05 indicated statistical significance. Without prior mammograms, significantly more annotations were made. When only positive cases were considered, no difference was observed. Reading performance was significantly better when prior screening mammograms were available. At fixed lesion localized fraction, nonlesion localized fraction was reduced by 44% (P<.001) on average when prior mammograms were read. Performance was also increased for combined reading mode (ie, when prior mammograms were available on request only). However, this increase was smaller than that when prior mammograms were always available. Prior mammograms were requested in 24%-33% of all cases and were requested more often in positive cases. Comparison with prior mammograms significantly improves overall performance and can reduce referrals due to nonlesion locations. Limiting the availability of prior mammograms to cases selected by the reader reduces the beneficial effect of prior mammograms.


Diarrheagenic Escherichia coli categories among the traditional enteropathogenic E. coli O serogroups--a review.
The so called enteropathogenic Escherichia coli (EPEC) O serogroups include typical and atypical EPEC, enterohaemorrragic E. coli, enterotoxigenic E. coli, and enteroaggregative E. coli. The aim of this article is to review the composition of each O serogroup and the major serotypes, clones, and additional virulence characteristics of each of these diarrheagenic categories. Their adherence patterns and genetic relationships are also presented. The review is based on the study of 805 strains of serogroups O26, O55, O86, O111, O114, O119, O125, O126, O1127, O128, and O142 most of which isolated in Sao Paulo from children with diarrhea between 1970 and 1990. Since some O serogroups include more than one diarrheagenic category O serogrouping only should be abandoned as a diagnostic method. However serotyping is a reliable method for those serotypes that correspond to clones.


A new route to multifunctionalized p-terphenyls and heteroaryl analogues via [5C + 1C(N)] annulation strategy.
p-Terphenyls and heteroaryl analogues including bipyridines were prepared via [5C + 1C(N)] annulation of alpha-aryl-alpha-alkenoyl ketene-(S,S)-acetals (five carbon 1,5-bielectrophilic species) with nitroethane or ammonium acetate. The reaction features mild conditions, multisubstitution, and functional group tolerance and is metal catalyst free. The present protocol provides a new alternative to the conventional methodologies for the synthesis of teraryls.


Hydrosonographic Assessment of the Effect of Two Different Suture Materials on Healing of the Uterine Scar after Cesarean Delivery: A Prospective Randomized Controlled Trial.
This study aimed to compare the effects of two different suture materials, monofilament synthetic absorbable sutures versus multifilament synthetic absorbable sutures, on healing the uterine scar after a cesarean delivery. A total of 95 women between the ages of 18 and 40 who had undergone a primary cesarean section (CS) after the 38th week of gestation. In Group I (n=48), continuous double-layer unlocked closure of the low transverse uterine incision was performed using monofilament synthetic absorbable sutures. In Group II (n=47), continuous double-layer unlocked closure of the low transverse uterine incision was performed using multifilament synthetic absorbable sutures. Six months after the operation, the integrity of the cesarean scar at the uterine incision site was assessed using hydrosonography. The healing ratio and the thickness of the residual myometrium covering the defect were calculated as markers of uterine scar healing. No statistically significant differences were observed between the groups with regard to the preoperative hemoglobin concentrations, the change in the hemoglobin concentrations, operating time, and the number of intraoperative additional hemostatic uterine sutures. Mean thickness of the residual myometrium covering the defect was thicker in the monofilament suture group in comparison to the multifilament suture group (7.76±2.11 vs. 5.96±1.69, respectively; p<0.01). The mean healing ratio was significantly higher in the monofilament suture group in comparison to the multifilament suture group (0.76±0.13 vs. 0.60±0.12, respectively; p<0.01) CONCLUSION: Continuous double-layer unlocked closure of the uterine incision at cesarean delivery using monofilament synthetic absorbable sutures decreases the risk of CS scar defect.


Deprotonation Induced Ligand Oxidation in a Ni(II) Complex of a Redox Noninnocent N(1)-(2-Aminophenyl)benzene-1,2-diamine and Its Use in Catalytic Alcohol Oxidation.
Two nickel(II)-complexes, [Ni(II)(H3L)2](ClO4)2 ([1](ClO4)2) and [Ni(II)(HL)2] (2), containing the redox-active tridentate ligand N(1)-(2-aminophenyl)benzene-1,2-diamine (H3L) have been synthesized. Complex [1](ClO4)2 is octahedral containing two neutral H3L ligands in a facial coordination mode, whereas complex 2 is a singlet diradical species with approximately planar configuration at the tetracoordinate metal atom with two pendant NH2 side arms from each of the coordinated ligands. Both complexes are found to be chemically interconvertible; complex [1](2+) gets converted to complex 2 when exposed to base and oxygen via simultaneous deprotonation and oxidation of the coordinated ligands. Molecular and electronic structures of the isolated complexes are scrutinized thoroughly by various spectroscopic techniques, single crystal X-ray crystallography, and density functional theory. The observed dissociation of a ligand arm upon oxidation of the ligand was exploited to bring about catalytic alcohol oxidation using coordinatively saturated complex [1](ClO4)2 as a catalyst precursor. Both the complexes [1](ClO4)2and 2 were tested for catalytic oxidation of both primary and secondary alcohols.


The structure and synthetic capabilities of a catalytic peptide formed by substrate-directed mechanism--implications to prebiotic catalysis.
Previously, we have shown that a small substrate may serve as a template in the formation of a specific catalytic peptide, a phenomenon which might have had a major role in prebiotic synthesis of peptide catalysts. This was demonstrated experimentally by the formation of a catalytic metallo-dipeptide, Cys2-Fe2+, around o-nitrophenyl beta-D-galactopyranoside (ONPG), by dicyandiamide (DCDA)-assisted condensation under aqueous conditions. This dipeptide was capable of hydrolyzing ONPG at a specific activity lower only 1000 fold than that of beta galactosidase. In the present paper we use molecular modeling techniques to elucidate the structure of this catalyst and its complex with the substrate and propose a putative mechanism for the catalyst formation and its mode of action as a "mini enzyme". This model suggests that interaction of Fe2+ ion with ONPG oxygens and with two cysteine SH groups promotes the specific formation of the Cys2-Fe2+ catalyst. Similarly, the interaction of the catalyst with ONPG is mediated by its Fe2+ with the substrate oxygens, leading to its hydrolysis. In addition, immobilized forms of the catalyst were synthesized on two carriers--Eupergit C and amino glass beads. These preparations were capable of catalyzing the formation of ONPG from beta-D-galactose and o-nitrophenol (ONP) under anhydrous conditions. The ability of the catalyst to synthesize the substrate that mediates its own formation creates an autocatalytic cycle where ONPG catalyzes the formation of a catalyst which, in turn, catalyzes ONPG formation. Such autocatalytic cycle can only operate by switching between high and low water activity conditions, such as in tidal pools cycling between wet and dry environments. Implications of the substrate-dependent formation of catalytically active peptides to prebiotic processes are discussed.


Pemphigoid gestationis: Toward a better understanding of the etiopathogenesis.
Pemphigoid gestationis (PG) is the only autoimmune disease exclusively emerging in pregnancy. It belongs to the pemphigoid group of disorders, a class of autoimmune blistering skin diseases featuring an immune response against different hemidesmosomal proteins. PG is caused by a break of immunotolerance against the hemidesmosomal protein BP180. Several lines of evidence suggest that this break of immunotolerance is linked to specific maternal major histocompatibility complex (MHC) class II gene variants and aberrant expression of MHC class II molecules in the placenta. The close time association of the emergence of PG with pregnancy and the obviously very short period required from the initial break of immunotolerance to the onset of skin inflammation set PG into a unique position among autoimmune diseases in view of the fact that, for other autoimmune diseases, the time and site of the break of immunotolerance are usually vastly elusive and the period of silent disease can only be speculated on. In this review we highlight the features of PG and summarize current knowledge about its pathogenesis. We believe that this disease offers the best opportunity to elucidate comprehensively all phases of the pathogenesis of an autoantibody-driven disease.


[Clinical and surgical gender differences in patients older than 75 years who underwent emergency percutaneous coronary intervention in acute myocardial infarction].
There were 85 cases of endovascular treatment of acute myocardial infarct (AMI) in patients older than 75 years old in our investigation. The age of patients was from 75 to 96 years, the average age - 82,6±1,3 years. As for gender, all patients were divided into 2 groups: men - 37 (43,5 %) and female - 48 (56,5 %). The study was conducted in the following areas: determination of the baseline status of patients, analysis of technical aspects of diagnostic and medical percutaneous coronary interventions (PCI), as well as the comparison of results. apart from gender identities, the following results were obtained (p>0,05): high prevalence of cardiac diseases and basic somatic diseases; the acute cardiac failure (pulmonary edema, cardiogenic shock) was registered in 25,8 % of cases; the proportion of patients who were admitted 6 hours later from the onset of disease and who have had delayed reperfusion therapy, was 37,5 %; significant improvement of coronary blood flow in infarct-related coronary artery (TIMI classification), from an average index 1,4±0,2 before coronary stenting to 2,7±0,1 after interventions; endovascular operations were conducted in patients with multiple pathology of coronary arteries in the setting of extended occlusive lesions of infarct-related coronary artery; high efficiency of application of aspiration catheters for the removal of thrombotic masses in acute occlusion, as well as special devices for closing a puncture hole in the femoral arteries. Reduction of mortality in AMI patients over 75 years old of both sexes is associated with an increase in the proportion of emergency PCI. In both gender groups endovascular intervention was characterized by a clinically significant restoration of coronary circulation. Specific complications of PCI are rare, and it proves the safety of reperfusion therapy in the studied age group.


Knowledge and practices related to salt consumption in China: findings from a national representative cross-sectional survey.
There is limited information on the knowledge and practice of salt-reduction in China. The purpose of this study was to describe the status of the knowledge and practice of salt-reduction among the Chinese population from a nationally representative survey stratified according to hypertension status. The association between hypertensive status and salt-reduction knowledge and practice was calculated using multivariate hierarchical logistic regression adjusting for related confounders. The study included 179,834 participants; 51.7% were women, and the mean age was 44 years. The levels of overall salt-reduction knowledge (7.9%) and practice (37.1%) were low. The percentage of the use of salt-control spoons and low-sodium salt was 10.7% and 12.2%. The aging population (≥60 years) had the lowest levels of salt-reduction knowledge (5.7%) than other age groups (P < 0.0001). People living in rural areas (OR = 0.64; 95% CI: 0.51, 0.81) had lower odds of using salt-control spoons. Females (OR = 1.23; 95% CI: 1.10, 1.36) had higher odds of using salt-control spoons. People living in rural areas (OR = 0.48; 95% CI: 0.36, 0.63) had lower odds of using low-sodium salt. Females (OR = 1.26; 95% CI: 1.13, 1.41) and people living in the southern region (OR = 1.43; 95% CI: 1.11, 1.83) had higher odds of using low-sodium salt. Our work highlights the need to promote education related to hypertension, salt-reduction knowledge and methods among the public and the need to strengthen strategies for the popularization of salt-reduction knowledge and practices among males, people living in rural areas, people living in the northern region and the aging population in China.


Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines.
Stress has long been believed to influence carcinogenesis, but little is known about physiological mechanisms that may underlie these effects. We have recently observed lower levels of vascular endothelial growth factor (VEGF) in ovarian cancer patients with greater social support, whereas higher VEGF was found in patients with greater distress. The goal of this study was to examine possible mechanisms underlying these relationships. The effects of stress-related mediators including norepinephrine (NE), epinephrine, isoproterenol (a nonspecific beta-adrenergic agonist), and cortisol on the production of VEGF by the ovarian cell lines SKOV3 and EG were investigated. NE and isoproterenol significantly enhanced VEGF production by SKOV3 cells, and all three of the adrenergic agonists enhanced VEGF production by EG cells. These effects were blocked by the beta antagonist propranolol, supporting a role for beta-adrenergic receptors in these effects. Reverse transcriptase-PCR studies indicated constitutive expression of beta-1 and beta-2 adrenergic receptors on both cell lines. Effects of cortisol on VEGF production varied according to the specific cell line and dose, with stimulating effects on SKOV3 at pharmacologic doses (1000 nM) and on EG at physiological stress level doses (10 nM), and inhibitory effects on EG at pharmacologic doses. Although priming with cortisol blunted NE-induced VEGF production from both cell lines at 3 h, significant increases in VEGF were still seen. Priming with cortisol enhanced isoproterenol-induced VEGF production from SKOV3. These findings provide the first experimental evidence of a pathway by which biobehavioral stress mediators could directly contribute to the progression of ovarian tumors.


Beyond exposure for posttraumatic stress disorder (PTSD) symptoms: broad-spectrum PTSD treatment strategies.
Although cases of posttraumatic stress disorder (PTSD) with comorbid disorders are common, the first generation of PTSD treatment approaches, including exposure and cognitive-behavioral therapy, generally ignore symptoms beyond those specific to PTSD. Optimum PTSD treatment outcome requires more comprehensive strategies, and the development and empirical testing of broader approaches is the focus of the articles that follow in this special issue. After providing some background on PTSD and PTSD treatment, this paper gives an overview of these treatment and prevention papers, which represent second-generation strategies to help trauma-exposed individuals.


Electron Transport in Multidimensional Fuzzy Graphene Nanostructures.
Atomically thin two-dimensional (2D) materials offer a range of superlative electronic and electrochemical properties that facilitate applications in sensing, energy conversion, and storage. Graphene, a 2D allotrope of carbon, has exceptional surface area per unit mass and highly catalytic edges. To leverage these properties, efforts have been made to synthesize complex three-dimensional (3D) geometries of graphene, with an eye toward integration into functional electronic devices. However, the electronic transport properties of such complex 3D structures are not well understood at a microscopic level. Here, we report electron transport in a 3D arrangement of free-standing 2D graphene flakes along an isolated one-dimensional Si nanowire. We show that transport through the free-standing graphene network is dominated by variable-range hopping and leads to negative magnetoresistance, from cryogenic conditions up to room temperature. Our findings lay the foundation for studying transport mechanisms in 2D material-based multidimensional nanostructures.


Analytic gradient for the multireference Brillouin-Wigner coupled cluster method and for the state-universal multireference coupled cluster method.
We present the analytic gradient theory and its pilot implementation for the multireference Brillouin-Wigner coupled cluster (BWCC) method and for the state-universal multireference coupled cluster method. The analytic gradient has been derived for three cases: (i) BWCC method without a size-extensivity correction, (ii) BWCC method with the iterative size-extensivity correction, and (iii) for the rigorously size-extensive state-universal method. The pilot implementation is based on full-configuration interaction expansions and is presently limited to single and double excitation levels; however, the resulting equations are general. For BWCC methods, they also do not contain terms explicitly mixing amplitudes of different reference configurations and can thus be implemented in an efficient way. The analytic gradients have been verified with respect to numerically computed ones on the example of CH2 molecule, and geometry optimizations of CH2 and SiH2 have been carried out.


Ferroptosis and its potential role in gestational diabetes mellitus: updated evidence from pathogenesis to therapy.
Studies have demonstrated that high iron status is positively associated with gestational diabetes mellitus (GDM), implying that iron overload and ferroptosis play important roles in the development of GDM. The aim of this study was to explore effective therapeutic drugs from traditional Chinese medicine (TCM)formulas for the treatment of GDM based on ferroptosis. In this study, the presence of ferroptosis in the placenta was verified through clinical and experimental data, and key genes were subsequently screened for association with ferroptosis in the development of GDM. The analysis was based on transcriptome sequencing of datasets combined with differentially expressed genes (DEGs) analysis and weighted gene correlation network analysis (WGCNA); functional enrichment analysis was also performed. A protein-protein interaction (PPI) network was constructed and pivotal genes were identified using Cytoscape. Finally, traditional Chinese medicine (TCM)formulas related to treating GDM were collected, then the proteins corresponding to the key genes were molecularly docked with the small molecular structures of clinically proven effective herbal tonics, and molecular dynamic simulations were performed to select the best candidates for pharmacological compounds. Elevated ferritin levels in patients with GDM were verified using clinical data. The presence of ferroptosis in placental tissues of patients with GDM was confirmed using electron microscopy and western blotting. Ninety-nine key genes with the highest correlation with ferroptosis were identified from DEGs and weighted gene co-expression network analysis (WGCNA). Analysis using the Kyoto Encyclopedia of Genes and Genomes demonstrated that the DEGs were primarily involved in the oxidative phosphorylation pathway. The key genes were further screened by PPI; two key genes, SF3B14 and BABAM1, were identified by combining the gene corresponding to protein structure and function, followed by molecular docking and molecular dynamic simulation. Coptis chinensis was proposed as the best candidate for herbal treatment at the molecular level. This data revealed the presence of ferroptosis in patients with GDM and identified possible modulatory roles of ferroptosis-related genes involved in the molecular mechanisms of GDM, providing new insights into the pathogenesis of GDM, which also provided new directions for the systematic optimization of TCM formulas for the management and targeted treatment of GDM.


Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma.
Cytochrome P450-2E1 (CYP2E1) is one of the major hepatic enzymes involved in the metabolism of procarcinogen. Our study aimed to investigate the differential expression level of CYP2E1 and its clinicopathological significance in hepatocellular carcinoma (HCC). CYP2E1 revealed low level of expression in 70% of the tumor tissues, when compared to the adjacent nontumor tissues, at both mRNA and protein levels. The low expression of CYP2E1 was significantly correlated with the aggressive tumor phenotype, including poor differentiation status (by the Edmondson grading system) (p=0.038), absence of tumor capsule (p=0.030) and younger age of the patients (p=0.002). Multivariate analysis indicated that CYP2E1 expression level and pTNM stage were independent prognostic factors for disease-free survival. CYP2E1 was also shown to have a differential expression level in different liver tissues. The level of CYP2E1 was significantly higher in nontumor tissues from HCC patients compared to the intermediate level in cirrhosis livers from noncancer patients and normal livers from healthy persons. Tumor tissues were shown to have the lowest expression level. In conclusion, our results have shown that CYP2E1 is upregulated in the nontumor tissue and downregulated in tumor tissue, which is associated with aggressive tumor type and poor prognosis of the patients. It suggested that the differential expression of CYP2E1 may play an important role in HCC tumorigenesis.


Expert systems as an aid for the pathologist's role of clinical consultant: CANCER-STAGE.
The traditional role of the pathologist as a clinical consultant for various clinical specialists has become more difficult with the explosion of information that has taken place in the past decades. Rule-based expert systems offer the ability to store and quickly and efficiently retrieve information that is relevant to specific clinical situations. They are ideally suited for simple repetitive tasks such as the staging of patients with cancer and the retrieval of therapeutic and prognostic information. A microcomputer-based expert system, CANCER-STAGE, is described that allows a pathologist to perform these tasks with minimal computer training. The system was constructed by utilizing an inexpensive expert system development package (EXSYS). The knowledge base from the literature is stored in 370 IF-THEN rules that have notes with therapeutic information and references. The computer user interacting with the system answers questions and is quickly provided with the TNM stage of a particular patient and a short summary with therapeutic options. The conditions can be changed and the results of various WHAT-IF simulations compared for educational purposes.


Molecular dynamics and pharmacophore modelling studies of different subtype (ALK and EGFR (T790M)) inhibitors in NSCLC.
Extensively validated 3D pharmacophore models for ALK (anaplastic lymphoma kinase) and EGFR (T790M) (epithelial growth factor receptor with acquired secondary mutation) were developed. The pharmacophore model for ALK (r2 = 0.96, q2 = 0.692) suggested that two hydrogen bond acceptors and three hydrophobic groups arranged in 3-D space are essential for the binding affinity of ALK inhibitors. Similarly, the pharmacophore model for EGFR (T790M) (r2 = 0.92, q2 = 0.72) suggested that the presence of a hydrogen bond acceptor, two hydrogen bond donors and a hydrophobic group plays vital role in binding of an inhibitor of EGFR (T790M). These pharmacophore models allowed searches for novel ALK and EGFR (T790M) dual inhibitors from multiconformer 3D databases (Asinex, Chembridge and Maybridge). Finally, the eight best hits were selected for molecular dynamics simulation, to study the stability of their complexes with both proteins and final binding orientations of these molecules. After molecular dynamics simulations, one hit has been predicted to possess good binding affinity for both ALK and EGFR (T790M), which can be further investigated for its experimental in-vitro/in-vivo activities.


Сlass II histone deacetylases in the post-stroke recovery period-expression, cellular, and subcellular localization-promising targets for neuroprotection.
Histone deacetylases (HDAC) inhibitors can protect nerve cells after a stroke, but it is unclear which HDAC isoform is involved in this effect. We studied cellular and intracellular rearrangement of class II HDACs at late periods after photothrombotic infarct (PTI) in the mouse sensorimotor cortex in the tissue surrounding the ischemia core and in the corresponding region of the contralateral hemisphere. We observed a decrease in HDAC4 in cortical neurons and an increase in its nuclear translocation. HDAC6 expression in neurons was also increased. Moreover, HDAC6-positive cells had elevated apoptosis. Tubostatin A (Tub A)-induced decrease in the activity of HDAC6 restored acetylation of α-tubulin during the early poststroke recovery period and reduced apoptosis of nerve cells thus protecting the brain tissue. Selective inhibition of HDAC6 elevated expression of growth-associated protein-43 (GAP43), which remained high up to 14 days after stroke and promoted axogenesis and recovery from the PTI-induced neurological deficit. Selective HDAC6 inhibitor Tub A markedly reduced neuronal death and increased acetylation of α-tubulin and the level of GAP43. Thus, HDAC6 inhibition could be a promising strategy for modulation of brain recovery as it can increase the intensity and reduce the duration of reparation processes in the brain after stroke.


Antiinflammatory effects of polypeptide growth factors. Platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor inhibit the cytokine-induced expression of the alternative complement pathway activator factor B in human fibroblasts.
The synthesis of complement components in human fibroblasts is modulated by mediators of inflammation such as cytokines. In particular, interleukin-1 (IL-1) and tumor necrosis factor (TNF) induce time- and dose-dependent increases in the synthesis of complement proteins factor B (FB), C3, and factor H (FH). Polypeptide growth factors are also soluble mediators released during inflammation and able to modulate many fibroblast functions. We have studied the effects of polypeptide growth factors platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) on the synthesis of complement proteins in cultured human fibroblasts. PDGF, EGF, and FGF alone did not affect the level of synthesis of any of the complement proteins analyzed, but simultaneous incubation of PDGF, EGF, or FGF with IL-1 and TNF resulted in a dose-dependent inhibition of the cytokine-enhanced expression of FB. Inhibition of FB synthesis was observed between 4 and 8 h of exposure to PDGF and persisted for 4 h after the removal of the growth factor. Analysis of steady-state levels of specific FB mRNA suggested that PDGF-induced inhibition of FB synthesis is mediated at a pretranslational level and that it requires new protein synthesis. The effect of the growth factors was limited to FB, with marginal or no inhibition on the cytokine-enhanced synthesis of C3 and FH, excluding the possibility that the inhibitory effects of PDGF, EGF, and FGF on FB synthesis were due to a negative modulation of the growth factors on cytokine cell membrane receptors. Specific inhibition of cytokine-induced increases in FB synthesis by the growth factors may represent down regulation of the acute inflammatory process, further permitting progression to processes of tissue repair and remodeling. Study of the interactions between cytokines and growth factors in the regulation of synthesis of complement proteins may also provide a system for investigating mechanisms of signal transduction of both polypeptide growth factors and cytokines.


Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in Caenorhabditis elegans.
Maintenance of lipid homeostasis is crucial for cells in response to lipid requirements or surplus. The SREBP transcription factors play essential roles in regulating lipid metabolism and are associated with many metabolic diseases. However, SREBP regulation of lipid metabolism is still not completely understood. Here, we showed that reduction of SBP-1, the only homolog of SREBPs in Caenorhabditis elegans, surprisingly led to a high level of zinc. On the contrary, zinc reduction by mutation of sur-7, encoding a member of the cation diffusion facilitator (CDF) family, restored the fat accumulation and fatty acid profile of the sbp-1(ep79) mutant. Zinc reduction resulted in iron overload, which thereby directly activated the conversion activity of stearoyl-CoA desaturase (SCD), a main target of SREBP, to promote lipid biosynthesis and accumulation. However, zinc reduction reversely repressed SBP-1 nuclear translocation and further downregulated the transcription expression of SCD for compensation. Collectively, we revealed zinc-mediated regulation of the SREBP-SCD axis in lipid metabolism, distinct from the negative regulation of SREBP-1 or SREBP-2 by phosphatidylcholine or cholesterol, respectively, thereby providing novel insights into the regulation of lipid homeostasis.


Roles of Exosomes from Mesenchymal Stem Cells in Treating Osteoarthritis.
Exosomes are small extracellular vesicles (EVs) with a diameter of 50-150 nm that play important roles in cell-to-cell communication through transportation of proteins, microRNAs, lncRNAs, and mRNAs. Some components, such as miRNAs, have been proven to be involved in inflammation regulation. Osteoarthritis (OA) is a progressive disease resulting in articular cartilage degeneration and subchondral bone deficiency. Complicated relationships between the breakdown of extracellular matrix and inflammation make it difficult to recover thoroughly. Current studies reported that exosomes secreted by mesenchymal stem cells (MSCs) can change disease evolution and protect the cartilage matrix in OA. In addition, exosomes obtained from human adipose derived stem cells downregulate inflammation and oxidative stress, which might mediate antisenescence in OA. The goal of this review is to describe and summarize the role of mesenchymal stem cell (MSC)-derived exosomes in OA, focusing on their potential mechanism and possible therapeutic strategies.


King eiders use an income strategy for egg production: a case study for incorporating individual dietary variation into nutrient allocation research.
The use of stored nutrients for reproduction represents an important component of life-history variation. Recent studies from several species have used stable isotopes to estimate the reliance on stored body reserves in reproduction. Such approaches rely on population-level dietary endpoints to characterize stored reserves ("capital") and current diet ("income"). Individual variation in diet choice has so far not been incorporated in such approaches, but is crucial for assessing variation in nutrient allocation strategies. We investigated nutrient allocation to egg production in a large-bodied sea duck in northern Alaska, the king eider (Somateria spectabilis). We first used Bayesian isotopic mixing models to quantify at the population level the amount of endogenous carbon and nitrogen invested into egg proteins based on carbon and nitrogen isotope ratios. We then defined the isotopic signature of the current diet of every nesting female based on isotope ratios of eggshell membranes, because diets varied isotopically among individual king eiders on breeding grounds. We used these individual-based dietary isotope signals to characterize nutrient allocation for each female in the study population. At the population level, the Bayesian and the individual-based approaches yielded identical results, and showed that king eiders used an income strategy for the synthesis of egg proteins. The majority of the carbon and nitrogen in albumen (C: 86 +/- 18%, N: 99 +/- 1%) and the nitrogen in lipid-free yolk (90 +/- 15%) were derived from food consumed on breeding grounds. Carbon in lipid-free yolk derived evenly from endogenous sources and current diet (exogenous C: 54 +/- 24%), but source contribution was highly variable among individual females. These results suggest that even large-bodied birds traditionally viewed as capital breeders use exogenous nutrients for reproduction. We recommend that investigations of nutrient allocation should incorporate individual variation into mixing models to reveal intraspecific variation in reproductive strategies.


Rolling circle DNA replication in vitro by a complex of herpes simplex virus type 1-encoded enzymes.
Extracts of insect cells infected with baculoviruses recombinant for the herpes simplex virus 1 (HSV-1)-encoded enzymes that are required for its replication can promote the rolling circle replication of circular plasmid templates. Replication is independent of a HSV-1 origin of replication (oris) or the HSV-1 origin binding protein and is inhibited by the origin binding protein when the plasmid contains oris. Replication is dependent on a complex composed of the HSV-1-encoded DNA polymerase and its processivity enhancing factor (the UL42 protein), ICP8 (the HSV-1-encoded single-strand DNA binding protein), and the HSV-1-encoded helicase-primase. The complex can be purified by size-exclusion and anion-exchange chromatography.


Cigarette smoke as a trigger for the dioxin receptor-mediated signaling pathway.
Dioxins and dioxin-like chemicals cause a wide range of pathologies including carcinogenesis, immune dysfunction, and developmental/reproductive abnormalities. Most of these toxic effects are mediated by aryl hydrocarbon receptor (AhR; also called the dioxin receptor), a ligand-activated transcription factor. Constitutive activation of AhR via genetic manipulation causes development of cancers, inflammation and immune abnormality in mice even without exposure to xenobiotic ligands. Recent investigation disclosed that cigarette smoke contains high levels of agonists for AhR and strongly activates the dioxin signaling pathway. In this review, we describe and discuss possible roles of AhR activation in cigarette smoke-related pathologies, especially focusing on carcinogenesis, inflammation, atherosclerosis, immune dysfunction and teratogenesis.


Beta-adrenergic pathways in human heart failure.
Beta-adrenergic receptor activation plays an important role in the progression of human heart failure and the treatment of patients with beta-blockers has greatly improved the outcome of the disease. However, heart failure still is one of the leading causes of death in various countries and there is an imperative need for additional targets for the treatment of the disease. Recent studies by various groups have analyzed the downstream signaling pathways activated in response to beta-adrenergic stimulation that have the potential to become important targets for future treatments of heart failure. This review focuses on the significance of these pathways in the pathophysiology of heart failure in response to beta-adrenergic stimulation. More specifically the roles of PDE3, phosphorylation of phospholamban, and CaMKII activation are extensively discussed.