Cell surface lipids and adhesion. III. The effects on cell adhesion of changes in plasmalemmal lipids.
The two preceding papers of this series suggest that the state of the plasmalemmal lipids affects cell adhesion. Plasmalemmal composition was altered by the experimental incorporation of fatty acids into R1 and R2 positions in the phosphatidyl components of the cell surface. In this paper we report that: (1) If the incorporation is of long chain length fatty acids (saturated) cell adhesion rises. (2) If the incorporation is of unsaturated fatty acids cell adhesion falls as the unsaturation increases. (3) Incorporation has to be extensive to produce a large change in adhesion. (4) Changes in adhesion parallel the plasmalemmal incorporation but do not follow the total cell incorporation. Item (4) argues that it is plasmalemmal and not other membrane lipids that are involved in cell adhesion. Item (3) suggests that bulk membrane properties and not some very specific grouping are involved in the effects of lipids on adhesion. The similar extents of incorporation of the various different fatty acids and the negligible amounts of lysophospholipids in the membranes of cells that have incorporated fatty acids argue that the effects are not due to differential accumulations of these lysolipids when incubations are done with different fatty acids. The changes in adhesion cannot be accounted for by changes in surface charge density since the electrophoretic mobility of the cells is unchanged by these incubations. It is suggested that these effects on adhesion due to changes in plasmalemmal lipids can be explained either in terms of the action of intermembrane van der Waals--London (electrodynamic) forces in cell adhesion or of changes in surface fluidity. These alternatives are discussed.


Insight Into the Optimal Timing of Percutaneous Coronary Intervention and Transcatheter Aortic Valve Replacement.
Patients being considered for transcatheter aortic valve replacement (TAVR) are frequently diagnosed with coronary artery disease. In patients requiring revascularization, there is a paucity of data informing when to perform percutaneous coronary artery intervention (PCI). We evaluated the impact of PCI timing on clinical outcomes and readmissions after TAVR. From the National Readmissions Database 2016 to 2019, we stratified the duration between PCI and TAVR into 3 groups: same-day PCI and TAVR, TAVR ≤30 days after PCI, and TAVR >30 days after PCI. We then compared primary and secondary outcomes among them. A total of 5207 patients were included, 1413 (27.1%) of whom underwent PCI and TAVR on the same day, while 2161 (41.5%) underwent TAVR ≤30 days after PCI, and 1632 (31.3%) underwent TAVR >30 days after PCI. There was no significant difference for in-hospital mortality among the groups (adjusted odds ratio [aOR] 0.49, 95% confidence interval [CI] 0.16-1.48, p = 0.203 for same-day versus ≤30 days; aOR 2.07, 95% CI 0.68-6.30, p = 0.199 for same-day versus >30 days). Patients who underwent TAVR ≤30 days after PCI had higher odds of acute kidney injury (aOR 1.49, 95% CI 1.05-2.10, p = 0.024), nonhome discharge (aOR 1.53, 95% CI 1.20-1.96, p = 0.001), and 90-day readmission (aOR 1.35, 95% CI 1.04-1.76, p = 0.026) compared with those who underwent same-day PCI and TAVR. Concomitant PCI and TAVR was associated with lower rates of 90-day readmissions and acute kidney injury compared with TAVR shortly after PCI (<30 days) and should be considered in select patients.


[Features of the pharmacosensitivity of smooth muscles of the lesser circulation circle artery walls in rabbits].
Features of the pharmacological sensitivity of smooth muscles in the walls of arteries of the lesser circulation circle in rabbits with respect to cholinergic, histaminergic, and adrenergic agents, as well as the influence of endothelium on the realization of contractile response to these agents have been investigated in rabbits. A special feature in the cholinergic relaxation of smooth muscles of a pulmonary artery is a two-componential character of the dose dependence. The low-threshold component of the relaxant action of pilocarpine exhibits the endothelium-dependent character. An important feature of the contractile reaction to histaminergic action is a direct contractile effect of histamine, which is not observed in vessels of the greater circulation circle. Endothelium produces an inhibiting effect on the histaminergic contractility. The basic feature in the response to adrenergic action is the beta-adrenergic contractility effect. Activation of the cAMP-dependent alarm system in smooth muscles of the pulmonary arteries leads to a constrictive effect. The established features of the pharmacological sensitivity of smooth muscles of the artery walls of the lesser circulation circle are important for the clinical pharmacology.


Deciphering the Space Charge Effect of the CoNiLDH/FeOOH n-n Heterojunction for Efficient Electrocatalytic Oxygen Evolution.
Space charge transfer is an effective strategy to regulate the electron density of narrow bandgap semiconductors for enhancing electrocatalytic activity. Herein, the CoNiLDH/FeOOH n-n heterojunction hollow nanocages structure is constructed. The hollow structure provides abundant catalytic active sites and enhances mass transfer. The space charge region in the n-n heterojunction significantly promotes the adsorption of OH- and electron transfer; and the built-in electric field accelerates the electron transport, optimizes the electronic structure during the catalytic reaction process, and ensures the stability of surface charged active center sites in the heterojunction. Thus, CoNiLDH/FeOOH delivers an excellent oxygen evolution reaction (OER) overpotential of 250 mV to achieve a current density of 10 mA cm-2 with a small Tafel slope of 60 mV dec-1 , and superior electrocatalytic durability for 210 h at a high current density. Density functional theory calculations further verify that the space charge effect and built-in electric field in the n-n heterojunction of CoNiLDH/FeOOH can improve the electron transfer and lower the adsorption energy of OH- and the reaction energy barrier of the rate-determining step. This work provides a new fundamental understanding of the space charge effect of semiconductor heterojunction during the electrocatalytic process for developing more efficient OER electrocatalysts.


Plasma-based ambient sampling/ionization/transmission integrated source for mass spectrometry.
Better sensitivity and interface of ambient sampling/ionization mass spectrometry remain a challenge. Herein, a novel, plasma-based, ambient sampling/ionization/transmission (PASIT) integrated source in a pin-to-funnel configuration was developed for the sensitive analysis of complex samples. With the funnel sleeve directly affected by direct-current discharge plasma, PASIT combines the ability to sample/ionize analyte molecules and then efficiently collect/transport charged mass species under atmospheric pressure and consequently shows an improved sensitivity. The integrated source enhances the signal intensity by more than 2 orders of magnitude compared with the previous pin-to-plate plasma source without significant background addition. A surface limit of detection (LOD) of 130 fmol mm-(2) (S/N = 3) has been achieved for clenbuterol on filter paper with an argon carrier gas. Demonstrated applications include the direct determination of active ingredients from drugs and symbolic compounds from natural plants and cholesterol from mouse brain tissue sections.


Preserving the pot and water: a traditional concept of reproductive health in a Yoruba community, Nigeria.
Within the background of the outcome of the 1994 Cairo Conference, this paper describes a traditional conceptualization of prenatal care in a Nigerian community and draws their implication for effective delivery of reproductive health services in the area. The data used were from qualitative interviews during 2 field trips to the community in 1988-89 and 1991. The finding of the study highlights a local metaphor that likened the risks of pregnancy and child birth to a group of women that trekked to a local brook to fetch water with their earthen pots: some fell, broke their pots; some missed steps and spilt their water but kept their pots, and others returned without any mishap. The first group represented cases of maternal mortality; the second group were cases of miscarriage, still-births or infant deaths, and the third group represented successful outcomes for both pregnancy and the resultant baby. Various steps that were traditionally taken to ensure that the mother neither lost her pot nor spilled her water are described. The implications of these findings for policy and research are discussed in the paper.


The Outcome of One-to-Four Muscle Surgery by Intraoperative Relaxed Muscle Positioning with Adjustable Suture Technique in Thyroid Eye Disease.
To identify the outcome of one-to-four muscle surgery by intraoperative relaxed muscle positioning with adjustable suture technique for the treatment of thyroid eye disease. Ninety patients diagnosed with thyroid eye disease who underwent intraoperative relaxed muscle positioning with adjustable suture technique at Ramathibodi Hospital from January 1, 2015 through December 31, 2020 were included in this retrospective study. The patient demographic data were evaluated. Pre- and post-operative ocular alignment and diplopia status were measured after a follow-up period of at least 6 months. Successful outcomes were categorized into two parts: motor outcome and sensory outcome. Successful motor outcome was defined as vertical deviation equal to 4 prism diopters or less and horizontal deviation equal to 10 prism diopters or less in primary position. Successful sensory outcome was defined as the absence of diplopia in primary position. Ninety patients were included in this study, and the mean age of strabismic surgery was 56.6 ± 10.1 years old. Thirty-nine patients had a history of orbital decompression surgery. Mean follow-up time was 33.7 ± 11.8 months. The success of motor and sensory outcomes exhibited a decrease from one-to-four muscle surgery. Motor success decreased from one-muscle to four-muscle surgery (84.62%, 81.58%, 75.00%, and 64.29%) and sensory success similarly decreased (84.62%, 84.21%, 75.00%, and 78.57%). However, the comparative outcomes of motor success and sensory success were not statistically different among groups (p = 0.58 and 0.84). Lower lid retractions were found in 12 patients (13.33%). Intraoperative relaxed muscle positioning technique might be a successful option for the correction of thyroid eye disease-associated strabismus. This technique may be done with one-to-four muscle surgery, which yields success in both motor and sensory outcomes.


Early induction of CCL7 downstream of TLR9 signaling promotes the development of robust immunity to cryptococcal infection.
We investigated mechanisms by which TLR9 signaling promoted the development of the protective response to Cryptococcus neoformans in mice with cryptococcal pneumonia. The afferent (week 1) and efferent (week 3) phase immune parameters were analyzed in the infected wild-type (TLR9(+/+)) and TLR-deficient (TLR9(-/-)) mice. TLR9 deletion diminished 1) accumulation and activation of CD11b(+) dendritic cells (DCs), 2) the induction of IFN-γ and CCR2 chemokines CCL7, CCL12, but not CCL2, at week 1, and 3) pulmonary accumulation and activation of the major effector cells CD4(+) and CD8(+) T cells, CD11b(+) lung DCs, and exudate macrophages at week 3. The significance of CCL7 induction downstream of TLR9 signaling was investigated by determining whether CCL7 reconstitution would improve immunological parameters in C. neoformans-infected TLR9(-/-) mice. Early reconstitution with CCL7 1) improved accumulation and activation of CD11b(+) DCs at week 1, 2) restored early IFN-γ production in the lungs, and 3) restored the accumulation of major effector cell subsets. CCL7 administration abolished the difference in lung fungal burdens between TLR9(+/+) and TLR9(-/-) mice at week 3; however, significant reduction of fungal burdens between PBS- and CCL7-treated mice has not been observed, suggesting that additional mechanism(s) apart from early CCL7 induction contribute to optimal fungal clearance in TLR9(+/+) mice. Collectively, we show that TLR9 signaling during the afferent phase contributes to the development of protective immunity by promoting the early induction of CCL7 and IFN-γ and the subsequent early recruitment and activation of DCs and additional effector cells in mice with cryptococcal pneumonia.


A randomized phase II study of docetaxel or vinorelbine in combination with cisplatin against inoperable, chemo-naïve non-small-cell lung cancer in Taiwan.
Cisplatin plus a third-generation anti-cancer drug, such as vinorelbine, gemcitabine, or the taxanes, are the standard regimen used in the first-line treatment of advanced non-small-cell lung cancer (NSCLC), and there is no significant difference in efficacy among the different regimens. Our aim was to evaluate the efficacy of docetaxel plus cisplatin (DC) versus vinorelbine plus cisplatin (VC) in chemo-naïve NSCLC patients. From December 2003 to May 2005, 94 patients were enrolled. The treatment dose was D 60 mg/m2 and C 60 mg/m2 intravenous infusion (IV) on day 1, or V 25 mg/m2 IV on days 1 and 8, and C 60 mg/m2 IV on day 1, every 3 weeks. In all, 209 cycles of DC and 230 cycles of VC were given to the patients in the DC (median five cycles) and VC (median five cycles) arms, respectively. There were 19 partial responses and one complete response (overall 43.5%) in the DC arm, and no complete responses, but 22 partial responses (overall 45.8%), in the VC arm. Myelosuppression was the major toxicity occurring in both arms, with grades 3 or 4 neutropenia occurring in 72.9% and 71.7% of patients, respectively. Except for alopecia (p=0.005) and diarrhea (p<0.001), which were more common in the DC arm, no significant differences in toxicity profiles were found between the two treatment arms. The median time to disease progression was 4.7 months in the DC arm and 6.3 months in the VC arm (p=0.7355). Median survival time was 13 months in the DC arm and 13.8 months in the VC arm (p=0.9656). The 1-year survival rate was 55.5% and 51.7%, respectively. After treatment, the Lung Cancer Symptom Scales showed no significant difference between the two treatment arms. We concluded that both DC and VC are appropriate regimens for use in the first-line treatment of Chinese NSCLC patients. Asthenia, one of the major side effects of docetaxel, was not a major problem in the present study. Although both regimens produced a high incidence of severe neutropenia, the majority of patients recovered rapidly without sequelae; and VC treatment is still a standard chemotherapy for Chinese NSCLC patients in Taiwan.


A Large-Scale High-Density Weighted Structural Connectome of the Macaque Brain Acquired by Predicting Missing Links.
As a substrate for function, large-scale brain structural networks are crucial for fundamental and systems-level understanding of primate brains. However, it is challenging to acquire a complete primate whole-brain structural connectome using track tracing techniques. Here, we acquired a weighted brain structural network across 91 cortical regions of a whole macaque brain hemisphere with a connectivity density of 59% by predicting missing links from the CoCoMac-based binary network with a low density of 26.3%. The prediction model combines three factors, including spatial proximity, topological similarity, and cytoarchitectural similarity-to predict missing links and assign connection weights. The model was tested on a recently obtained high connectivity density yet partial-coverage experimental weighted network connecting 91 sources to 29 target regions; the model showed a prediction sensitivity of 74.1% in the predicted network. This predicted macaque hemisphere-wide weighted network has module segregation closely matching functional domains. Interestingly, the areas that act as integrators linking the segregated modules are mainly distributed in the frontoparietal network and correspond to the regions with large wiring costs in the predicted weighted network. This predicted weighted network provides a high-density structural dataset for further exploration of relationships between structure, function, and metabolism in the primate brain.


The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury.
Altered Cl- homeostasis and GABAergic function are associated with nociceptive input hypersensitivity. This study investigated the role of two major intracellular Cl- regulatory proteins, Na+-K+-Cl- cotransporter 1 (NKCC1) and K+-Cl- cotransporter 2 (KCC2), in neuropathic pain following spinal cord injury (SCI). Sprague-Dawley rats underwent a contusive SCI at T9 using the MASCIS impactor. The rats developed hyperalgesia between days 21 and 42 post-SCI. Thermal hyperalgesia (TH) was determined by a decrease in hindpaw thermal withdrawal latency time (WLT) between days 21 and 42 post-SCI. Rats with TH were then treated with either vehicle (saline containing 0.25% NaOH) or NKCC1 inhibitor bumetanide (BU, 30 mg/kg, i.p.) in vehicle. TH was then re-measured at 1 h post-injection. Administration of BU significantly increased the mean WLT in rats (p < 0.05). The group administered with the vehicle alone showed no anti-hyperalgesic effects. Moreover, an increase in NKCC1 protein expression occurred in the lesion epicenter of the spinal cord during day 2-14 post-SCI and peaked on day 14 post-SCI (p < 0.05). Concurrently, a down-regulation of KCC2 protein was detected during day 2-14 post-SCI. The rats with TH exhibited a sustained loss of KCC2 protein during post-SCI days 21-42. No significant changes of these proteins were detected in the rostral region of the spinal cord. Taken together, expression of NKCC1 and KCC2 proteins was differentially altered following SCI. The anti-hyperalgesic effect of NKCC1 inhibition suggests that normal or elevated NKCC1 function and loss of KCC2 function play a role in the development and maintenance of SCI-induced neuropathic pain.


The affinity of D2-like dopamine receptor antagonists determines the time to maximal effect on cocaine self-administration.
Differences in the time to maximal effect (T(max)) of a series of dopamine receptor antagonists on the self-administration of cocaine are not consistent with their lipophilicity (octanol-water partition coefficients at pH 7.4) and expected rapid entry into the brain after intravenous injection. It was hypothesized that the T(max) reflects the time required for maximal occupancy of receptors, which would occur as equilibrium was approached. If so, the T(max) should be related to the affinity for the relevant receptor population. This hypothesis was tested using a series of nine antagonists having a 2500-fold range of K(i) or K(d) values for D(2)-like dopamine receptors. Rats self-administered cocaine at regular intervals and then were injected intravenously with a dose of antagonist, and the self-administration of cocaine was continued for 6 to 10 h. The level of cocaine at the time of every self-administration (satiety threshold) was calculated throughout the session. The satiety threshold was stable before the injection of antagonist and then increased approximately 3-fold over the baseline value at doses of antagonists selected to produce this approximately equivalent maximal magnitude of effect (maximum increase in the equiactive cocaine concentration, satiety threshold; C(max)). Despite the similar C(max), the mean T(max) varied between 5 and 157 min across this series of antagonists. Furthermore, there was a strong and significant correlation between the in vivo T(max) values for each antagonist and the affinity for D(2)-like dopamine receptors measured in vitro. It is concluded that the cocaine self-administration paradigm offers a reliable and predictive bioassay for measuring the affinity of a competitive antagonist for D(2)-like dopamine receptors.


Hydrogen sulfide and ischemia-reperfusion injury.
Gasotransmitters are lipid soluble, endogenously produced gaseous signaling molecules that freely permeate the plasma membrane of a cell to directly activate intracellular targets, thus alleviating the need for membrane-bound receptors. The gasotransmitter family consists of three members: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H(2)S). H(2)S is the latest gasotransmitter to be identified and characterized and like the other members of the gasotransmitter family, H(2)S was historically considered to be a toxic gas and an environmental/occupational hazard. However with the discovery of its presence and enzymatic production in mammalian tissues, H(2)S has gained much attention as a physiological signaling molecule. Also, much like NO and CO, H(2)S's role in ischemia/reperfusion (I/R) injury has recently begun to be elucidated. As such, modulation of endogenous H(2)S and administration of exogenous H(2)S has now been demonstrated to be cytoprotective in various organ systems through diverse signaling mechanisms. This review will provide a detailed description of the role H(2)S plays in different model systems of I/R injury and will also detail some of the mechanisms involved with its cytoprotection.


Comparison of Bruker Biotyper® and Vitek® MS matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry platforms for the identification of filamentous fungi.
Aims: To evaluate the performance of two matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry platforms to identify molds isolated from clinical specimens. Methods: Fifty mold isolates were analyzed on Bruker Biotyper® and Vitek® MS platforms. Two Bruker Biotyper extraction protocols were assessed alongside the US FDA-approved extraction protocol for Vitek MS. Results: The Bruker Biotyper modified NIH-developed extraction protocol correctly identified more isolates than Bruker's protocol (56 vs 33%). For species in the manufacturers' databases, Vitek MS correctly identified 85% of isolates, with 8% misidentifications. The Bruker Biotyper identified 64%, with no misidentifications. For isolates not in the databases, the Bruker Biotyper did not misidentify any, and Vitek MS misidentified 36%. Conclusion: Both the Vitek MS and Bruker Biotyper accurately identified the fungal isolates, however Vitek MS was more likely to misidentify isolates than the Bruker Biotyper.


Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors.
The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant PDAC, and PDAC growth is reliant on autophagy. However, inhibition of autophagy as monotherapy using the lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy. To identify strategies that can improve PDAC sensitivity to HCQ, we applied a CRISPR-Cas9 loss-of-function screen and found that a top sensitizer was the receptor tyrosine kinase (RTK) insulin-like growth factor 1 receptor (IGF1R). Additionally, reverse phase protein array pathway activation mapping profiled the signaling pathways altered by chloroquine (CQ) treatment. Activating phosphorylation of RTKs, including IGF1R, was a common compensatory increase in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Cotargeting both IGF1R and pathways that antagonize autophagy, such as ERK-MAPK axis, was strongly synergistic. IGF1R and ERK inhibition converged on suppression of glycolysis, leading to enhanced dependence on autophagy. Accordingly, concurrent inhibition of IGF1R, ERK, and autophagy induced cytotoxicity in PDAC cell lines and decreased viability in human PDAC organoids. In conclusion, targeting IGF1R together with ERK enhances the effectiveness of autophagy inhibitors in PDAC. Compensatory upregulation of IGF1R and ERK-MAPK signaling limits the efficacy of autophagy inhibitors chloroquine and hydroxychloroquine, and their concurrent inhibition synergistically increases autophagy dependence and chloroquine sensitivity in pancreatic ductal adenocarcinoma.


Thermogelling aqueous fluids containing low concentrations of Pluronic F127 and laponite nanoparticles.
The triblock copolymer Pluronic F127 (PF127) is frequently used in colloidal and pharmaceutical formulations. Concentrated aqueous solutions of PF127 (>15 wt %) are known to undergo thermogelling (i.e., a sol-to-gel transition upon heating), which is attributed to the formation of a volume-filling cubic array of micelles. Here, we report that thermogelling can occur at much lower PF127 concentrations (1.2 to 8 wt %) if nanoparticles of laponite (25-nm-diameter disks) are also present in the formulation. Thermogelling in laponite/PF127 mixtures requires each component to be present above a minimum level. The gels have moduli around 100 Pa, and they can be reversibly liquefied to sols upon cooling. Rheological techniques, small-angle neutron scattering (SANS), and transmission electron microscopy (TEM) are used to characterize the thermogels. We attribute the onset of thermogelling to depletion flocculation of the laponite particles into a network by spherical micelles of PF127.


Protective effect of HLA-DRB1 11 and predisposition of HLA-C 04 in the development of severe liver damage in Brazilian patients with chronic hepatitis C virus infection.
The objective of this study was to investigate human leucocyte antigen (HLA) genes in patients chronically infected with hepatitis C virus (HCV) and to analyse the possible role of these genes in the progression of chronic hepatitis C. One hundred and forty-five (145) Brazilian patients infected only with HCV genotype 1 were evaluated. HLA class I (A, B, C) and class II (DRB1, DQA1, DQB1) typing were carried out by PCR-SSO, through Luminex technology. Associations were found with protection against development of liver damage by both DRB1 11 (5.0% versus 18.2%, P=0.0016, OR=0.23, CI 95% = 0.09-0.58; Pc=0.0208) and DRB1 11-DQA1 05-DQB1 03 haplotype (4.2% versus 15.3%, P=0.0032; OR = 0.24, CI 95% = 0.08-0.64). Liver damage was associated with HLA-C 04 in patients with <20 years of infection (38.4% versus 9.1%, P = 0.002, OR = 6.25, CI 95%=1.97-19.7; Pc=0.0238). It is concluded that HLA alleles can influence the development of liver damage in HCV type-1 chronically infected Brazilian patients.


The ambiguous "new history of psychology": New questions for Brock (2017).
In 2006, Benjamin J. Lovett published the first critique of the "new history of psychology" in History of Psychology (Lovett, 2006). The first reply to it, from Adrian C. Brock, did not come until a decade later. The present article answers Brock's (2017) comments by asking new (rhetorical) questions. The author claims that both Lovett and Brock misunderstood the ambiguity of the term "new history," which refers simultaneously to critical narratives in general and to a particular rhetoric about the commitments of critical historiography (e.g., externalism, historicism, anti-Whiggism). Although Lovett's article does present shortcomings, it is argued that many of his claims are still valid because his critique focused on the rhetoric of "new history." Brock, for his part, uses the term "new history" in its full ambiguity and attempts to defend critical histories with the rhetoric of "new history." As a result, Brock ends up reproducing many of the problems criticized by Lovett. (PsycINFO Database Record


Domestic HPV vaccine price and economic returns for cervical cancer prevention in China: a cost-effectiveness analysis.
Coinciding with the release of the first Chinese domestic human papillomavirus (HPV) vaccine Cecolin in 2019, and the substantial advancements in cervical cancer screening technology, we aimed to evaluate the cost-effectiveness of the combined strategies of cervical cancer screening programmes and universal vaccination of girls (aged 9-14 years) with Cecolin in China. We did a cost-effectiveness analysis in China, in which we developed a Markov model of cervical cancer to evaluate the incremental cost-effectiveness ratios of 61 intervention strategies, including a combination of various screening methods at different frequencies with and without vaccination, and also vaccination alone, from a health-care system perspective. We did univariate and probabilistic sensitivity analyses to assess the robustness of the model's findings. Compared with no intervention, various combined screening and vaccination strategies would incur an additional cost of US$6 157 000-22 146 000 and result in 691-970 quality-adjusted life-years (QALYs) gained in a designated cohort of 100 000 girls aged 9-14 years over a lifetime. With a willingness-to-pay threshold of three times the Chinese per-capita gross domestic product (GDP), careHPV screening (a rapid HPV test) once every 5 years with vaccination would be the most cost-effective strategy with an incremental cost-effectiveness ratio of $21 799 per QALY compared with the lower-cost non-dominated strategy on the cost-effectiveness frontier, and the probability of it being cost-effective (44%) outperformed other strategies. Strategies that combined screening and vaccination would be more cost-effective than screening alone strategies when the vaccination cost was less than $50 for two doses, even with a lower willingness-to-pay of one times the per-capita GDP. careHPV screening once every 5 years with vaccination is the most cost-effective strategy for cervical cancer prevention in China. A reduction in the domestic HPV vaccine price is necessary to ascertain a good economic return for the future vaccination programme. The findings provide important evidence that informs health policies for cervical cancer prevention in China. National Natural Science Foundation of China.


Axis I disorders in ER patients with atypical chest pain.
To examine the contribution of psychopathology to emergency room (ER) visits for atypical chest pain, we administered two screening measures and the Structured Clinical Interview for DSM III-R (SCID) to thirty-five subjects within seventy-two hours of their ER visit. Follow-up SCID interviews were completed in thirty subjects at five to twelve months. Sixty percent of the sample had an initial Axis I diagnosis, predominately affective (34%) and anxiety (46%) disorders. Forty percent had multiple diagnoses initially. The most common diagnoses were panic disorder (31%) and major depression (23%). At follow-up 47 percent had Axis I diagnoses, 30 percent had multiple diagnoses, with only slightly decreases rates for panic disorder (27%) and major depression (17%). Many subjects had lost, gained, or switched diagnoses by follow-up, in spite of one consistent rater and a few subjects seeking treatment. ER physicians often do not recognize these psychiatric disorders in chest pain patients. The high risk of suicide in panic disorder and depression, and the high cost of disability in recurrent chest pain make it essential that ER physicians include these disorders in the differential of atypical chest pain.


Smoking and intoxication after alcohol challenge in women and men: genetic influences.
In an earlier analysis, men and women who were current or former smokers were found to report feeling less intoxicated on average than nonsmokers after ingestion of a challenge dose of alcohol. Here, we examine whether differences in subjective response to alcohol and a tendency to smoke cigarettes are transmitted together in families; and, if so, whether this association might be entirely explained by the same heritable factors that influence alcohol intake (as we might expect if both smoking and subjective intoxication are influenced by some general susceptibility for substance use). Alcohol challenge data on 388 Australian male and female twins (194 complete pairs) were reanalyzed using multivariate genetic analysis to evaluate the association between cigarette smoking and self-report intoxication after a standard dose of alcohol. In women, we could not reject the hypothesis of complete genetic overlap between effects on intoxication rating and history of smoking, and a significant residual genetic correlation between smoking and postalcohol intoxication persisted even when genetic influences on alcohol consumption were controlled for. In men, the familial association seemed to be largely environmentally mediated and associated with differences in drinking history. These findings prompt the question of whether, in some individuals, cigarette smoking may contribute to the development of tolerance to the effects of alcohol.


Cancer classification from gene expression data by NPPC ensemble.
The most important application of microarray in gene expression analysis is to classify the unknown tissue samples according to their gene expression levels with the help of known sample expression levels. In this paper, we present a nonparallel plane proximal classifier (NPPC) ensemble that ensures high classification accuracy of test samples in a computer-aided diagnosis (CAD) framework than that of a single NPPC model. For each data set only, a few genes are selected by using a mutual information criterion. Then a genetic algorithm-based simultaneous feature and model selection scheme is used to train a number of NPPC expert models in multiple subspaces by maximizing cross-validation accuracy. The members of the ensemble are selected by the performance of the trained models on a validation set. Besides the usual majority voting method, we have introduced minimum average proximity-based decision combiner for NPPC ensemble. The effectiveness of the NPPC ensemble and the proposed new approach of combining decisions for cancer diagnosis are studied and compared with support vector machine (SVM) classifier in a similar framework. Experimental results on cancer data sets show that the NPPC ensemble offers comparable testing accuracy to that of SVM ensemble with reduced training time on average.


Interactions of NIP-taurine, NAP-taurine, and Cl- with the human erythrocyte anion exchange system.
N-(4-isothiocyano-2-nitrophenyl)-2-aminoethanesulfonate (NIP-taurine), a newly synthesized isothiocyano derivative of N-(4-azido-2-nitrophenyl)-2-aminoethanesulfonate (NAP-taurine), is a potent inhibitor of human erythrocyte chloride exchange. At 0 degrees C, the inhibition is reversible, but at 37 degrees C, NIP-taurine inhibits irreversibly, indicating that it may be a useful label for its binding site. When present at the outside of the cell, NIP-taurine binds with low affinity to a site that seems to be the Cl- transport site (on the basis of its affinity for Cl-) and with much higher affinity to a different site, MN, which has a much lower affinity for Cl-. In this respect, NIP-taurine resembles NAP-taurine, and an analysis of interactions between these two probes is consistent with the idea that they bind to the same two sites. The affinity of NIP-taurine for the high-affinity MN site is enhanced by about fourfold when the transport protein, band 3, is in the conformation with the transport site facing outward (Eo), as compared with the conformation with the transport site facing inward (Ei). External Cl-, but not cytoplasmic Cl-, competes with NIP-taurine for binding to the external, high affinity site. Thus NIP-taurine provides a label for an external site, at which Cl- and perhaps other anions bind, which is separate from both the transport site and the cytoplasmic modifier site at which high Cl- concentrations inhibit Cl- exchange.


[Legal framework of postgraduate nursing education in spain].
Being part of the first report of the SEEIUC Forum on the training of nurses in critical care units, this article shows the different postgraduation training paths which Spanish legislation establishes. The "Titulos Oficiales de Especialización Profesional" ("Official Degrees on Professional Specialization") settle the seven nursing specialties regulated by the Decreto 992/1987. Following a second path, "Titulos de Postgraduado no Oficiales" ("Non-official postgraduation degrees"), every University acknowledged by the LRU and creating them as their Own Degrees, may organize Master courses, University experts, University specialists and Postgraduation university degrees, according to their autonomy. So that this autonomous offer is as homogeneous as possible, there is an interuniversity agreement which encompasses 24 national universities and gathers the general criteria for the academic organization of such courses. The report is completed by an analysis of the training offer for critical care nursing, developed during the 1995/1996 course in Spain.


Comparative genomics of cultured and uncultured strains suggests genes essential for free-living growth of Liberibacter.
The full genomes of two uncultured plant pathogenic Liberibacter, Ca. Liberibacter asiaticus and Ca. Liberibacter solanacearum, are publicly available. Recently, the larger genome of a closely related cultured strain, Liberibacter crescens BT-1, was described. To gain insights into our current inability to culture most Liberibacter, a comparative genomics analysis was done based on the RAST, KEGG, and manual annotations of these three organisms. In addition, pathogenicity genes were examined in all three bacteria. Key deficiencies were identified in Ca. L. asiaticus and Ca. L. solanacearum that might suggest why these organisms have not yet been cultured. Over 100 genes involved in amino acid and vitamin synthesis were annotated exclusively in L. crescens BT-1. However, none of these deficiencies are limiting in the rich media used to date. Other genes exclusive to L. crescens BT-1 include those involved in cell division, the stringent response regulatory pathway, and multiple two component regulatory systems. These results indicate that L. crescens is capable of growth under a much wider range of conditions than the uncultured Liberibacter strains. No outstanding differences were noted in pathogenicity-associated systems, suggesting that L. crescens BT-1 may be a plant pathogen on an as yet unidentified host.


A schizophrenia gene locus on chromosome 17q21 in a new set of families of Mexican and central american ancestry: evidence from the NIMH Genetics of schizophrenia in latino populations study.
The present study investigated a new set of families of Latin American ancestry in order to detect the location of genes predisposing to schizophrenia and related psychotic disorders. A genome-wide scan was performed for 175 newly recruited families with at least two siblings suffering from a psychotic disorder. Best-estimate consensus procedures were used to arrive at diagnoses, and nonparametric allele-sharing statistics were calculated to detect linkage. Genome-wide significant evidence for linkage for the phenotype of DSM-IV schizophrenia or schizoaffective disorder was found in a region on chromosome 17q21 (lod score, 3.33). A region on chromosome 15q22-23 showed suggestive evidence of linkage with this same phenotype (lod score, 2.11). Analyses using a broader model (any psychosis) yielded evidence of suggestive linkage for the 17q21 region only, and no region achieved genome-wide significance of linkage. The new set of 175 families of Mexican and Central American ancestry delineates two new loci likely to harbor predisposition genes for schizophrenia and schizoaffective disorder. The region with the strongest support for linkage in this sample, 17q21, has been implicated in meta-analyses of schizophrenia genome screens, but the authors found no previous reports of it as a locus for schizophrenia in specific population- or family-based studies, and it may represent the location of a schizophrenia predisposition gene (or genes) of special relevance in Mexican and Central American populations.


Knowledge of radiation exposure in common radiological investigations: a comparison between radiologists and non-radiologists.
Radiological examinations are commonly requested for patients to aid clinical diagnosis. However, many doctors do not realise how much radiation dosage their patients are exposed to during radiological investigations. This study aims to assess and compare the knowledge of radiologists and non-radiologists about radiation doses of common radiological investigations. A prospective questionnaire study of doctors about the dosage of commonly performed radiological investigations in a university teaching hospital in Hong Kong. Participants were asked to indicate the average dose of radiation (in mSv) for a standard chest x-ray exposure. Doctors were then asked to estimate the doses of radiation (measured in chest x-ray equivalents) for various radiological procedures. The results of radiologists and non-radiologists were compared. 158 doctors (25 radiologists and 133 non-radiologists) completed the questionnaire. The overall accuracy was 40% for radiologists and 16% for non-radiologists. One-third of non-radiologists could not distinguish radiological examinations with or without ionising radiation. No non-radiologists correctly stated the radiation dose (in mSv) of a conventional chest x-ray, and 77% underestimated the dose of radiological examinations. For radiologists, only 32% were correct for the radiation dose of a conventional chest x-ray while 7% underestimated the radiation doses. Knowledge of radiation doses of investigation is generally inadequate among radiologists, and particularly poor in non-radiologists. Underestimation of radiation doses may expose patients to increasing radiological investigation and exposure to radiation hazards. Awareness of the radiation hazard of radiological examinations should be raised among medical professionals.


A charged multivesicular body protein (CHMP4B) is required for lens growth and differentiation.
Charged multivesicular body protein 4B (CHMP4B) functions as a core component of the endosome sorting complex required for transport-III (ESCRT-III) machinery that facilitates diverse membrane remodeling and scission processes in eukaryotes. Mutations in the human CHMP4B gene underlie rare, inherited forms of early-onset lens opacities or cataract. Here we have characterized the lens phenotypes of mutant (knock-in) mice harboring a human cataract-associated mutation (p.D129V) in CHMP4B (Chmp4b-mutant) and conditional knockdown mice deficient in lens CHMP4B (Chmp4b-CKD). In situ hybridization localized Chmp4b transcripts to lens epithelial cells and elongating fiber cells at the lens equator. Heterozygous Chmp4b-mutant (D/V) mice were viable and fertile with lenses grossly similar to those of wild-type. However, homozygous Chmp4b-mutant (V/V) mice died by embryonic day 15.5 (E15.5) with grossly abnormal eye and brain histology. Chmp4b-CKD mice displayed variable degrees of lens dysmorphology including lens ablation. Immuno-localization of aquaporin-0 (AQP0) revealed lens fiber cell degeneration in homozygous Chmp4b-mutant (V/V) mouse embryos and in embryonic and postnatal Chmp4b-CKD mice. DNA fragmentation (TUNEL) analysis revealed global cell death in homozygous Chmp4b-mutant (V/V) embryos, whereas, cell death was confined to the lens of Chmp4b-CKD mice. Immuno-localization of the monocyte/macrophage marker macrosialin (CD68) suggested that severe lens degeneration in Chmp4b-CKD mice resulted in an ocular immune cell response. Collectively, these mouse data suggest that (1) heterozygous, germ-line mutations in Chmp4b may not manifest as cataract, (2) homozygous, germ-line mutations in Chmp4b are embryonic lethal, and (3) conditional loss of Chmp4b results in arrest of lens growth and differentiation.


Diagnostic accuracy of upper tract urothelial carcinoma: how samples are collected matters.
The aims of this study were to determine the accuracy and reliability of cytology, histopathology and ploidy of specimens obtained at ureterorenoscopy, to evaluate the importance of how samples are collected and to determine whether cytology is an alternative to histology of biopsies. This prospective study investigated the accuracy of grading of endoscopically taken cytology and histopathology samples from 45 consecutive patients by comparing these with subsequent nephroureterectomy specimens. Histopathology grading was done according to WHO 1999 and 2004 classifications. Ploidy was determined using photospectrometry. Forty-five patients were included. Both cytology and histopathology identified almost all cancers (91% and 94%, respectively) in collected samples. In cytology as well as in histopathology, agreement in grade between barbotage and nephroureterectomy specimens was statistically significant for both 1999 and 2004 WHO classifications. All cancers in the endoscopic biopsies were identified as pathological, although the grading was not correct in all cases. A statistically significant correlation was found between grade and ploidy in grade 1 and grade 3 nephroureterectomy specimens. Specimens collected at ureterorenoscopy (biopsies for histology, barbotages for cytology and analysis of ploidy) proved to be relevant and useful. Barbotage cytology identified 91% of all cancers, a high rate compared to techniques used in other studies, and was also sensitive in detecting low-grade tumours. Barbotage cytology and biopsy histology were equally efficient in detecting cancer. The authors recommend that both barbotage and biopsy be performed in addition to complete ureterorenoscopy. Moreover, if there is no visible lesion, cytology is the only reliable option.


CD109 attenuates TGF-β1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells.
CD109 is a glycosylphosphatidylinositol-anchored cell surface protein that is frequently detected in squamous cell carcinomas. CD109 is a negative regulator of TGF-β1 signaling in human keratinocytes, and the N-terminal fragment of CD109 secreted from cells after cleavage by the furin protease is important for modulating TGF-β1 signaling. Previously, we found that CD109 is expressed in human glioblastoma cells; however, the role of CD109 in glioblastoma cells is not established. Here, we describe the effects of CD109 in human glioblastoma cell lines. Three glioblastoma cell lines, SK-MG-1, U251MG and MG178, were tested and CD109 overexpression attenuated TGF-β1 signaling and enhanced EGF signaling in SK-MG-1, but not in U251MG or MG178. The N-terminal CD109 fragment in SK-MG-1 was hyperglycosylated compared with that in MG178 or U251MG. The conditioned medium of CD109-overexpressing SK-MG-1, containing the secreted N-terminal CD109, had a negative effect on TGF-β1 signaling in wild-type SK-MG-1 and MG178, whereas it did not show any effect on EGF signaling. In addition, cell surface CD109 interacts with EGF receptor in SK-MG-1 overexpressing CD109, and exhibited enhanced cell migration and invasion. These findings suggest that CD109 attenuates TGF-β1 signaling and enhances EGF signaling in SK-MG-1 cells and that the membrane-anchored CD109 may play major roles in the EGF signaling pathway.


Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia.
The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.


Surgical management of congenital conductive deafness.
Today's otologic surgeon has the opportunity to restore normal serviceable hearing in patients with congenital conductive deafness using tympanoplasty with ossicular chain reconstruction, stapedectomy, or fenestration of the horizontal semicircular canal. The particular surgical approach used is determined by the abnormalities found in the congenitally deformed ear. I report a series of 18 patients who had operation for congenital conductive deafness during a four-year period at the Farrior Clinic. The study results show the efficacy of surgical reconstruction in producing an improvement in hearing.


Trends and Determinants of Osteoporosis Treatment and Screening in Patients With Rheumatoid Arthritis Compared to Osteoarthritis.
To profile osteoporosis (OP) care in patients with rheumatoid arthritis (RA) over the past decade. Patients with RA or osteoarthritis (OA) were followed from 2003 through 2014. OP care was defined as receipt of OP treatment (with the exception of calcium/vitamin D) or screening (OPTS). Adjusted trends over followup, and the factors associated with OP care, were examined using multivariable Cox proportional hazards. OPTS was reported in 67.4% of 11,669 RA patients and in 64.6% of 2,829 OA patients during a median (interquartile range) 5.5 (2-9) years of followup. In patients for whom treatment was recommended by the 2010 American College of Rheumatology (ACR) glucocorticoid-induced OP (GIOP) guidelines (48.4% of RA patients and 17.6% of OA patients), approximately 55% overall reported OP medication use. RA patients were not more likely to undergo OPTS compared to OA patients (hazard ratio 1.04 [95% confidence interval 0.94-1.15]). Adjusted models showed a stable trend for OPTS between 2004 and 2008 compared to 2003, with a significant downward trend after 2008 in both RA and OA patients. Factors associated with receipt of OP care in RA patients were older age, postmenopausal state, prior fragility fracture or diagnosis of OP, any duration of glucocorticoid treatment, and use of biologic agents. Approximately half of RA patients for whom treatment was indicated never received an OP medication. OP care in RA patients was not better than in OA patients, and the relative risk of the application of this care has been decreasing in RA and OA patients since 2008 without improvement after the release of the 2010 ACR GIOP guideline.


Interplay of reverse transcriptase inhibitor therapy and gag p6 diversity in HIV type 1 subtype G and CRF02_AG.
Abstract The gag p6 region of HIV-1 has various nonsubstitutionary mutations, including insertions, duplications, deletions, and premature stop codons. Studies have linked gag p6 mutations to reduced susceptibility to antiretroviral therapy in HIV-1 subtype B. This study examined the relationship between antiretroviral therapy and gag p6 diversity in HIV-1 CRF02_AG and subtype G. p6 data were generated for secondary analyses following Viroseq genotyping of pol gene sequences in plasma samples from HIV-1-infected Nigerians on reverse transcriptase inhibitor therapy, with virologic failure (repeat VL > 2000 copies/ml). p6 sequence chromatograms were available for 40 CRF02_AG and 43 subtype G-infected individuals. Subjects who had not received their supply of antiretroviral drugs for at least 2 months prior to the plasma sampling were classified as nonadherent. p6 sequences from therapy-adherent individuals had more nonsubstitutionary mutations than sequences from drug-naive individuals (p = 0.0005). The P5L/T mutation was inversely correlated with the presence of K27Q/N in p6, with each mutation being more prominent in subtype G and CRF02_AG, respectively. The data also suggested that P5L/T may be a compensatory mutation for the loss of an essential phosphorylation site in p6. In addition, there was an inverse association between P5L/T mutations in p6 and thymidine analog mutations in reverse transcriptase (p = 0.0001), and drug nonadherence was associated with an 8-fold lower risk of having a nonsubstitutionary mutation in p6 (95% CI = 1.27-52.57). Our data suggest that antiretroviral therapy influences gag p6 diversity, but further studies are needed to clarify these observations.


Development and validation of the Collaborative Health Outcomes Information Registry body map.
Critical for the diagnosis and treatment of chronic pain is the anatomical distribution of pain. Several body maps allow patients to indicate pain areas on paper; however, each has its limitations. To provide a comprehensive body map that can be universally applied across pain conditions, we developed the electronic Collaborative Health Outcomes Information Registry (CHOIR) self-report body map by performing an environmental scan and assessing existing body maps. After initial validation using a Delphi technique, we compared (1) pain location questionnaire responses of 530 participants with chronic pain with (2) their pain endorsements on the CHOIR body map (CBM) graphic. A subset of participants (n = 278) repeated the survey 1 week later to assess test-retest reliability. Finally, we interviewed a patient cohort from a tertiary pain management clinic (n = 28) to identify reasons for endorsement discordances. The intraclass correlation coefficient between the total number of body areas endorsed on the survey and those from the body map was 0.86 and improved to 0.93 at follow-up. The intraclass correlation coefficient of the 2 body map graphics separated by 1 week was 0.93. Further examination demonstrated high consistency between the questionnaire and CBM graphic (<10% discordance) in most body areas except for the back and shoulders (≈15-19% discordance). Participants attributed inconsistencies to misinterpretation of body regions and laterality, the latter of which was addressed by modifying the instructions. Our data suggest that the CBM is a valid and reliable instrument for assessing the distribution of pain.


Mania and bipolar depression: complementing not opposing poles-a post-hoc analysis of mixed features in manic and hypomanic episodes.
Depending on the classification system used, 5-40% of manic subjects present with concomitant depressive symptoms. This post-hoc analysis evaluates the hypothesis that (hypo)manic subjects have a higher burden of depression than non-(hypo)manic subjects. Data from 806 Bipolar I or II participants of the Stanley Foundation Bipolar Network (SFBN) were analyzed, comprising 17,937 visits. A split data approach was used to separate evaluation and verification in independent samples. For verification of our hypotheses, we compared mean IDS-C scores ratings of non-manic, hypomanic and manic patients. Data were stored on an SQL-server and extracted using standard SQL functions. Linear correlation coefficients and pivotal tables were used to characterize patient groups. Mean age of participants was 40 ± 12 years (range 18-81). 460 patients (57.1%) were female and 624 were diagnosed as having bipolar I disorder (77.4%) and 182 with bipolar II (22.6%). Data of 17,937 visits were available for analyses, split into odd and even patient numbers and stratified into three groups by YMRS-scores: not manic < 12, hypomanic < 21, manic < 30. Average IDS-C sum scores in manic or hypomanic states were significantly higher (p < .001) than for non-manic states. (Hypo)manic female patients were likely to show more depressive symptoms than males (p < .001). Similar results were obtained when only the core items of the YMRS or only the number of depressive symptoms were considered. Analyzing the frequency of (hypo)manic mixed states applying a proxy of the DSM-5 mixed features specifier extracted from the IDS-C, we found that almost 50% of the (hypo)manic group visits fulfilled DSM-5 mixed features specifier criteria. Subjects with a higher manic symptom load are also significantly more likely to experience a higher number of depressive symptoms. Mania and depression are not opposing poles of bipolarity but complement each other.


Recent Advances in Alkaline Exchange Membrane Water Electrolysis and Electrode Manufacturing.
Water electrolysis to obtain hydrogen in combination with intermittent renewable energy resources is an emerging sustainable alternative to fossil fuels. Among the available electrolyzer technologies, anion exchange membrane water electrolysis (AEMWE) has been paid much attention because of its advantageous behavior compared to other more traditional approaches such as solid oxide electrolyzer cells, and alkaline or proton exchange membrane water electrolyzers. Recently, very promising results have been obtained in the AEMWE technology. This review paper is focused on recent advances in membrane electrode assembly components, paying particular attention to the preparation methods for catalyst coated on gas diffusion layers, which has not been previously reported in the literature for this type of electrolyzers. The most successful methodologies utilized for the preparation of catalysts, including co-precipitation, electrodeposition, sol-gel, hydrothermal, chemical vapor deposition, atomic layer deposition, ion beam sputtering, and magnetron sputtering deposition techniques, have been detailed. Besides a description of these procedures, in this review, we also present a critical appraisal of the efficiency of the water electrolysis carried out with cells fitted with electrodes prepared with these procedures. Based on this analysis, a critical comparison of cell performance is carried out, and future prospects and expected developments of the AEMWE are discussed.


Next-generation phenotyping: requirements and strategies for enhancing our understanding of genotype-phenotype relationships and its relevance to crop improvement.
More accurate and precise phenotyping strategies are necessary to empower high-resolution linkage mapping and genome-wide association studies and for training genomic selection models in plant improvement. Within this framework, the objective of modern phenotyping is to increase the accuracy, precision and throughput of phenotypic estimation at all levels of biological organization while reducing costs and minimizing labor through automation, remote sensing, improved data integration and experimental design. Much like the efforts to optimize genotyping during the 1980s and 1990s, designing effective phenotyping initiatives today requires multi-faceted collaborations between biologists, computer scientists, statisticians and engineers. Robust phenotyping systems are needed to characterize the full suite of genetic factors that contribute to quantitative phenotypic variation across cells, organs and tissues, developmental stages, years, environments, species and research programs. Next-generation phenotyping generates significantly more data than previously and requires novel data management, access and storage systems, increased use of ontologies to facilitate data integration, and new statistical tools for enhancing experimental design and extracting biologically meaningful signal from environmental and experimental noise. To ensure relevance, the implementation of efficient and informative phenotyping experiments also requires familiarity with diverse germplasm resources, population structures, and target populations of environments. Today, phenotyping is quickly emerging as the major operational bottleneck limiting the power of genetic analysis and genomic prediction. The challenge for the next generation of quantitative geneticists and plant breeders is not only to understand the genetic basis of complex trait variation, but also to use that knowledge to efficiently synthesize twenty-first century crop varieties.


Mixing short- and long-acting local anaesthetics in peripheral nerve blocks: Protocol for a systematic review and meta-analysis.
This protocol describes a systematic review and meta-analysis to evaluate the clinical effects of mixing short- and long-acting local anaesthetics in peripheral nerve blocks. Clinicians often combine short- and long-acting local anaesthetics to achieve a briefer onset time. However, this may come with a prize, namely a shorter total duration of the block, which is of clinical importance. This systematic review aims to strengthen the knowledge of the clinical effects associated with this practice. The primary outcome is the duration of block analgesia. Secondary outcomes are block onset time, sensory and motor block duration. Exploratory outcomes are postoperative pain scores, cumulative 24-h opioid consumption and the prevalence of serious adverse events. We will conduct a meta-analysis of the extracted data, and the risk of bias for each study will be evaluated. We will perform a Trial Sequential Analysis, subgroup, and sensitivity analyses and assess the overall risk of publication bias. Finally, we will evaluate the review using the GRADE principles.


[The surgical characteristics of patients with postburn vascularized leukomas].
In order to avoid neovascularization of corneal grafts in keratoplasty, 3 variants of keratoplasty are proposed for surgical treatment of after-burn vascularized leukomas of category III and IV. The variants were used for treatment of 25 patients with sequelae after chemical and thermic eye burns of degree II and III. The variants of keratoplasty were differentially used depending on the severity and the character of cicatricial after-burn changes in the eye. The schemes of the variants are proposed. The analysis of immediate and remote results (from 5 months to 4 years) after the usage of the three variants of keratoplasty has shown effectiveness of the proposed reconstructive interventions, the expediency of a differential approach to the choice of the method of keratoplasty, the importance of using collagenic coverings for protection of the graft from a mechanic trauma, infection as well as for stimulating the growth corneal epithelium.


Life's Essential 8 and risk of incident heart failure in community population without cardiovascular disease: Results of the sub-cohort of China PEACE Million Persons Project.
The American Heart Association has introduced the Life's Essential 8 metrics to evaluate and promote cardiovascular health (CVH) and we aimed to evaluate the association of CVH and incident heart failure (HF). The China PEACE Million Persons Project is a population-based cardiovascular disease (CVD) screening study. This was a sub-cohort of the project that included individuals free of CVD at baseline. Components and classifications of CVH, including diet, physical activity, smoking status, sleep status, body mass index (BMI), non-high density lipoprotein (non-HDL), blood glucose and blood pressure, were determined based on the Life's Essential 8. CVH status was categorized as poor, intermediate and ideal status. HF cases were identified by linking hospital records. Among the cohort (n = 38,571, median age 54 years and women 60.5%), proportion of individuals with poor, intermediate and ideal CVH was 30.7%, 56.9% and 12.4%. After a median follow-up of 3.56 years, the incidence of HF in individuals with poor, intermediate and ideal CVH was 2.5%, 1.1% and 0.5% respectively. Compared to poor CVH, intermediate (adjusted HR: 0.52 [95% CI: 0.43-0.61]) and ideal CVH (adjusted HR: 0.38 [95% CI: 0.26-0.57]) were associated with a lower HF risk. A gradient of association between CVH and HF risk was observed (P-trend<0.001). Ideal physical activity, ideal smoking status, and intermediate and ideal status of BMI, blood glucose and blood pressure were associated with a lower HF risk. Poor CVH was associated with an increased risk of HF, and promotion of CVH may help prevent HF development.


A Sensitive LC-MS/MS Method for Palytoxin Using Lithium Cationization.
Palytoxin (PlTX) and analogues are produced by certain dinoflagellates, sea anemones, corals and cyanobacteria. PlTX can accumulate in the food chain and when consumed it may cause intoxication with symptoms like myalgia, weakness, fever, nausea, and vomiting. The analysis of PlTXs is challenging, and because of the large molecular structure, it is difficult to develop a sensitive and selective liquid chromatography-mass spectrometry (LC-MS/MS) method. In this work, an LC-MS/MS method was developed to analyse PlTXs with use of lithium iodine and formic acid as additives in the mobile phase. For method development, initially, LC-hrMS was used to accurately determine the elemental composition of the precursor and product ions. The main adduct formed was [M + H + 2Li]3+. Fragments were identified with LC-hrMS and these were incorporated in the LC-MS/MS method. A method of 10 min was developed and a solid phase extraction clean-up procedure was optimised for shellfish matrix. The determined limits of detection were respectively 8 and 22 µg PlTX kg-1 for mussel and oyster matrix. Oysters gave a low recovery of approximately 50% for PlTX during extraction. The method was successfully in-house validated, repeatability had a relative standard deviation less than 20% (n = 5) at 30 µg PlTX kg-1 in mussel, cockle, and ensis, and at 60 µg PlTX kg-1 in oyster.


Use of reality "female condoms" for anal sex by US men who have sex with men. HIVNET Vaccine Preparedness Study Protocol Team.
This study assessed use of Reality "female condoms" for anal sex by HIV-seronegative men who have sex with men and are at high risk for HIV infection. Self-administered questionnaires were completed by 2277 participants in a 6-city prospective cohort study. Of the 1084 (48%) men who had heard of using the female condom for anal sex, 145 (13%) reported using it in the prior 6 months. Users were at greater risk than nonusers: 47 receptive and 35 insertive users reported problems, including bleeding by the receptive partner (4). Redesign of the female condom could increase acceptability and use by men who have sex with men and could address possible safety concerns.


Presacral arteriovenous fistula: case report.
We describe a case of arteriovenous fistula in front of the sacrum. Drainage induced epidural venous dilation in the sacral spinal canal. The fistula was embolized endoarterially with n-butyl-2-cyanoacrylate via its iliac arterial feeders. In follow-up digital subtraction angiography 1 month later, the fistula was found to be totally closed. The patient was followed up clinically for 2.5 years. She has remained symptom-free. A previously healthy 43-year-old woman presented with severe gluteal and perineal pain and a local sensation of hyperesthesia. The primary computed tomographic scan of the lumbosacral spine was normal, and emergency laparoscopy showed no signs of any pathological lesions. Magnetic resonance imaging discovered an unidentified mass in the sacral spinal canal, and the patient was hospitalized for neurosurgery. However, surgery on this mass had to be discontinued because of profuse bleeding, and the patient was referred for angiography. Diagnostic catheter angiography revealed a high-flow arteriovenous fistula anterior to the sacrum, and the mass detected earlier by magnetic resonance imaging seemed to be a dilated epidural vein draining the fistula. The feeders of the fistula originated in both internal iliac arteries, and the fistula was occluded via these arteries in two angiographic sessions. A paraspinal arteriovenous fistula may have venous drainage through the epidural venous plexus, and the ectatic veins may induce radicular symptomology. To the best of our knowledge, a paraspinal fistula at such a presacral location has not been documented previously. An unidentified mass in the sacral spinal canal should be suspected of being a dilated vascular structure. Prompt angiographic examinations with an option for embolization should be performed, and open surgical intervention should be avoided.


QT dispersion in single coronary artery disease: is there a relation between QT dispersion and diseased coronary artery or lesion localization?
It has been shown that QT dispersion (QTD) increases during episodes of myocardial ischemia or infarction. However, no extensive data on the relation between the diseased coronary artery or the localization of stenosis and the QTD are available. The aim of the study was to examine the relation between QTD and diseased coronary artery and lesion localization during exercise stress test in patients with single coronary artery disease without prior myocardial infarction. One hundred nineteen patients with single coronary artery disease and 53 patients with normal coronary arteries were enrolled in study. All patients underwent exercise stress test with modified Bruce protocol, and QT interval parameters were measured at rest and at minute 2 of the recovery (rec-2) period. QT dispersion at rest was found higher in all single-vessel disease groups compared with that in the control group, and corrected QT dispersion at rec-2 period was also markedly higher in left anterior descending, circumflex, and right coronary artery groups compared with that in the control group. No relation was found between QT dispersion and diseased coronary artery or the lesion localization. In conclusion, no qualitative difference was found between QT dispersion and diseased coronary artery or proximal or distal lesion localization. However, it was observed that patients with single-vessel disease had wider baseline QT dispersion as compared with that in the control group, which further increased significantly with exercise. This finding supports the idea that severity of localized ischemia rather than extent of coronary artery disease would be expected to have a greater effect on inducible QT dispersion.


A facile method for preparation of uniform polymeric vesicles with tunable size.
Vesicle size and size uniformity determine whether the vesicle can realize its full potential in a wide range of biological and biomedical applications. Herein, we reported a simple yet general cosolvent method to directly prepare uniform polymeric vesicles with a tunable size ranging from 100 nm to 150 nm formed from the amphiphilic diblock copolymer poly(4-vinylpyridine)-block-polystyrene (P4VP77-b-PS318). The uniform polymeric vesicles can be easily obtained by adding plenty of selective solvent only once into the polymer solution and then resting overnight. It is found that uniform vesicles are formed with a fixed size. There is no further fusion between vesicles. The PDI of the vesicles measured by DLS can be as low as 0.03. Moreover, the size of these uniform vesicles can be controlled by the content of the selective solvent. The higher the content of the selective solvent, the smaller the vesicles that form. Monte Carlo simulation was also performed in this study. The simulation results indicated that the vesicle size indeed decreases with an increase in the content of the selective solvent. Two reasons leading to the decrease in vesicle size are elucidated. In addition, the simulations reveal that the size uniformity of the vesicle is essentially determined by the interactive enthalpy of the system.


Microfabrication as a scientific tool.
Research in microfabrication not only serves the microelectronics industry but also can provide research tools for studying the behavior of matter at submicrometer dimensions. A variety of techniques including optical, x-ray, and electron beam lithography and reactive ion etching can be used to make structures, devices, and arrays only hundreds of atoms across. Microfabrication techniques have been applied to experiments on surface-enhanced Raman scattering, transport in one-dimensional conductors, and macroscopic quantum tunneling. Recent progress is extending these techniques to scales of less than 100 angstroms.


Clinical significance of knee joint changes after meniscectomy.
The incidence of Fairbank's radiologic knee joint changes after unilateral meniscectomy was investigated in 180 patients. All patients who had a fracture, cartilage disorders, and/or ligamentous instability at the time of operation or suffered from identical lesions during the follow-up period were excluded. The degree of Fairbank's changes, squaring and sclerosis of the tibial and femoral chondylar articular surfaces, was compared with the postoperative results. The assessment of the results was based on the patient's history. An unsatisfactory postoperative result appeared to coincide more often with Fairbank's changes, but no relation could be demonstrated between the degree of Fairbank's changes and the postoperative result. Fairbank's changes were observed in 77 (42.8%) of the patients. No relation could be demonstrated between the length of the follow-up period and the degree of Fairbank's changes.


Artificial Intelligence-Enabled Model for Early Detection of Left Ventricular Hypertrophy and Mortality Prediction in Young to Middle-Aged Adults.
Concealed left ventricular hypertrophy (LVH) is a prevalent condition that is correlated with a substantial risk of cardiovascular events and mortality, especially in young to middle-aged adults. Early identification of LVH is warranted. In this work, we aimed to develop an artificial intelligence (AI)-enabled model for early detection and risk stratification of LVH using 12-lead ECGs. By deep learning techniques on the ECG recordings from 28 745 patients (20-60 years old), the AI model was developed to detect verified LVH from transthoracic echocardiography and evaluated on an independent cohort. Two hundred twenty-five patients from Japan were externally validated. Cardiologists' diagnosis of LVH was based on conventional ECG criteria. The area under the curve (AUC), sensitivity, and specificity were applied to evaluate the model performance. A Cox regression model estimated the independent effects of AI-predicted LVH on cardiovascular or all-cause death. The AUC of the AI model in diagnosing LVH was 0.89 (sensitivity: 90.3%, specificity: 69.3%), which was significantly better than that of the cardiologists' diagnosis (AUC, 0.64). In the second independent cohort, the diagnostic performance of the AI model was consistent (AUC, 0.86; sensitivity: 85.4%, specificity: 67.0%). After a follow-up of 6 years, AI-predicted LVH was independently associated with higher cardiovascular or all-cause mortality (hazard ratio, 1.91 [1.04-3.49] and 1.54 [1.20-1.97], respectively). The predictive power of the AI model for mortality was consistently valid among patients of different ages, sexes, and comorbidities, including hypertension, diabetes, stroke, heart failure, and myocardial infarction. Last, we also validated the model in the international independent cohort from Japan (AUC, 0.83). The AI model improved the detection of LVH and mortality prediction in the young to middle-aged population and represented an attractive tool for risk stratification. Early identification by the AI model gives every chance for timely treatment to reverse adverse outcomes.


Role of the middle residue in the triple tryptophan electron transfer chain of DNA photolyase: ultrafast spectroscopy of a Trp-->Phe mutant.
Photoreduction of the semi-reduced flavin adenine dinucleotide cofactor FADH* in DNA photolyase from Escherichia coli into FADH- involves three tryptophan (W) residues that form a closely spaced electron-transfer chain FADH*-W382-W359-W306. To investigate this process, we have constructed a mutant photolyase in which W359 is replaced by phenylalanine (F). Monitoring its photoproducts by femtosecond spectroscopy, the excited-state FADH* was found to decay in approximately 30 ps, similar as in wild type (WT) photolyase. In contrast to WT, however, in W359F mutant photolyase the ground-state FADH* fully recovered virtually concomitantly with the decay of its excited state and, despite the presence of the primary electron donor W382, no measurable flavin reduction was observed at any time. Thus, W359F photolyase appears to behave like many other flavoproteins, where flavin excited states are quenched by very short-lived oxidation of aromatic residues. Our analysis indicates that both charge recombination of the primary charge separation state FADH-W382*+ and (in WT) electron transfer from W359 to W382*+ occur with time constants <4 ps, considerably faster than the initial W382-->FADH* electron-transfer step. Our results provide a first experimental indication that electron transfer between aromatic residues can take place on the time scale of approximately 10(-12) s.


Interconnected Hierarchical ZSM-5 with Tunable Acidity Prepared by a Dealumination-Realumination Process: A Superior MTP Catalyst.
ZSM-5 that uses TPAOH as a template has an Al-rich exterior and defective Si-rich interior; thus, a simple base leaching selectively removed the Si-rich interior while the Al-rich exterior was protected. This catalyst showed no change in stability comparing with parent ZSM-5 during the MTP reaction that was attributed to the enclosed hollow structure and richly acidic outer shell. A preliminary fluorination, however, both removed defective Si-sites and caused distortion in tetrahedral aluminum that made the outer shell susceptible to alkaline treatment. These distorted tetrahedral Al were mostly leached out by NaOH in 1 min. Furthermore, aluminum in the filtrate was slowly redeposited onto the zeolite, serving as external pore-directing agents to control silicon dissolution from the Si-rich interior. This dealumination-realumination alkaline treatment process led to a higher solid yield and a uniform opened-mesopore structure with mesopores around 13 nm in diameter. This material was characterized by SEM, TEM, N2 adsorption, and mercury porosimetry. In addition, NH3-TPD, OH-IR, 27Al MAS NMR, and 1H MAS NMR results demonstrated that the reinserted Al were unlike the framework Al, contributing less to acidity. The dealumination-realumination process, therefore, was also capable of tuning the acidity of the mesoporous ZSM-5. This mesoporous catalyst exhibited a longer lifetime and a higher propylene selectivity than other catalysts with an enclosed mesopore structure.


Nursing patients with epilepsy in secondary care settings.
This article gives a brief overview of epilepsy and how a diagnosis is made. It highlights the importance of good observation and communication in its ongoing management. Long-term management of the condition and the acute management of seizures are considered. The article emphasises the effect on the individual, family and carers, identifies the key legislation and highlights the crucial role of secondary care nurses.


A generic and robust system for automated patient-specific classification of ECG signals.
This paper presents a generic and patient-specific classification system designed for robust and accurate detection of ECG heartbeat patterns. The proposed feature extraction process utilizes morphological wavelet transform features, which are projected onto a lower dimensional feature space using principal component analysis, and temporal features from the ECG data. For the pattern recognition unit, feedforward and fully connected artificial neural networks, which are optimally designed for each patient by the proposed multidimensional particle swarm optimization technique, are employed. By using relatively small common and patient-specific training data, the proposed classification system can adapt to significant interpatient variations in ECG patterns by training the optimal network structure, and thus, achieves higher accuracy over larger datasets. The classification experiments over a benchmark database demonstrate that the proposed system achieves such average accuracies and sensitivities better than most of the current state-of-the-art algorithms for detection of ventricular ectopic beats (VEBs) and supra-VEBs (SVEBs). Over the entire database, the average accuracy-sensitivity performances of the proposed system for VEB and SVEB detections are 98.3%-84.6% and 97.4%-63.5%, respectively. Finally, due to its parameter-invariant nature, the proposed system is highly generic, and thus, applicable to any ECG dataset.


Parsimonious Eurolung risk models to predict cardiopulmonary morbidity and mortality following anatomic lung resections: an updated analysis from the European Society of Thoracic Surgeons database.
To develop a simplified version of the Eurolung risk model to predict cardiopulmonary morbidity and 30-day mortality after lung resection from the ESTS database. A total of 82 383 lung resections (63 681 lobectomies, 3617 bilobectomies, 7667 pneumonectomies and 7418 segmentectomies) recorded in the ESTS database (January 2007-December 2018) were analysed. Multiple imputations with chained equations were performed on the predictors included in the original Eurolung models. Stepwise selection was then applied for determining the best logistic model. To develop the parsimonious models, different models were tested eliminating variables one by one starting from the less significant. The models' prediction power was evaluated estimating area under curve (AUC) with the 10-fold cross-validation technique. Cardiopulmonary morbidity model (Eurolung1): the best parsimonious Eurolung1 model contains 5 variables. The logit of the parsimonious Eurolung1 model was as follows: -2.852 + 0.021 × age + 0.472 × male -0.015 × ppoFEV1 + 0.662×thoracotomy + 0.324 × extended resection. Pooled AUC is 0.710 [95% confidence interval (CI) 0.677-0.743]. Mortality model (Eurolung2): the best parsimonious model contains 6 variables. The logit of the parsimonious Eurolung2 model was as follows: -6.350 + 0.047 × age + 0.889 × male -0.055 × BMI -0.010 × ppoFEV1 + 0.892 × thoracotomy + 0.983 × pneumonectomy. Pooled AUC is 0.737 (95% CI 0.702-0.770). An aggregate parsimonious Eurolung2 was also generated by repeating the logistic regression after categorization of the numeric variables. Patients were grouped into 7 risk classes showing incremental risk of mortality (P < 0.0001). We were able to develop simplified and updated versions of the Eurolung risk models retaining the predictive ability of the full original models. They represent a more user-friendly tool designed to inform the multidisciplinary discussion and shared decision-making process of lung resection candidates.


GeneFISH--an in situ technique for linking gene presence and cell identity in environmental microorganisms.
Our knowledge concerning the metabolic potentials of as yet to be cultured microorganisms has increased tremendously with the advance of sequencing technologies and the consequent discoveries of novel genes. On the other hand, it is often difficult to reliably assign a particular gene to a phylogenetic clade, because these sequences are usually found on genomic fragments that carry no direct marker of cell identity, such as rRNA genes. Therefore, the aim of the present study was to develop geneFISH - a protocol for linking gene presence with cell identity in environmental samples, the signals of which can be visualized at a single cell level. This protocol combines rRNA-targeted catalysed reporter deposition - fluorescence in situ hybridization and in situ gene detection. To test the protocol, it was applied to seawater samples from the Benguela upwelling system. For gene detection, a polynucleotide probe mix was used, which was designed based on crenarchaeotal amoA clone libraries prepared from each seawater sample. Each probe in the mix was selected to bind to targets with up to 5% mismatches. To determine the hybridization parameters, the T(m) of probes, targets and hybrids was estimated based on theoretical calculations and in vitro measurements. It was shown that at least 30%, but potentially the majority of the Crenarchaeota present in these samples harboured the amoA gene and were therefore likely to be catalysing the oxidation of ammonia.


Absorption coefficients of highly transparent solids: photoacoustic theory for cylindrical configurations.
The development of highly transparent solids for fiber optics, integrated optics, and high power lasers requires improved methods to measure very low absorption coefficients. For the case in which a laser beam, modulated at angular frequency omega, passes through a weakly absorbing solid which is surrounded by a confined, nonabsorbing gas, the temperature profiles in the solid and the temperature and pressure profiles in the gas have been calculated. The calculations suggest that for sufficiently low frequencies and high ambient gas pressures, enough heat transfers from the solid to the gas to produce a detectable acoustic-pressure signal at angular frequency omega in the gas. They also indicate that an absorbing layer at the solid-gas interface is not an essential mechanism for producing these detectable acoustic pressure signals. The model assumes that bulk absorption in the solid is the mechanism by which energy is transferred from the laser beam. Numerical examples for a typical laser glass are given.


The transcription factor TFII-I promotes DNA translesion synthesis and genomic stability.
Translesion synthesis (TLS) enables DNA replication through damaged bases, increases cellular DNA damage tolerance, and maintains genomic stability. The sliding clamp PCNA and the adaptor polymerase Rev1 coordinate polymerase switching during TLS. The polymerases Pol η, ι, and κ insert nucleotides opposite damaged bases. Pol ζ, consisting of the catalytic subunit Rev3 and the regulatory subunit Rev7, then extends DNA synthesis past the lesion. Here, we show that Rev7 binds to the transcription factor TFII-I in human cells. TFII-I is required for TLS and DNA damage tolerance. The TLS function of TFII-I appears to be independent of its role in transcription, but requires homodimerization and binding to PCNA. We propose that TFII-I bridges PCNA and Pol ζ to promote TLS. Our findings extend the general principle of component sharing among divergent nuclear processes and implicate TLS deficiency as a possible contributing factor in Williams-Beuren syndrome.


Tear and serum antibody response to Chlamydia trachomatis antigens during acute chlamydial conjunctivitis in monkeys as determined by immunoblotting.
In this study, we examined the temporal antibody response by immunoblotting analysis in tears and sera of three cynomolgus monkeys (Macaca fasicularis) with primary acute Chlamydia trachomatis serovar B conjunctivitis. The objective was to identify chlamydial antigens stimulating antibody during the host responses in the course of this self-limiting infection with the rationale that they may be protective antigens. The major outer membrane protein (MOMP), lipopolysaccharide (LPS), and polypeptides of 60 and 68 kilodaltons (kDa) were the predominant antigens recognized by immunoglobulin A (IgA) in monkey tears. Tear IgA antibody specific for the MOMP was first detected 14 days postinfection, whereas tear IgA reactive with LPS or the 68- and 60-kDa polypeptides was first detectable on day 21. Tear IgA antibodies specific for each of these antigens persisted in tears through day 56, 4 weeks after both peak clinical disease and recovery of the organism from the conjunctivae. In contrast, tear IgG antibodies peaked at approximately 28 days postinfection, the time of maximal inflammatory response. The IgG response in monkey sera was similar to that observed for tear antibodies, in that the MOMP, 60-, and 68-kDa polypeptides were the primary immunogens. The exception was that IgG antibody against these antigens was detected 1 week later than that observed for tear IgA antibodies. Of three monkeys that responded with tear IgA antibody against LPS, one did not have detectable serum IgG LPS antibody. The specificity of the tear IgA antibody response of monkeys was determined by immunoblotting nine other C. trachomatis serovars in addition to the homologous B serovar. The tear IgA response to the MOMP was predominantly B complex subspecies-specific (serovars B, Ba, D, and E), whereas the response to chlamydial LPS was found to be species-specific. The significance of these observations in relation to previous vaccine studies in nonhuman primates is discussed.


Contribution of lateral gene transfers to the genome composition and parasitic ability of root-knot nematodes.
Lateral gene transfers (LGT), species to species transmission of genes by means other than direct inheritance from a common ancestor, have played significant role in shaping prokaryotic genomes and are involved in gain or transfer of important biological processes. Whether LGT significantly contributed to the composition of an animal genome is currently unclear. In nematodes, multiple LGT are suspected to have favored emergence of plant-parasitism. With the availability of whole genome sequences it is now possible to assess whether LGT have significantly contributed to the composition of an animal genome and to establish a comprehensive list of these events. We generated clusters of homologous genes and automated phylogenetic inference, to detect LGT in the genomes of root-knot nematodes and found that up to 3.34% of the genes originate from LGT of non-metazoan origin. After their acquisition, the majority of genes underwent series of duplications. Compared to the rest of the genes in these species, several predicted functional categories showed a skewed distribution in the set of genes acquired via LGT. Interestingly, functions related to metabolism, degradation or modification of carbohydrates or proteins were substantially more frequent. This suggests that genes involved in these processes, related to a parasitic lifestyle, have been more frequently fixed in these parasites after their acquisition. Genes from soil bacteria, including plant-pathogens were the most frequent closest relatives, suggesting donors were preferentially bacteria from the rhizosphere. Several of these bacterial genes are plasmid-borne, pointing to a possible role of these mobile genetic elements in the transfer mechanism. Our analysis provides the first comprehensive description of the ensemble of genes of non-metazoan origin in an animal genome. Besides being involved in important processes regarding plant-parasitism, genes acquired via LGT now constitute a substantial proportion of protein-coding genes in these nematode genomes.


The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.
RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.


One-step enzyme extraction and immobilization for biocatalysis applications.
An extraction/immobilization method for HIs(6) -tagged enzymes for use in synthesis applications is presented. By modifying silica oxide beads to be able to accommodate metal ions, the enzyme was tethered to the beads after adsorption of Co(II). The beads were successfully used for direct extraction of C. antarctica lipase B (CalB) from a periplasmic preparation with a minimum of 58% activity yield, creating a quick one-step extraction-immobilization protocol. This method, named HisSi Immobilization, was evaluated with five different enzymes [Candida antarctica lipase B (CalB), Bacillus subtilis lipase A (BslA), Bacillus subtilis esterase (BS2), Pseudomonas fluorescence esterase (PFE), and Solanum tuberosum epoxide hydrolase 1 (StEH1)]. Immobilized CalB was effectively employed in organic solvent (cyclohexane and acetonitrile) in a transacylation reaction and in aqueous buffer for ester hydrolysis. For the remaining enzymes some activity in organic solvent could be shown, whereas the non-immobilized enzymes were found inactive. The protocol presented in this work provides a facile immobilization method by utilization of the common His(6) -tag, offering specific and defined means of binding a protein in a specific location, which is applicable for a wide range of enzymes.


[Chromosomal anomalies in men with infertility].
Out of 35 sterile males with impaired spermatogenesis two patients had "XX-male" syndrome and one patient had Y-chromosome deprived of a long arm. The three patients presented with similar clinical manifestations: short height, non manifest malformations, impaired spermatogenesis, sterility.


Prochlorococcus extracellular vesicles: molecular composition and adsorption to diverse microbes.
Extracellular vesicles are small (~50-200 nm diameter) membrane-bound structures released by cells from all domains of life. While vesicles are abundant in the oceans, their functions, both for cells themselves and the emergent ecosystem, remain a mystery. To better characterize these particles - a prerequisite for determining function - we analysed the lipid, protein, and metabolite content of vesicles produced by the marine cyanobacterium Prochlorococcus. We show that Prochlorococcus exports a diverse array of cellular compounds into the surrounding seawater enclosed within discrete vesicles. Vesicles produced by two different strains contain some materials in common, but also display numerous strain-specific differences, reflecting functional complexity within vesicle populations. The vesicles contain active enzymes, indicating that they can mediate extracellular biogeochemical reactions in the ocean. We further demonstrate that vesicles from Prochlorococcus and other bacteria associate with diverse microbes including the most abundant marine bacterium, Pelagibacter. Together, our data point toward hypotheses concerning the functional roles of vesicles in marine ecosystems including, but not limited to, possibly mediating energy and nutrient transfers, catalysing extracellular biochemical reactions, and mitigating toxicity of reactive oxygen species.