Trait rumination in post-stress growth among Chinese college students: the chain mediating effect of distress disclosure and perceived social support.
Rumination has emerged as a significant factor contributing to personal growth following periods of stress or trauma. The present study aimed to investigate the relationship between trait rumination and post-stress growth (PSG) within the context of Chinese college students who encounter mild stressors in their daily lives. Moreover, we aim to evaluate the potential mediating roles played by both distress disclosure and perceived social support in this dynamic relationship. All participants completed assessments using the Adolescent Self-Rating Life Events Checklist, Rumination Response Scale, Post-Stress Growth Inventory, Distress Disclosure Index, and Perceived Social Support Scale. Correlation and mediation analyses were conducted using SPSS PROCESS 4 MACRO. All students reported experiencing mild psychological impacts as a result of negative life events in the past year and displayed moderate levels of PSG. There was no significant correlation observed between the effects of negative life events and PSG. Significant negative correlations were found between trait rumination and distress disclosure, perceived social support, and PSG. Distress disclosure and perceived social support jointly operated as sequential mediators in the relationship between trait rumination and PSG among all the participants. Qualitative analyses revealed different correlation patterns of high- versus low-ruminator. Trait rumination affects PSG both directly and indirectly, through its influence on distress disclosure and perceived social support. Our results emphasize the significance of actively participating in distress disclosure and nurturing a robust sense of social support to counteract the detrimental effects of rumination on post-stress growth among Chinese college students.


Human papillomavirus infection and cervical cancer precursor lesions in women living by Amazon rivers: investigation of relations with markers of oxidative stress.
Objective To investigate the relation between oxidative stress markers, human papillomavirus infection and cervical cancer precursor lesions. Methods The study comprised women aged 14 to 60 years living in communities located by Amazon rivers in the state of Pará (Itaituba, Limoeiro do Ajuru and Bragança, 126, 68 and 43 women respectively). Papanicolau smears and polymerase chain reaction tests for human papillomavirus DNA detection were performed. Blood samples were collected to test malondialdehyde, total and oxidized glutathione levels. Results Malondialdehyde, total and oxidized glutathione concentrations did not differ significantly (p>0.05) between women with and without low-grade squamous intraepithelial lesions across communities. Malondialdehyde levels (8.02nmols/mL) were almost five times higher in human papillomavirus-positive compared to human papillomavirus-negative women (1.70nmols/mL) living in Itaituba (statistically significant difference; p<0.05). Malondialdehyde levels did not differ significantly (p>0.05) between human papillomavirus-positive and human papillomavirus-negative women living in remaining communities. Significant (p<0.05) differences in total glutathione levels between human papillomavirus-positive and human papillomavirus-negative women (8.20μg/mL and 1.47μg/mL, respectively) were limited to those living in Bragança. Conclusion Malondialdehyde and total glutathione levels were significantly associated with human papillomavirus infection. However, lack of similar associations with squamous lesions suggest oxidative stress alone does not explain correlations with cervical carcinogenesis. Other factors may therefore be involved.


Predicting death despite therapeutic hypothermia in infants with hypoxic-ischaemic encephalopathy.
To determine precooling attributes possibly predicting death in infants with hypoxic-ischaemic encephalopathy (HIE) despite therapeutic cooling. Eighty-five consecutive infants of ≥36 weeks' gestation who received cooling for HIE were reviewed. Logistic regression analysis was performed using precooling clinical and laboratory variables with death related to HIE during the first 9 months of life as the primary outcome. Thirteen (15%) of the 85 infants died during 9-18 months of follow-up despite cooling. 27 of the 85 were asystolic at birth but only 12 had Apgar scores of zero at both 5 and 10 min. Univariate analysis identified Apgar scores of zero at 5 and 10 min, pH <6.7, base deficit >22 mmol/l, and absent spontaneous movement as significantly associated with death during the first 9 months despite cooling. On multivariate analysis, only the Apgar score of zero at 10 min (p<0.001, OR 51.7, 95% CI 9.9 to 269.5) remained significantly associated with the primary outcome of death from HIE. Of the 12 infants who were asystolic at and beyond 10 min of life, nine died from HIE, two had spastic quadriparesis and global delay at 18-24 months, and one had extensive encephalomalacia on brain MRI during follow-up. Of the selected precooling variables, only the 10 min Apgar score is independently associated with death despite therapeutic cooling in infants with HIE. Infants who remain asystolic at 10 min and beyond are unlikely to survive despite cooling, and the rare survivor is likely to have severe disability.


Biochemical characterization of human tissue kallikrein 15 and examination of its potential role in cancer.
Human tissue kallikrein 15 (KLK15) is the last cloned member of the KLK-related gene family. Despite being implicated in multiple cancers, its pathophysiological role remains unknown. We aimed to biochemically characterize KLK15 and preliminarily study its role in cancer. Recombinant KLK15 protein was produced, purified to homogeneity and quantified by mass spectrometry (parallel reaction monitoring analysis). We profiled the enzymatic activity of KLK15 using fluorogenic peptide substrates, and performed kinetic analysis to discover the cleavage sites. As KLK15 has mainly been associated with prostate cancer, we used a degradomic approach and subsequent KEGG pathway analysis to identify a number of putative protein substrates in the KLK15-treated prostate cancer cell line PC3. We discovered trypsin-like activity in KLK15, finding that it cleaves preferentially after arginine (R). The enzymatic activity of KLK15 was regulated by different factors such as pH, cations and serine protease inhibitors. Notably, we revealed that KLK15 most likely interacts with the extracellular matrix (ECM) receptor group. To our knowledge, this is the first study that experimentally verifies the trypsin-like activity of KLK15. We show here for the first time that KLK15 may be able to cleave many ECM components, similar to several members of the KLK family. Thus the protease could potentially be linked to tumorigenesis by promoting metastasis via this mechanism.


Deletion of Bid impedes cell proliferation and hepatic carcinogenesis.
Mechanisms that control the proliferation capability of the initiated cells during hepatocarcinogenesis are still largely unclear. We investigated the role of a pro-death Bcl-2 family protein, Bid, in liver tumor development using a neonatal diethylnitrosamine model. Diethylnitrosamine was administrated to 15-day-old wild-type and bid-null mice. The development of microfoci at the early stage and of gross tumors at the later stage was compared between the two groups of mice. Both microfoci and gross tumor development were significantly retarded in the bid-null mice, despite reduced cell death as measured by TUNEL staining. Further studies indicated that there were significantly less proliferating cells in diethylnitrosamine-treated bid-null livers. The regulation of cell proliferation by Bid was confirmed in two other systems not involving carcinogenesis. Hepatocyte proliferation following partial hepatectomy and T lymphocyte proliferation following anti-CD3 stimulation were both retarded in bid-null mice. Thus, these studies revealed a previously undisclosed function of Bid in regulating cell proliferation, which can be important to tumor development. Furthermore, the role of Bid in promoting hepatocarcinogenesis is in contrast to its reported role in suppressing myeloid leukemia and thus suggests an organ- and/or etiology-specific role of the Bcl-2 family proteins in regulating oncogenesis.


Spontaneous globe subluxation: a case report and review of the literature.
Spontaneous globe subluxation (SGS) is an atraumatic anterior dislocation of the eyeball. It is exceedingly rare. Understanding SGS predisposing factors may help uncover its etiology and undertake vision-saving management. A 48-year-old female presented to the ED with her right eye out of its socket. She reported blurry vision, photophobia, and pain in the affected eye. She was unable to close her right eyelid and was in obvious distress. On arrival, her blood pressure was elevated. Her medical history was notable for hypertension and obesity. On physical examination, extraocular eye movements were not intact, and the globe appeared whole and round. She was also unable to count fingers with the affected eye. There was no visible trauma to the face. Multiple wet gauzes with sterile saline were placed over the displaced eyeball. Direct and even pressure was applied on the globe. Within 30 s, the globe was reduced back in. The patient was able to close her eyelids and reports substantial pain relief with reduction. A CT scan of the orbits was then obtained, demonstrating mild bilateral proptosis. The globes were normal and symmetric. No intraconal or extraconal abscess or infection was seen. There were no intraconal or extraconal masses. There was no acute orbital traumatic injury, no avulsion of the optic nerve, ocular rupture, or retrobulbar hematoma. After reviewing the case with an ophthalmologist, a follow-up appointment with the ophthalmologist was arranged. The patient was discharged on erythromycin ointment. Post-discharge investigation of the CT imaging revealed dilated optic nerve sheaths, tortuosity of the optic nerve, and empty sella. In addition to causing distress and severe anxiety, SGS poses numerous immediate as well as long-term complications. Traction of the optic nerve and retinal vasculature may potentially cause retinal venous congestion and loss of visual acuity with potential vision loss. In the absence of known risk factors or disease processes, orbital imaging and serological studies for thyroid ophthalmopathy should be considered.


Assessing the status and trend of bat populations across broad geographic regions with dynamic distribution models.
Bats face unprecedented threats from habitat loss, climate change, disease, and wind power development, and populations of many species are in decline. A better ability to quantify bat population status and trend is urgently needed in order to develop effective conservation strategies. We used a Bayesian autoregressive approach to develop dynamic distribution models for Myotis lucifugus, the little brown bat, across a large portion of northwestern USA, using a four-year detection history matrix obtained from a regional monitoring program. This widespread and abundant species has experienced precipitous local population declines in northeastern USA resulting from the novel disease white-nose syndrome, and is facing likely range-wide declines. Our models were temporally dynamic and accounted for imperfect detection. Drawing on species-energy theory, we included measures of net primary productivity (NPP) and forest cover in models, predicting that M. lucifugus occurrence probabilities would covary positively along those gradients. Despite its common status, M. lucifugus was only detected during -50% of the surveys in occupied sample units. The overall naive estimate for the proportion of the study region occupied by the species was 0.69, but after accounting for imperfect detection, this increased to -0.90. Our models provide evidence of an association between NPP and forest cover and M. lucifugus distribution, with implications for the projected effects of accelerated climate change in the region, which include net aridification as snowpack and stream flows decline. Annual turnover, the probability that an occupied sample unit was a newly occupied one, was estimated to be low (-0.04-0.14), resulting in flat trend estimated with relatively high precision (SD = 0.04). We mapped the variation in predicted occurrence probabilities and corresponding prediction uncertainty along the productivity gradient. Our results provide a much needed baseline against which future anticipated declines in M. lucifugus occurrence can be measured. The dynamic distribution modeling approach has broad applicability to regional bat monitoring efforts now underway in several countries and we suggest ways to improve and expand our grid-based monitoring program to gain robust insights into bat population status and trend across large portions of North America.


The oceanic budgets of nickel and zinc isotopes: the importance of sulfidic environments as illustrated by the Black Sea.
Isotopic data collected to date as part of the GEOTRACES and other programmes show that the oceanic dissolved pool is isotopically heavy relative to the inputs for zinc (Zn) and nickel (Ni). All Zn sinks measured until recently, and the only output yet measured for Ni, are isotopically heavier than the dissolved pool. This would require either a non-steady-state ocean or other unidentified sinks. Recently, isotopically light Zn has been measured in organic carbon-rich sediments from productive upwelling margins, providing a potential resolution of this issue, at least for Zn. However, the origin of the isotopically light sedimentary Zn signal is uncertain. Cellular uptake of isotopically light Zn followed by transfer to sediment does not appear to be a quantitatively important process. Here, we present Zn and Ni isotope data for the water column and sediments of the Black Sea. These data demonstrate that isotopically light Zn and Ni are extracted from the water column, probably through an equilibrium fractionation between different dissolved species followed by sequestration of light Zn and Ni in sulfide species to particulates and the sediment. We suggest that a similar, non-quantitative, process, operating in porewaters, explains the Zn data from organic carbon-rich sediments.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.


The use of tacit and explicit knowledge in public health: a qualitative study.
Planning a public health initiative is both a science and an art. Public health practitioners work in a complex, often time-constrained environment, where formal research literature can be unavailable or uncertain. Consequently, public health practitioners often draw upon other forms of knowledge. Through use of one-on-one interviews and focus groups, we aimed to gain a better understanding of how tacit knowledge is used to inform program initiatives in public health. This study was designed as a narrative inquiry, which is based on the assumption that we make sense of the world by telling stories. Four public health units were purposively selected for maximum variation, based on geography and academic affiliation. Analysis revealed different ways in which tacit knowledge was used to plan the public health program or initiative, including discovering the opportunity, bringing a team together, and working out program details (such as partnering, funding). The findings of this study demonstrate that tacit knowledge is drawn upon, and embedded within, various stages of the process of program planning in public health. The results will be useful in guiding the development of future knowledge translation strategies for public health organizations and decision makers.


Changing habitat associations of a thermally constrained species, the silver-spotted skipper butterfly, in response to climate warming.
1. The impact of climate change on the distribution, abundance, phenology and ecophysiology of species is already well documented, whereas the influence of climate change on habitat choice and utilization has received little attention. Here we report the changing habitat associations of a thermally constrained grassland butterfly, Hesperia comma, over 20 years. 2. Between 1982 and 2001-2, the optimum percentage of bare ground within habitat used for egg-laying shifted from 41% to 21%. 3. Egg-laying rates are temperature-dependent and females actively adjust microhabitat usage in response to temperature variations; relatively warmer host plants are chosen or oviposition at low ambient temperatures, and cooler host plants at high ambient temperatures. 4. Climate warming has increased the availability of thermally suitable habitat for H. comma at the cool, northern edge of the species' distribution, therefore increasing: (a) egg-laying rate and potentially the realized rate of population increase; (b) effective area of habitat patches as more microhabitats within a given vegetation fragment are now suitable for egg-laying; (c) buffering of populations against environmental variation as eggs are laid within a wider range of microhabitats; and (d) the number of habitat patches in the landscape that are currently available for colonization (including the use of more northerly facing aspects; Thomas et al., Nature, 2001, 411, 577-581). 5. Conservationists often assume the habitat requirements of a species to be constant, and manage habitats to maintain these conditions. For many species, these requirements are likely to change in response to climate warming, and care must be taken not to manage habitats based on outdated prescriptions.


Retinal disease course in Usher syndrome 1B due to MYO7A mutations.
PURPOSE. To determine the disease course in Usher syndrome type IB (USH1B) caused by myosin 7A (MYO7A) gene mutations. METHODS. USH1B patients (n = 33, ages 2-61) representing 25 different families were studied by ocular examination, kinetic and chromatic static perimetry, dark adaptometry, and optical coherence tomography (OCT). Consequences of the mutant alleles were predicted. RESULTS. All MYO7A patients had severely abnormal ERGs, but kinetic fields revealed regional patterns of visual loss that suggested a disease sequence. Rod-mediated vision could be lost to different degrees in the first decades of life. Cone vision followed a more predictable and slower decline. Central vision ranged from normal to reduced in the first four decades of life and thereafter was severely abnormal. Dark adaptation kinetics was normal. Photoreceptor layer thickness in a wide region of central retina could differ dramatically between patients of comparable ages; and there were examples of severe losses in childhood as well as relative preservation in patients in the third decade of life. Comparisons were made between the mutant alleles in mild versus more severe phenotypes. CONCLUSIONS. A disease sequence in USH1B leads from generally full but impaired visual fields to residual small central islands. At most disease stages, there was preserved temporal peripheral field, a potential target for early phase clinical trials of gene therapy. From data comparing patients' rod disease in this cohort, the authors speculate that null MYO7A alleles could be associated with milder dysfunction and fewer photoreceptor structural losses at ages when other genotypes show more severe phenotypes.


Salmonellosis in goats.
Three episodes of salmonellosis in goats were similar to the disease described in neonatal calves, 2- to 4-week-old calves, and adult cattle. However, bloody diarrhea so often associated with salmonellosis in other animals was not seen in any of the goats. Mortality was high despite fluid therapy and the use of antibiotics shown to be effective in vitro. The importance of specific etiologic diagnosis was emphasized, inasmuch as salmonellosis of goats can be confused with other, more common diseases and, though other measures can be used to treat or control these similar diseases, strict sanitation and management changes were the only means found to be effective in the control of caprine salmonellosis.


STAT1 regulates human glutaminase 1 promoter activity through multiple binding sites in HIV-1 infected macrophages.
Mononuclear phagocytes (MP, macrophages and microglia), the main targets of HIV-1 infection in the brain, play a pathogenic role in HIV-associated neurocognitive disorders (HAND) through the production and release of various soluble neurotoxic factors including glutamate. We have previously reported that glutaminase (GLS), the glutamate-generating enzyme, is upregulated in HIV-1 infected MP and in the brain tissues of HIV dementia individuals, and that HIV-1 or interferon-α (IFN-α) regulates human glutaminase 1 (GLS1) promoter through signal transducer and activator of transcription 1 (STAT1) phosphorylation in macrophages. However, there are multiple putative STAT1 binding sites in human GLS1 promoter, the exact molecular mechanism of how HIV-1 or IFN-α regulates human GLS1 promoter remains unclear. To further study the function of the putative STAT1 binding sites, we mutated the sequence of each binding site to ACTAGTCTC and found that six mutants (mut 1,3,4,5,7,8) had significantly higher promoter activity and two mutants (mut 2 and mut 6) completely lost the promoter activity compared with the wild type. To determine whether sites 2 and 6 could interfere with other inhibitory sites, particularly the nearby inhibitory sites 3 and 5, we made double mutants dmut 2/3 and dmut 5/6, and found that both the double mutants had significantly higher activity than the wild type, indicating that sites 3 and 5 are critical inhibitory elements, while sites 2 and 6 are excitatory elements. ChIP assay verified that STAT1 could bind with sites 2/3 and 5/6 within human GLS1 promoter in IFN-α stimulated or HIV-1-infected monocyte-derived macrophages. Interestingly, we found that rat Gls1 promoter was regulated through a similar way as human GLS1 promoter. Together, our data identified critical elements that regulate GLS1 promoter activity.


Ferric carboxymaltose: A revolution in the treatment of postpartum anemia in Indian women.
The objective of the present study is to compare the safety and efficacy of ferric carboxymaltose (FCM), intravenous (IV) iron sucrose and oral iron in the treatment of post = partum anemia (PPA). A total of 366 women admitted to SCB Medical College, Cuttack between September 2010 and August 2012 suffering from PPA hemoglobin (Hb) <10 g/dL were randomly assigned to receive either oral iron or IV FCM or iron sucrose. FCM, IV iron sucrose, and oral iron were given as per the protocol. Changes in hemoglobin (Hb) and serum ferritin levels at 2 and 6 weeks after treatment were measured and analyzed using ANOVA. Adverse effects to drug administration were also recorded. A statistically significant increase in Hb and serum ferritin level were observed in all three groups, but the increase in FCM group was significantly higher (P < 0.0001) than conventional iron sucrose and oral iron group. The mean increase in Hb after 2 weeks was 0.8, 2.4, and 3.2 g/dL and 2.1, 3.4, and 4.4 g/dL at 6 weeks in oral iron, iron sucrose and FCM groups, respectively. The mean increase in serum ferritin levels after 2 weeks was 2.5, 193.1, and 307.1 and 14.2, 64, and 106.7 ng/mL after 6 weeks in oral iron, iron sucrose and FCM groups, respectively. Adverse drug reactions were significantly less (P < 0.001) in FCM group when compared with other two groups. Ferric carboxymaltose elevates Hb level and restores iron stores faster than IV iron sucrose and oral iron, without any severe adverse reactions. There was better overall satisfaction reported by the patients who received FCM treatment.


Adoption of anesthesia information management systems by academic departments in the United States.
Information technology has been promoted as a way to improve patient care and outcomes. Whereas information technology systems for ancillary hospital services (e.g., radiology, pharmacy) are deployed commonly, it has been estimated that anesthesia information management systems (AIMS) are only installed in a small fraction of United States (US) operating rooms. In this study, we assessed the adoption of AIMS at academic anesthesia departments and explored the motivations for and resistance to AIMS adoption. Members of the Society of Academic Anesthesiology Chairs and the Association of Anesthesiology Program Directors were solicited by e-mail to participate in an online survey of AIMS adoption. Two months after closing the survey, another e-mail was sent with a single question asking for an update to their AIMS implementation status. Surveys were fully completed by 48 (34%) of the 140 Society of Academic Anesthesiology Chairs and Association of Anesthesiology Program Directors departments surveyed, with 72 (51%) providing AIMS status information. Twenty of these 72 departments have an AIMS installed, 12 are currently implementing, 11 have selected but not yet installed, and 18 are planning to purchase an AIMS in 2008 or 2009. Therefore, at least 61 (44%) of all 140 US academic anesthesia departments have committed to AIMS. This estimated adoption rate is conservative because the numerator equals the affirmative responses, whereas the denominator equals the total population of academic departments. Among adopters, the top ranked anticipated benefits from installing an AIMS included improved clinical documentation, improved data collection for clinical research, enhancement of quality improvement programs, and compliance with requirements of regulatory authorities. The hospital provided funding in almost all facilities (90%), with co-funding by the anesthesia group in 35%. At least 61 or 44% of the 140 US academic departments surveyed in this study have already implemented, are planning to acquire, or are currently searching for an AIMS. Adoption of AIMS technology appears to have reached sufficient momentum within academic anesthesiology departments to result in a fundamental change.


Thermal rectification in multilayer phase change material structures for energy storage applications.
Solid-state thermal control devices that present an asymmetric heat flow depending on thermal bias directionality, referred to as thermal diodes, have recently received increased attention for energy management. The use of materials that can change phase is a common approach to design thermal diodes, but typical sizes, moderate rectification ratios, and narrow thermal tunability limit their potential applications. In this work, we propose a multilayer thermal diode made of a combination of phase change and invariant materials. This device presents state-of-the-art thermal rectification ratios up to 136% for a temperature range between 300 K and 500 K. Importantly, this design allows to switch between distinct rectification states that can be modulated with temperature, achieving an additional degree of thermal control compared with single-rectification-state devices. We analyze the relevance of our thermal diodes for retaining heat more efficiently in thermal storage elements.


External validation of four nephrometry scores for trans-peritoneal robotic partial nephrectomy.
External validation of four nephrometry scores (NS): Centrality index (C-index), arterial based complexity (ABC), preoperative aspects and dimensions used for an anatomical (PADUA) and radius expohytic/endophytic nearness anterior/posterior location (RENAL) scoring systems in patients who have undergone trans-peritoneal robotic assisted partial nephrectomy (RAPN). A prospective database for RAPN has been maintained. Individual NSs were performed on 3-dimensional reconstructions of MDCT/MRI studies retrospectively by a board certified uroradiologist. Univariate Cox Proportional-Hazard Regression Analysis was performed for each NSs to valuate its predictability for the following parameters: Warm Ischemia Time (WIT), Estimated Blood Loss (EBL), Operative Time (OT), Complication Rates and Positive Margin Rates. 78 RAPNs were performed for suspected renal malignancies. The mean OT, EBL and WIT time was 186.5 minutes (SD - 33.8), 125.5 mls (SD - 188.91) and 16.7 minutes (SD - 5.6) respectively. The overall complication rate was 20.5% (16/78) of which only 2.6% (2/78) were Clavien Grade 3 or higher complications. The mean change in creatinine change at Day - 1 was 12.54 μmol/L (SD - 18.05). On the Cox regression analysis only the Centrality index predicted prolonged WIT with statistical significance: C-Index (0.02), ABC (0.2), PADUA (0.2), RENAL (0.9). ABC predicted operative time with statistical significance: C-index (0.45), ABC (0.0004), PADUA (0.25), RENAL (0.3). None of the NSs could predict overall complication: C-index (0.5), ABC (0.2), PADUA (0.13), RENAL (0.5). None of the NSs predicted EBL: C-index (0.3)0, ABC (0.8), PADUA (0.2), RENAL (0.7). None of the NSs predicted Positive Margin Rates: C-index (0.4), ABC (0.4), PADUA (0.9), RENAL (0.8). C-index was able to predict prolonged WIT. ABC was a strong predictor of OT. PADUA and RENAL were poor predictors for all measured parameters.


Risk of Ipsilateral Deep Vein Thrombosis After Use of AngioSeal Closure Device in Aneurysmal Subarachnoid Hemorrhage Patients.
Deep vein thrombosis (DVT) is a known complication in patients with aneurysmal subarachnoid hemorrhage (aSAH). This study investigated the association between use of the AngioSeal (St. Jude Medical, Minnetonka, MN) vascular closure device and the risk of ipsilateral and any DVT event after angiography in patients with aSAH. We conducted a review of our institutional cerebral angiography database for the years 2005-2018 to identify all adult patients who underwent angiography for aSAH. We compared the incidence of DVT (occurring within 14 days) between aSAH patients who underwent manual compression versus the AngioSeal closure device. A total of 459 aSAH patients underwent angiography; 262 underwent manual compression (57.1%) and 197 received AngioSeal (42.9%). There was a 3.4% rate of ipsilateral DVT in the manual compression group and 7.6% in the AngioSeal closure device group (χ2 test, P = 0.04). Similarly, the rate of any DVT was 8.8% for manual compression and 16.8% for patients who received AngioSeal (χ2 test, P = 0.01). On multivariate analysis, AngioSeal remained a significant independent predictor of ipsilateral DVT (odds ratio 2.4, P = 0.04) and any DVT (odds ratio 2.3, P = 0.01). In aSAH patients undergoing cerebral angiographic procedures with access through the femoral artery, the use of AngioSeal closure device was found to be associated with a significantly increased risk of ipsilateral DVT within 14 days.


Plasminogen: purification from human plasma by affinity chromatography.
Plasminogen was prepared from human plasma by affinity chromatography on L-lysine-substituted Sepharose. Thirty milligrams of plasminogen, with a specific activity of 100 caseinolytic units (Committee on Thrombolytic Agents) per milligram of nitrogen, were obtained from 340 milliliters of plasma. This corresponds to over 200-fold purification from plasma. Disc-gel electrophoresis at pH 8.3 indicated seven distinct bands, all of which contained activity.


Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells.
We report here homologous recombination (HR)-mediated gene targeting of two different genes in human iPS cells (hiPSCs) and human ES cells (hESCs). HR-mediated correction of a chromosomally integrated mutant GFP reporter gene reaches efficiencies of 0.14%-0.24% in both cell types transfected by donor DNA with plasmids expressing zinc finger nucleases (ZFNs). Engineered ZFNs that induce a sequence-specific double-strand break in the GFP gene enhanced HR-mediated correction by > 1400-fold without detectable alterations in stem cell karyotypes or pluripotency. Efficient HR-mediated insertional mutagenesis was also achieved at the endogenous PIG-A locus, with a > 200-fold enhancement by ZFNs targeted to that gene. Clonal PIG-A null hESCs and iPSCs with normal karyotypes were readily obtained. The phenotypic and biological defects were rescued by PIG-A transgene expression. Our study provides the first demonstration of HR-mediated gene targeting in hiPSCs and shows the power of ZFNs for inducing specific genetic modifications in hiPSCs, as well as hESCs.


Control of Aedes albopictus in waste tire piles with reduced rates of temephos-treated granules.
Two days following treatment, larval populations of Aedes albopictus in waste tires treated with granular formulations of temephos were reduced 90% at the 0.11 kg AI/ha rate, 98% at the 0.56 kg AI/ha rate, and 100% at the 1.12, 11.21, and 22.42 kg AI/ha rates. Nearly 100% control was achieved for 8 wk at the 0.5 kg AI/ha rate, for 7 wk at the 1.12 kg AI/ha rate in one replicate, and for at least 5 months at the 11.21 and 22.42 kg AI/ha rates. These results indicate that prolonged control can be achieved with granular formulations at half (11.21 kg/ha) the maximum label rate and that excellent immediate control can be expected at 2.5% the maximum label rate.


Positive inotropic effects of acetylcholine and BAY K 8644 in embryonic chick ventricle.
BAY K 8644 augmented Ca2+-dependent action potentials and evoked a positive inotropic effect in embryonic chick ventricle. These effects are consistent with the properties of this Ca channel "agonist" whose actions are independent of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphorylation. At low to intermediate concentrations (10(-8) to 10(-6) M), the cholinergic agonists acetylcholine, carbachol, and oxotremorine inhibit Ca2+-dependent action potentials and contractions in embryonic ventricle only in the presence of drugs that cause cAMP accumulation. The prediction that low to intermediate concentrations of these cholinergic agonists should not inhibit the effects of BAY K 8644 on Ca2+-dependent action potentials and contractions was borne out experimentally. This result is consistent with the cAMP hypothesis for muscarinic inhibition. It is noteworthy that all cholinergic agonists tested evoked a positive inotropic effect at high concentrations (greater than 10(-6) M) in the presence or absence of BAY K 8644. The positive inotropic effect was initiated by muscarinic receptors for it was blocked by atropine and was independent of endogenous catecholamines, since it occurred in the presence of propranolol. It is speculated that the positive inotropic effect of muscarinic agonists in embryonic heart muscle is related to stimulation of phosphoinositide metabolism.


[Follow-up study of fistula in Crohn's disease].
Sixteen Crohn's disease patients with fistulae were studied. They had overall 29 fistulae, 10 treated surgically and 19 with drugs, which were followed regarding to the healing and improvement of the process.


Allyl Isothiocyanate: A TAS2R38 Receptor-Dependent Immune Modulator at the Interface Between Personalized Medicine and Nutrition.
Understanding individual responses to nutrition and medicine is of growing interest and importance. There is evidence that differences in bitter taste receptor (TAS2R) genes which give rise to two frequent haplotypes, TAS2R38-PAV (functional) and TAS2R38-AVI (non-functional), may impact inter-individual differences in health status. We here analyzed the relevance of the TAS2R38 receptor in the regulation of the human immune response using the TAS2R38 agonist allyl isothiocyanate (AITC) from Brassica plants. A differential response in calcium mobilization upon AITC treatment in leucocytes from healthy humans confirmed a relevance of TAS2R38 functionality, independent from cation channel TRPV1 or TRPA1 activation. We further identified a TAS2R38-dependence of MAPK and AKT signaling activity, bactericidal (toxicity against E. coli) and anti-inflammatory activity (TNF-alpha inhibition upon cell stimulation). These in vitro results were derived at relevant human plasma levels in the low micro molar range as shown here in a human intervention trial with AITC-containing food.


How long does it take to describe what one sees? The first step using picture description tasks.
The study explored the dependences between quantifiable features of a picture and the time it takes to describe it. Six native English speakers and six bilinguals watched pictures presented on the monitor and described them "as quickly and accurately as possible". The bilingual participants performed the test twice, in English and in their native language. The pictures could contain one to six objects. There were four series of trials that differed in the number of characteristics of the objects the participants were instructed to describe. Reaction time showed a modest, close to linear scaling with the number of objects. Both reaction time and speech time were significantly longer for the bilingual participants performing in English as compared to their performance in the native language and to the English speaking participants. The difference in reaction time did not depend on the number of objects. Speech time showed a close to linear scaling with the number of objects within each of the four series. The linear regression coefficient in this relationship increased linearly with the number of characteristics of the objects across all series. The results are discussed in relation to speed-accuracy trade-off and different strategies of picture description.


Phthalate catabolic gene cluster is linked to the angular dioxygenase gene in Terrabacter sp. strain DBF63.
Phthalate is a metabolic intermediate of the pathway of fluorene (FN) degradation via angular dioxygenation. A gene cluster responsible for the conversion of phthalate to protocatechuate was cloned from the dibenzofuran (DF)- and FN-degrading bacterium Terrabacter sp. strain DBF63 and sequenced. The genes encoding seven catabolic enzymes, oxygenase large subunit of phthalate 3,4-dioxygenase (phtA1), oxygenase small subunit of phthalate 3,4-dioxygenase (phtA2), cis-3,4-dihydroxy-3,4-dihydrophthalate dehydrogenase (phtB), [3Fe-4S] or [4Fe-4S] type of ferredoxin (phtA3), ferredoxin reductase (phtA4), 3,4-dihydroxyphthalate decarboxylase (phtC) and putative regulatory protein (phtR), were found in the upstream region of the angular dioxygenase gene (dbfA1A2), encoded in this order. Escherichia coli carrying phtA1A2BA3A4 genes converted phthalate to 3,4-dihydroxyphthalate, and the 3,4-dihydroxyphthalate decarboxylase activity by E. coli cells carrying phtC was finally detected with the introduction of a Shine-Dalgarno sequence in the upstream region of its initiation codon. Homology analysis on the upstream region of the pht gene cluster revealed that there was an insertion sequence (IS) (ISTesp2; ORF14 and its flanking region), part of which was almost 100% identical to the orf1 and its flanking region adjacent to the extradiol dioxygenase gene ( bphC1) involved in the DF degradation of Terrabacter sp. strain DPO360 [Schmid et al. (1997) J Bacteriol 179:53-62]. This suggests that ISTesp2 plays a role in the metabolism of aromatic compounds in Terrabacter sp. strains DBF63 and DPO360.


De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry.
Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.


Therapeutic Strategies in the Development of Anti-viral Drugs and Vaccines Against SARS-CoV-2 Infection.
The whole world is currently facing a pandemic of an infectious disease known as novel coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) . This outbreak emerged unexpectedly and imposed a potential threat to humans, associated with the social and economic burden on the individual and federal governments. COVID-19, which initially started in Wuhan City of China and then spread to the whole world, has been declared a Public Health Emergency of International Concern. The continuous increase in the number of confirmed cases leads to high mortality across the world. Growing evidence indicates that the mortality rate is very predominant in elderly people and those with preexisting health conditions. However, the potential pathogenesis of SARS-CoV-2 infection in humans is still unknown. The dysregulated/exuberant immune response may have substantially contributed to the SARS-CoV-2-mediated pathology. Nevertheless, there is no clinically approved drug/vaccine currently available that can restrict its pathogenesis. However, several drugs are currently shown to provide some therapeutic benefits for COVID-19 patients, including antiviral drugs that might have a significant role in restricting the current pandemic of COVID-19. In this article, we highlighted the pharmacological treatment strategies for COVID-19 and purposed the therapeutic targets for the development of vaccines or anti-viral drug molecules against SARS-CoV-2 infection in humans.


T-cell Receptor and K-deleting Recombination Excision Circles in Newborn Screening of T- and B-cell Defects: Review of the Literature and Future Challenges.
Since its introduction as a public health programme in the United States in the early 1960s, newborn blood screening (NBS) has evolved from the detection of phenylalanine levels on filter paper to the application of DNA-based technologies to identify T-cell lymphopenia in infants with severe combined immunodeficiency. This latter use of NBS has required the development of an assay for T-cell lymphopenia based on the quantification of T-cell receptor excision circles (TRECs) that could be performed on dried blood spots routinely collected from newborn infants. The TREC-based NBS was developed six years ago, and there have already been 7 successful pilot studies since then. Similarly, efforts are now being made to establish a screen for B-cell defects, in particular agammaglobulinaemia, taking advantage of the introduction of the method for the quantification of K-deleting recombination excision circles (KRECs). A further achievement of NBS could be the simultaneous recognition of T- and B-cell defects using the combined quantification of TRECs and KRECs from Guthrie card blood spots. This approach may help the early identification of infants with T- and B-cell deficiencies so that they can then be referred to specialised paediatric centres, where a precise diagnosis of severe combined immunodeficiency and agammaglobulinaemia can be performed, and where then they can immediately receive specific therapy. Simultaneous TREC and KREC quantification should also allow classification of patients into subgroups and help identify children with less serious primary immunodeficiencies. This would help avoid the opportunistic infections and frequent hospitalisations that result from a late or lack of diagnosis.


Local anesthesia in otolaryngology. A re-evaluation.
Almost a half century following attempts to ban its use, cocaine remains at the pinnacle of topical anesthesia in otolaryngology. To understand how nonaddicting synthetic substitutes such as procaine, dibucaine, tetracaine and lidocaine have not totally supplanted cocaine, requires an in-depth analysis of its unique pharmological properties, untoward effects and potential substitutes. Almost all of the reported cocaine deaths occurred after subcutaneous injection; when used topically, cocaine's toxicity has been confined to an occasional reaction. Certain variables under physician control may be manipulated to reduce the chance of reaction to a minimum. For example, intermittent application of a particular dosage results in lower blood levels, and allowing sufficient time between doses reduces the amount necessary to obtain the desired anesthesia. If total dosage is kept below 200 mg there are few reactions. A singular advantage of cocaine over other topical anesthetics is its inherent ability to cause vasoconstriction, thus retarding its own absorption. The addition of a topical vasoconstrictor such as epinephrine is thus redundant, and may actually be harmful as cocaine sensitizes the patient to exogenous epinephrine. Finally, the usual preoperative dosages of barbiturates are entirely inadequate to prevent or treat cocaine reactions. Why, then, have synthetic local anesthetics not replaced cocaine? Inherent differences in topical effectiveness, duration of anesthesia and toxicity provide the answer. Of other local anesthetics possessing topical effectiveness tetracaine is about six times more toxic than cocaine. Dibucaine is as toxic as tetracaine, and lidocaine, while relatively nontoxic, provides only a 15 minute duration of topical anesthesia. A review of cocaine and its potential substitutes thus leads to the conclusion that cocaine is still a vital and necessary instrument in the otolaryngologist's armamentarium, singularly providing excellent topical anesthesia of usable duration, vasoconstriction, and shrinkage of mucous membranes, all with a quite acceptable margin of safety.


Distribution and excretion of 2,3,7,8-tetrachlorodibenzo-p-dioxin in congenic strains of mice which differ at the Ah locus.
The effect of the genetic background on the distribution and excretion of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in two sets of congenic mouse strains in which the congenic pairs differed only at the Ah locus. Male C57BL/6J mice which were either Ahb/Ahd or Ahd/Ahd and female DBA/2J mice which were also Ahb/Ahd or Ahd/Ahd were treated with 500 ng/kg 3H-TCDD and held from 1 to 42 days in individual metabolism cages. Daily excretion and tissue distribution at eight time points were determined. The Ah locus had no effect on the distribution of TCDD-derived radioactivity to the major tissue depots of adipose tissue, skin, kidney, carcass, and blood but seemed to cause elevated levels in the liver. The Ah locus also played no role in either the rate or the extent of urinary and/or fecal excretion. However, the route and rates of excretion did vary between the congenic sets with the male C57BL/6J mice excreting greater amounts of radioactivity in the urine and less in the feces than the female DBA/2J mice. The Ah locus also had no effect on the liver weight or adipose tissue volume in either congenic set. Thus, at the dose level studied, the distribution and excretion of TCDD were primarily governed by the total genetic background rather than the allele present at the Ah locus.


Living-donor liver transplantation in patients with concurrent active tuberculosis at transplantation.
Although active tuberculosis (TB) is a contraindication for liver transplantation (LT), LT may be the only possible treatment option in patients with irreversible liver failure and concurrent TB. To assess the outcome of LT in patients with concurrent TB and liver failure. We retrospectively evaluated the clinical outcomes of nine LT recipients with concurrent TB in Korea, an intermediate TB burden country. The primary causes of living-donor LT (LDLT) in nine patients were anti-tuberculosis drug-induced fulminant hepatic failure (n = 4) and end-stage liver disease (n = 5). The sites of active TB were the lungs (n = 5), lymph nodes (n = 3) and pleura (n = 1). After LDLT, most patients were treated with less hepatotoxic drugs, including fluoroquinolones, ethambutol and cycloserine; none was treated with pyrazinamide. One patient experienced acute rejection, probably attributable to an interaction between rifampicin and cyclosporine. All nine patients, including one taking rifabutin, successfully completed anti-tuberculosis treatment and have been followed up for a median of 926 days after LDLT, without relapse of TB. When properly managed, the prognosis of LDLT recipients with concurrently active TB at transplantation is very favourable. The current protocol, which considers active TB an absolute contraindication for LT, should be modified or relaxed, particularly for patients with LDLT.


π-Rich σ(2)P-heterocycles: bent η(1)-P- and μ(2)-P-coordinated 1,3-benzazaphosphole copper(I) halide complexes.
The reaction of 1-neopentyl-1,3-benzazaphosphole 1 with CuCl, CuBr, or Cu(SMe2)Br in THF at room temperature provides sparingly soluble [Cu7(μ(2)-L6)(μ(2)-X7)](+)[CuX2](-) cluster complexes 2a,b (L indicates coordinated 1, a X = Cl, b X = Br), with loosely bound THF, in high yields. The conversions proceed via transient THF-soluble labile [(L2CuX)2] complexes. Separation before complete conversion, combined with suitable conditions for crystallization, allowed these intermediates to be trapped. Depending on the reactant ratios, crystals of the clusters or of dimeric L2CuX complexes were formed. The crystal structure analyses of 2a·4THF and the dimers 3b [{Cu(η(1)-L)2(μ(2)-Br)}2], 4b [{Cu(μ(2)-L)(η(1)-L)(κBr)}2], 5a·2MeOH, and 5b·2MeOH [{Cu(μ(2)-L)(η(1)-L)(κX···HOMe)}2] generally display μ(2)-P- and/or tilted η(1)-P-coordination, contrasting with the preference for the η(1)-P in-plane coordination mode of phosphinine ligands in their copper(I) halide complexes. DFT studies of geometry-optimized monomers LCuBr, L(CuBr)2, L2CuBr, and the dimers 3b and 4b, calculated at the ωB97xD/cc-PVDZ level, suggest that weak competing interactions with the solvent THF and the entropy factor of the dimerization result in lability and a subtle balance between the different complexes in solution, whereas the particular coordination observed in the crystals is attributable to conservation of the delocalized π-system in the ligand. The HOMO of 4b is composed of Cu d orbitals and the π-type HOMO of the bridging ligand. Interestingly, despite the rather short Cu···Cu interatomic separation (2.726 Ǻ), no bond critical point could be located in 4b, indicating the absence of weak cuprophilic interactions in this compound.


Giftedness: an exceptionality examined.
The study of giftedness has practical origins. High-level performance intrigues people. Theoretically, the study of giftedness is related to the psychology of individual differences and has focused on the constructs of intelligence, creativity, and motivation. At a practical level, the research is largely related to school and family contexts, which develop gifts and talents in children and youth. Although broadened definitions of giftedness have emerged, the most extensive body of research available for review concentrates on intellectual giftedness. The varying definitions of giftedness and the impact of social context and diversity on the development of talent pose significant challenges for the field. Finally, the study of exceptionally advanced performance provides insight into basic psychological processes and the school contexts that develop talents in children and youth.


The metabolites NADP+ and NADPH are the targets of the circadian protein Nocturnin (Curled).
Nocturnin (NOCT) is a rhythmically expressed protein that regulates metabolism under the control of circadian clock. It has been proposed that NOCT deadenylates and regulates metabolic enzyme mRNAs. However, in contrast to other deadenylases, purified NOCT lacks the deadenylase activity. To identify the substrate of NOCT, we conducted a mass spectrometry screen and report that NOCT specifically and directly converts the dinucleotide NADP+ into NAD+ and NADPH into NADH. Further, we demonstrate that the Drosophila NOCT ortholog, Curled, has the same enzymatic activity. We obtained the 2.7 Å crystal structure of the human NOCT•NADPH complex, which revealed that NOCT recognizes the chemically unique ribose-phosphate backbone of the metabolite, placing the 2'-terminal phosphate productively for removal. We provide evidence for NOCT targeting to mitochondria and propose that NADP(H) regulation, which takes place at least in part in mitochondria, establishes the molecular link between circadian clock and metabolism.


Individualized behavior-based safety-leadership training: A randomized controlled trial.
Construction site managers play a critical role in occupational safety in the construction industry. This study aimed to develop and test a method for training construction site managers in positive feedback and active listening by incorporating the behavioral training components of behavior analysis, goal setting, practice with behavior feedback, homework, and maintenance planning into individualized behavior-based safety-leadership training (IBST), and to assess the effect of IBST on construction site managers' safety-leadership behaviors and performance. In a naturalistic randomized controlled trial, construction site managers were randomly assigned to an experimental group (n = 16) or a control group (n = 19). The experimental-group managers received IBST, while the control-group managers received no training. Paired sample t-tests on pre- to post-training (i.e., six weeks after the final training session) were performed separately for the experimental- and control-group managers. The safety-leadership behaviors of the experimental-group managers improved in terms of favorable feedback (d = 0.99, p <.01), safety-specific feedback (d = 0.89, p =.02), behavior-specific feedback (d = 0.66, p =.02), antecedent listening (d = 0.68, p =.02), and consequential listening (d = 0.78, p =.01). In addition, safety-leadership performance improved in terms of transformational leadership (d = 0.78, p =.01) and contingent-reward leadership (d = 0.64, p =.02). No significant change was found for the control-group managers. The results indicate that behavior analysis, goal setting, practice with behavior feedback, homework, and maintenance planning are effective behavioral training components of safety-leadership training. Positive feedback and active listening were also found to be important behavioral requisites for transformational and contingent-reward leadership. IBST can be used to develop occupational safety in the construction industry by improving construction site managers' safety-leadership behaviors and performance.


Heart failure and atrial fibrillation: tachycardia-mediated acute decompensation.
Tachycardia is a reversible event that may cause hemodynamic decompensation but may not necessarily cause direct damages to the myocardium. To evaluate the clinical outcomes of patients with heart failure (HF) and atrial fibrillation (AF), whose acute decompensation was tachycardia mediated. The Korean Acute Heart Failure registry was a prospective registry that consecutively enrolled 5625 patients with acute HF. Patients were classified into three groups according to the rhythm and aggravating factor: (i) 3664 (65.1%) patients with sinus rhythm (SR), (ii) 1033 (18.4%) patients with AF whose decompensation was tachycardia-mediated, AF-TM (+), and (iii) N = 928 (16.5%) patients with AF whose decompensation was not tachycardia-mediated, AF-TM (-). The primary outcomes were in-hospital and post-discharge 1 year all-cause mortality. At admission, the mean heart rate was 90.8 ± 23.4, 86.8 ± 26.8, and 106.3 ± 29.7 beats per minute for the SR, AF-TM (-), and AF-TM (+) groups, respectively. The AF-TM (+) group had more favourable characteristics such as de novo onset HF, less diabetes, ischaemic heart disease, and higher blood pressure than the AF-TM (-) group. In-hospital mortality rates were 5.1%, 6.5%, and 1.7% for SR, AF-TM (-), and AF-TM (+) groups, respectively. In logistic regression analysis, the AF-TM (+) group had lower in-hospital mortality after adjusting the significant covariates (odds ratio, 0.49; 95% confidence interval, 0.26-0.93). The mortality rate did not differ between SR and AF-TM (-) groups. During 1 year follow-up, 990 (18.5%) patients died. In univariate and multivariate Cox proportional regression analyses, there was no difference in 1-year all-cause mortality between the three groups. In patients with HF and AF, patients whose acute decompensation is tachycardia-mediated have better in-hospital, but similar post-discharge outcomes compared with those with SR or those with AF whose decompensation is not tachycardia-mediated. ClinicalTrial.gov NCT01389843.


NCOA5 Haploinsufficiency in Myeloid-Lineage Cells Sufficiently Causes Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma.
The nuclear receptor coactivator 5 (NCOA5) is a putative type 2 diabetes susceptibility gene. NCOA5 haploinsufficiency results in the spontaneous development of nonalcoholic fatty liver disease (NAFLD), insulin resistance, and hepatocellular carcinoma (HCC) in male mice; however, the cell-specific effect of NCOA5 haploinsufficiency in various types of cells, including macrophages, on the development of NAFLD and HCC remains unknown. Control and myeloid-lineage-specific Ncoa5 deletion (Ncoa5ΔM/+) mice fed a normal diet were examined for the development of NAFLD, nonalcoholic steatohepatitis (NASH), and HCC. Altered genes and signaling pathways in the intrahepatic macrophages of Ncoa5ΔM/+ male mice were analyzed and compared with those of obese human individuals. The role of platelet factor 4 (PF4) in macrophages and the underlying mechanism by which PF4 affects NAFLD/NASH were explored in vitro and in vivo. PF4 expression in HCC patient specimens and prognosis was examined. Myeloid-lineage-specific Ncoa5 deletion sufficiently causes spontaneous NASH and HCC development in male mice fed a normal diet. PF4 overexpression in Ncoa5ΔM/+ intrahepatic macrophages is identified as a potent mediator to trigger lipid accumulation in hepatocytes by inducing lipogenesis-promoting gene expression. The transcriptome of intrahepatic macrophages from Ncoa5ΔM/+ male mice resembles that of obese human individuals. High PF4 expression correlated with poor prognosis of HCC patients and increased infiltrations of M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells in HCCs. Our findings reveal a novel mechanism for the onset of NAFLD/NASH and HCC initiated by NCOA5-deficient macrophages, suggesting the NCOA5-PF4 axis in macrophages as a potential target for developing preventive and therapeutic interventions against NAFLD/NASH and HCC.


Use of Hepatitis C-Positive Deceased Liver Donors in Response to the Organ Shortage in an Endemic Area.
The region of Sicily, Italy, is witnessing a chronic organ shortage. Thus, to face this critical issue, the use of marginal donors has increased over time. An example of marginal donor expansion is the use of liver donors who are positive for the hepatitis C antibody (HCV+) for HCV+ patients requiring liver transplantation (LT). In view of new advances in HCV therapy, including direct-acting agents (DAAs) to treat HCV in the post-transplant setting, our study focused on a monocentric experience in a series of consecutive LTs performed in adult patients receiving HCV+ liver donor allografts. From 2003 to 2016 at our institute we performed 10 LT using HCV+ deceased donors. In particular, the pre-LT histological examination in 1 case showed a framework of moderate steatosis (35% microvesicular and 10% macrovesicular) with micro/macrovesicular steatosis <10% in all the other cases. A fibrous framework of 1/6 according to the Ishak score in a single case, and 2/6 in 2 cases, were highlighted, while there was no fibrosis in the other 7 cases. A picture of periportal inflammation was still detected in 4 cases, with no evidence of inflammatory lesions in the remaining cases. The patient survival was 100% at 1 and 3 years, and 85.7% at 5 years post-LT. One-, three- and five-year graft survivals were 100.0%, 88.9%, and 71.4%, respectively. Only 1 patient underwent re-LT after 2 years, because of chronic rejection. Based on our experience using HCV+ deceased liver donors with a moderate degree of fibrosis, we believe that accepting marginal donors is a feasible therapeutic option when facing a liver donor shortage.


Characterization of recombinant Francisella tularensis acid phosphatase A.
Francisella tularensis is the etiologic agent of the potentially fatal human disease tularemia and is capable of survival and multiplication within professional phagocytes of the host. While the mechanisms that allow intracellular survival of the bacterium are only now beginning to be elucidated at the molecular level, previous work demonstrated that F. tularensis produces copious levels of an acid phosphatase which in crude and purified form affected the dose-dependent abrogation of the respiratory burst of stimulated neutrophils. The work presented here was undertaken to provide a source of recombinant F. tularensis acid phosphatase for detailed biochemical, biological, and structural studies. Results from this work are consistent with the ability to generate milligram amounts of recombinant enzyme whose attributes are demonstrably equivalent to those of the native enzyme. Such properties include molecular mass, broad substrate specificity, sensitivity and resistance to various inhibitors, pH optimum, and reactivity with rabbit polyclonal antibody to the native enzyme.


Assessment of prevalence, knowledge and health-related practices of dysmenorrhea among Malaysian women in Kuala Lumpur: a cross-sectional survey.
Menstruation is a natural phenomenon considered an important indicator of women's health, reflecting their endocrine function. Women in low middle income countries face substantial menstrual hygiene management challenges. Data on the knowledge of dysmenorrhea and health-related practices among Malaysian women are scarce. The present study aimed to investigate the prevalence of dysmenorrhea among Malaysian women in Kuala Lumpur and its association with socio-demographic factors, knowledge level, and general practices. A cross-sectional study was carried out among Malaysian women in Kuala Lumpur. A total of 362 unmarried women, nulliparous and aged between 18 and 25 years old, were included in this study. Participants were conveniently recruited through online platforms as well as face to face using a self-administered questionnaire with five sections consisting of demographics, menstrual characteristics, Working ability, Location, Intensity, Days of pain, Dysmenorrhea (WaLIDD) score for diagnosing and assessing the severity of dysmenorrhea as well as an evaluation of respondents' general knowledge and practices towards dysmenorrhea. The collected data were analysed using the SPSS tool, a descriptive statistic was used to report demographic characteristics. Inferential statistics was used to report the differentiation, association, and correlations of the variables. The prevalence of primary dysmenorrhea was 73.2%. It was found that the majority of the respondents had poor knowledge (60%) and poor practices (61.88%) of dysmenorrhea. The most common preventive practices among the respondents were using dietary supplements, and herbs, taking a rest and exercising. The findings also indicated that dysmenorrhea among the respondents was significantly associated with family history of dysmenorrhea (p = 0.002), monthly income (p = 0.001), and knowledge level (p = 0.001). Dysmenorrhea has a high prevalence among women in Malaysia in Kula Lumpur driven by low knowledge and lack of evidence-based practices among these women. Thus, it is critical for Government and healthcare authorities to promote education related to women health among Malaysian women.


Role of granulocytes and C5a in myocardial response to zymosan-activated serum.
Although previous studies have demonstrated that complement (C)5a causes myocardial ischemia and mechanical dysfunction, the cardiac response of endogenously produced C5a and C5a des-Arg in zymosan-activated serum (ZAS) and the critical role of granulocytes in this process are poorly understood. Therefore, we compared the coronary and cardiac effects of ZAS and purified C5a and investigated the role of leukocyte adhesion-promoting receptors (i.e., CD11/CD18). Like purified C5a, ZAS (0.5 ml) significantly reduced coronary artery blood flow and regional segment shortening, whereas coronary venous granulocyte concentration and myocardial lactate extraction were significantly decreased. A monoclonal antibody (MoAb) to C5a/C5a des-Arg attenuated ZAS-induced cardiac alterations. Three minutes of continuous infusion of C5a or ZAS induced sustained decreases in coronary venous granulocyte concentrations, although coronary flow and segment shortening returned to control levels after 2 min. Another MoAb, IB4, directed against CD18, significantly inhibited ZAS-induced granulocyte extraction and associated cardiac effects. Thus, cardiac dysfunction occurs after activation of the complement cascade with zymosan resulting in extraction of granulocytes mediated by the CD18 adherence glycoprotein. Furthermore, intramyocardial retention of granulocytes appears necessary for the initial and full ZAS-induced cardiac dysfunction.


Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease.
Nitric oxide (NO)- and prostacyclin-independent vasodilatation in several vascular beds has been linked to the activation of cytochrome P450 (CYP) epoxygenases expressed in endothelial cells. However, these enzymes, which generate vasodilator epoxyeicosatrienoic acids, may also produce oxygen-derived free radicals, which attenuate the bioavailability of NO. Here, we studied the involvement of CYP 2C9 in modulating endothelium-dependent and -independent changes in forearm blood flow (FBF) in healthy volunteers and in patients with manifest coronary artery disease. The effects of sulfaphenazole, a selective inhibitor of CYP 2C9, on endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside, SNP) FBF responses were measured by venous occlusion plethysmography in 5 healthy subjects and in 16 patients with angiographically documented stable coronary artery disease. Sulfaphenazole did not modify FBF responses to acetylcholine or SNP in healthy subjects. In contrast, sulfaphenazole markedly and dose-dependently enhanced the FBF response to acetylcholine without affecting the response to SNP. Vitamin C also increased the FBF response to acetylcholine, but this effect was further potentiated by sulfaphenazole. In the presence of N(omega)-monomethyl-l-arginine, sulfaphenazole failed to significantly improve acetylcholine-induced vasodilatation. The oxidation of serum proteins was enhanced in patients with coronary artery disease, and this effect was significantly attenuated by sulfaphenazole. The CYP 2C9 inhibitor sulfaphenazole enhances endothelium-dependent vasodilator responses in patients with manifest coronary artery disease. This effect seems to be related to an increase in the bioavailability of NO, probably as a consequence of an attenuated generation of reactive oxygen species by CYP 2C9 in endothelial cells.


UV photo-dissociation and photodesorption of N2O on Ag(111).
Nanosecond laser induced photoreactions of N2O adsorbed on Ag(111) have been studied by temperature programmed desorption (TPD) and mass-selected, angle-dependent time-of-flight (MS-TOF) measurements of neutral desorbing particles. N2O molecules in the first monolayer are thermally inert but photo-dissociate into N2 + O, or photodesorb molecularly or dissociatively, at photon energies above 3.5 eV. We have found that TOF spectra of photodesorbed N2 as well as of N2O measured at hν = 4.7 eV consist of two velocity components. The desorption flux of the fastest component of N2O peaks ∼ 25° off the surface normal, whereas the others are directed in the surface normal. Origins and photo-excitation as well as photodesorption mechanisms of the N2O and N2 signals are discussed.


CSF 5-HIAA and aggression in female macaque monkeys: species and interindividual differences.
While the relationship among CSF 5-HIAA, impulsivity, and aggression is well characterized in males, its investigation in females is limited, and no studies have assessed its generalizability across primates by making simultaneous comparisons between and within closely-related species. We tested three hypotheses. First, that female rhesus macaques would have lower CSF 5-HIAA concentrations and be more aggressive than would female pigtailed macaques. Second, that females of both macaque species would exhibit an inverse relationship between interindividual differences in CSF 5-HIAA concentrations and rates of severe aggression. Third, that subjects with high CSF 5-HIAA concentrations would be higher in social dominance within their respective groups than would subjects with low CSF 5-HIAA concentrations. We obtained CSF samples from 61 individually housed female primates of two closely related species: rhesus macaques (Macaca mulatta) and pigtailed macaques (Macaca nemestrina). We later placed subjects in unisex social groups, and correlated interindividual differences in CSF 5-HIAA with aggression, wounding, and acquisition of social dominance rank. Between-species analyses indicated higher CSF 5-HIAA concentrations in pigtailed macaques, and higher rates of high-intensity aggression, escalated aggression, and wounds requiring medical treatment in rhesus macaques. Within-species analyses indicated that interindividual differences in CSF 5-HIAA concentrations were inversely correlated with escalated aggression and positively correlated with social dominance rank. These findings show that agonistic and social differences between closely-related species are correlated with CNS serotonin activity, as species that show relatively high rates of severe aggression also tend to have low concentrations of CSF 5-HIAA. We conclude that serotonergic functioning plays an important role in controlling impulses that regulate severe aggression and social dominance relationships in both male and female primates, and that between-species differences in agonistic temperament can be predicted by species typical CNS serotonin functioning.


Emerging role of Radium-223 in the growing therapeutic armamentarium of metastatic castration-resistant prostate cancer.
During the last few years, the therapeutic armamentarium of castration resistant prostate cancer (mCRPC) has been enriched with the introduction of new effective therapies with proved survival benefit and quality of life gain, including cabazitaxel, abiraterone, enzalutamide, and Radium-223. Areas covered: Bone metastases represent a substantial cause of morbidity in mCRPC with a high rate of related skeletal events (SREs). In case of multifocal pain due to diffuse osteoblastic metastases, treatment with bone-targeting radiopharmaceutical agents can provide palliation from pain. Radium-223, a calcium-mimetic, is the first α-particle emitting radiopharmaceutical that prolonged overall survival, delayed symptomatic skeletal events and improved quality of life in mCRPC. Expert opinion: In this therapeutic scenario, no clear evidences support the best way to sequence these available agents and there is an urgent need for prospective studies to define it. 223Ra is a firmly established therapeutic option in CRPC with symptomatic bone metastases and no visceral/bulky nodal involvement, with an undeniable advantage over new hormonal agents, given its peculiar mechanism of action. Current ongoing randomized clinical trials will clarify the optimal use of this effective therapy in the therapeutic armamentarium of CRPC either alone or combined with other new approved agents and whether there is a role in patients with asymptomatic disease.


Hydrophobic drug-triggered self-assembly of nanoparticles from silk-elastin-like protein polymers for drug delivery.
Silk-elastin-like protein polymers (SELPs) combine the mechanical and biological properties of silk and elastin. These properties have led to the development of various SELP-based materials for drug delivery. However, SELPs have rarely been developed into nanoparticles, partially due to the complicated fabrication procedures, nor assessed for potential as an anticancer drug delivery system. We have recently constructed a series of SELPs (SE8Y, S2E8Y, and S4E8Y) with various ratios of silk to elastin blocks and described their capacity to form micellar-like nanoparticles upon thermal triggering. In this study, we demonstrate that doxorubicin, a hydrophobic antitumor drug, can efficiently trigger the self-assembly of SE8Y (SELPs with silk to elastin ratio of 1:8) into uniform micellar-like nanoparticles. The drug can be loaded in the SE8Y nanoparticles with an efficiency around 6.5% (65 ng doxorubicin/μg SE8Y), S2E8Y with 6%, and S4E8Y with 4%, respectively. In vitro studies with HeLa cell lines demonstrate that the protein polymers are not cytotoxic (IC50 > 200 μg/mL), while the doxorubicin-loaded SE8Y nanoparticles showed a 1.8-fold higher cytotoxicity than the free drug. Confocal laser scanning microscopy (CLSM) and flow cytometry indicate significant uptake of the SE8Y nanoparticles by the cells and suggest internalization of the nanoparticles through endocytosis. This study provides an all-aqueous, facile method to prepare nanoscale, drug-loaded SELPs packages with potential for tumor cell treatments.


Adenoid cystic carcinoma.
Adenoid cystic carcinoma is a malignant tumor with a deceptively benign histologic appearance characterized by indolent, locally invasive growth with high propensity for local recurrence and distant metastasis. The tumor is composed of basaloid cells with small, angulated, and hyperchromatic nuclei and scant cytoplasm arranged into 3 prognostically significant patterns: cribriform, tubular, and solid. Some tumors undergo dedifferentiation into a high-grade form. Numerous studies have attempted to elucidate accurate histologic prognostic features but have often yielded conflicting results. Microarray analysis and gene expression profiling have provided new potential diagnostic and prognostic markers. However, tumor grade, stage, lymph node metastasis, invasion of major nerves, and margin status remain the most consistent predictors of prognosis. The combination of surgery and postoperative radiation therapy has improved locoregional control of the disease. Despite this achievement, late local recurrence and distant metastasis rates remain high and may occur decades after initial diagnosis.


Effects of continuous and intermittent magnetic fields on oxidative parameters in vivo.
Continuous and intermittent 50 Hz, 1.5 mT magnetic field with the exposure period of 4 h/day for 4 days was used to investigate its possible effect on adult guinea pigs. Tissues and plasma specimens were assessed by biochemical parameters. Malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO) levels and myeloperoxidase activity (MPO) were examined in plasma, liver and brain tissues. All parameters were determined by spectrophotometer. While intermittent magnetic field was effective on plasma lipid peroxidation, continuous magnetic field was found to be effective on plasma MPO activity and NO levels. Augmentation of lipid peroxidation was also observed in liver tissue both intermittent and continuous magnetic field exposures. These results indicate that both the intermittent and continuous magnetic field exposures affect various tissues in a distinct manner because of having different tissue antioxidant status and responses.


Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy.
Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.


Characterization of the glutathione binding site of aldose reductase.
Despite extensive investigations, the physiological role of the polyol pathway enzyme-aldose reductase (AR) remains obscure. While the enzyme reduces glucose in vivo and in vitro, kinetic and structural studies indicate inefficient carbohydrate binding to the active site of the enzyme. The active site is lined by hydrophobic residues and appears more compatible with the binding of medium- to long-chain aliphatic aldehydes or hydrophobic aromatic aldehydes. In addition, our recent studies show that glutathione (GS) conjugates are also reduced efficiently by the enzyme. For instance, the GS conjugate of acrolein is reduced with a catalytic efficiency 1000-fold higher than the parent aldehyde, indicating specific recognition of glutathione by the active site residues of AR. An increase in the catalytic efficiency upon glutathiolation was also observed with trans-2-nonenal, trans-2-hexenal and trans, trans-2,4-decadienal, establishing that enhancement of catalytic efficiency was specifically due to the glutathione backbone and not specific to the aldehyde. Structure-activity relationships with substitution or deletion of amino acids of GSH indicated specific interactions of the active site with gamma-Glu1 and Cys of GSH. Molecular modeling revealed that the glutathione-propanal conjugate could bind in two distinct orientations. In orientation 1, gamma-Glu1 of the conjugate interacts with Trp20, Lys21 and Val47, and Gly3 interacts with Ser302 and Leu301, whereas in orientation 2, the molecule is inverted with gamma-Glu1 interacting with Ser302, and Leu301. Taken together, these data suggest that glutathiolation of aldehydes enhances their compatibility with the AR active site, which may be of physiological significance in detoxification of endogenous and xenobiotic aldehydes.


Therapy-related acute promyelocytic leukemia: a systematic review.
The incidence of therapy-related acute promyelocytic leukemia (t-APL) is apparently rising. We systematically reviewed the English literature until March 15, 2013, and collected a total of 326 t-APL cases, with the following results: (1) t-APL affects predominantly middle-aged adults with a median age at diagnosis of 47 years and a female-to-male ratio of 1.7:1; (2) after an incidence peak at 2 years following the completion of treatment for the primary antecedent disease, the risk of developing t-APL quickly diminishes with time; (3) the four most common primary antecedent conditions are breast cancer, hematological malignancies, multiple sclerosis, and genitourinary malignancies; (4) topoisomerase II inhibitors and radiation represent the most common potential risk factors; (5) despite different DNA damage "hot spot" sites, t-APL has no significant clinicopathologic differences from de novo APL (dn-APL); (6) t(15;17) is the sole cytogenetic abnormality in the vast majority of patients; (7) only a small minority of cases have a myelodysplastic or pancytopenic preleukemic phase; (8) more than one-third of patients come to medical attention incidentally (i.e., due to laboratory abnormalities), while the most common symptom is mucocutaneous bleeding, and 79 % have clinical DIC; and (9) the remission rate of t-APL is about 80 %, similar to dn-APL.


Fitting of electronic elbow on an elbow disarticulated patient by means of a new surgical technique.
Rehabilitation of trans-humeral amputees represents a challenge. One of the difficulties to overcome is prosthetic suspension. In the case of elbow disarticulation the presence of humeral condyles permits better suspension, but there is no room for elbow joints, particularly electronic ones, and the only available mechanisms are provided by external hinges. The purpose of this report is to present a case of a primarily elbow disarticulated patient, with indication for surgical revision due to bad skin coverage, neuroma and the wish to improve prosthetic fitting. The surgical plan outlined was to produce a shortening of the humerus, by means of an osteotomy just above the humeral condyles, preserving them for prosthetic suspension. This bone reduction was carried out with complementary shaping of bone segments with an indentation to enhance fixation. The operation was completed with neuroma resection, myodesis and removal of the skin grafted area. Preservation of the humeral condyles actually produced effective suspension. For final fitting a Utah Arm II was used, with wrist rotator, and interchangeable hand and Greifer for terminal devices. Good initial results and at nine months follow-up suggest this procedure should be considered in other elective situations.


Derived Coarse-Grained Potentials for Semicrystalline Polymers with a Blended Multistate Iterative Boltzmann Inversion Method.
In this article, we employ the multistate iterative Boltzmann inversion (MS-IBI) method to develop coarse-grained potentials capable of representing molecular structure in both the amorphous and crystalline phases of semicrystalline polymers with improved accuracy while allowing for tunable control over the dynamics governing the α-relaxation process. A unique feature of this method is that the potentials are blended using the product of the target structural distributions, for example, the radial density function, for each phase and a weighting factor. To demonstrate this approach, a family of potentials for polyethylene is developed where the weighting factor of the crystalline phase ranges is varied from zero, incorporating information only from the amorphous phase, to unity, where the model is trained from only the crystalline phase. The most accurate representation of structural distributions was obtained when the crystalline phases is weighted at 50%. However, we show that when the crystalline phase is weighted at 90%, the model more accurately represents dynamics of the α-relaxation process, with realistic predicted values of activation energy and diffusion rates, with relatively minor impact on accuracy in structure.


Image motion estimation algorithms using cumulants.
A class of algorithms is presented that estimates the displacement vector from two successive image frames consisting of signal plus noise. In the model, the signals are assumed to be either non-Gaussian or (quasistationary) deterministic; and, via a consistency result for cumulant estimators, the authors unify the stochastic and deterministic signal viewpoints. The noise sources are assumed to be Gaussian (perhaps spatially and temporally correlated) and of unknown covariance. Viewing image motion estimation as a 2D time delay estimation problem, the displacement vector of a moving object is estimated by solving linear equations involving third-order auto-cumulants and cross-cumulants. Additionally, a block-matching algorithm is developed that follows from a cumulant-error optimality criterion. Finally, the displacement vector for each pel is estimated using a recursive algorithm that minimizes a mean 2D fourth-order cumulant criterion. Simulation results are presented and discussed.


Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation.
Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.


[Patient safety and quality problems--what is the cost?].
Available evidence indicates a sizable "poor quality and safety" problem in health care. Costs can be assigned but few studies have done so. This article, the second in a series of three, summarises research which has calculated the economic cost of these problems. Adverse drug events account for a major part of the problem and have been estimated to be approximately 1.5% of the UK NHS annual budget. Other quality deficiency problems that have been costed in various studies are the use of inefficient medical procedures, hospital acquired infections and variation in clinical practice. There are only a few studies reporting the effectiveness of different actions to reduce adverse events and waste, and even less evidence about the cost of these different interventions. There is, however, sufficient evidence to suggest certain actions would not only relieve considerable patient suffering, but would make significant economic savings for health care and society. When planning for interventions to improve quality and reduce safety deficiencies, the costs of the problem should be calculated and weighed against the costs of the intervention, i.e the "quality cost" should be estimated. It should be decided how a potential saving could be retained by a unit which has invested in such an intervention. The third article describes methods for estimating quality costs in health care.


Uncovering two kinetic factors in the controlled growth of topologically distinct core-shell metal-organic frameworks.
Constructing core-shell metal-organic frameworks (MOFs) based on two topologically distinct MOFs is a great way to increase MOF material complexity and explore their new functions. However, such a nucleation process is energetically less favored compared to epitaxial growth due to mismatched unit cell parameters. Here, two kinetic factors, nucleation kinetics and dissolution kinetics, are revealed to be two key factors in overcoming this challenge. Through kinetic control, we demonstrate the growth of 4 types of Zr/Hf-MOF shells uniformly and contiguously on 7 different core MOFs including ZIF-8, an acid labile core. Taking advantage of the modular synthesis of Zr-MOFs, we demonstrate that post-synthetic covalent surface modification on a non-functionalizable MOF surface can be made possible through core-shell construction. We also demonstrated that the size selective catalytic behavior can be systematically tuned through changing either the ligand length or ligand functionality.


Anesthesia for liver transplantation.
Orthotopic liver transplantation is the only definitive treatment for end-stage liver disease. More than 6000 procedures are performed in the United States annually with excellent survival rates. The shortage of donor organs leads to continued interest in techniques to enlarge the potential donor pool. Patients presenting for liver transplant suffer from important cardiovascular, respiratory, renal, neurological, and gastroenterological comorbidity. In the Western world, liver failure is increasingly caused by steatohepatitis, and transplant candidates are thus becoming older and more comorbid. The role of the transplant anesthesiologist is highly important in the preoperative assessment, intraoperative management, and postoperative care of these complex and sick patients. Appropriate investigation and management of comorbidities such as coronary artery disease and portopulmonary hypertension is controversial and differs between programs. The transplant procedure is a major surgery, and although massive transfusion is no longer commonplace, there is potential for significant hemodynamic instability, coagulopathy, and metabolic disturbance. Liver transplant surgery can be divided into the preanhepatic phase, the anhepatic phase, and the reperfusion phase, with important anesthetic considerations at each point. An understanding of the surgical techniques used for vascular exclusion of the liver and the role of venovenous bypass is crucial for the anesthesiologist. Recent trends in perioperative care include the use of antifibrinolytic drugs and point-of-care coagulation tests, intraoperative renal replacement therapy, and "fast-track" extubation and postoperative care. Care of patients with fulminant hepatic failure or those receiving split-liver grafts requires special consideration.


Profiling novel pharmacology of receptor complexes using Receptor-HIT.
Many receptors are able to undergo heteromerisation, leading to the formation of receptor complexes that may have pharmacological profiles distinct from those of the individual receptors. As a consequence of this, receptor heteromers can be classed as new drug targets, with the potential for achieving greater specificity and selectivity over targeting their constituent receptors. We have developed the Receptor-Heteromer Investigation Technology (Receptor-HIT), which enables the detection of receptor heteromers using a proximity-based reporter system such as bioluminescence resonance energy transfer (BRET). Receptor-HIT detects heteromers in live cells and in real time, by utilising ligand-induced signals that arise from altered interactions with specific biomolecules, such as ligands or proteins. Furthermore, monitoring the interaction between the receptors and the specific biomolecules generates functional information about the heteromer that can be pharmacologically quantified. This review will discuss various applications of Receptor-HIT, including its use with different classes of receptors (e.g. G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and others), its use to monitor receptor interactions both intracellularly and extracellularly, and also its use with genome-edited endogenous proteins.


1/f noise in graphene nanopores.
Graphene nanopores are receiving great attention due to their atomically thin membranes and intrinsic electrical properties that appear greatly beneficial for biosensing and DNA sequencing. Here, we present an extensive study of the low-frequency 1/f noise in the ionic current through graphene nanopores and compare it to noise levels in silicon nitride pore currents. We find that the 1/f noise magnitude is very high for graphene nanopores: typically two orders of magnitude higher than for silicon nitride pores. This is a drawback as it significantly lowers the signal-to-noise ratio in DNA translocation experiments. We evaluate possible explanations for these exceptionally high noise levels in graphene pores. From examining the noise for pores of different diameters and at various salt concentrations, we find that in contrast to silicon nitride pores, the 1/f noise in graphene pores does not follow Hooge's relation. In addition, from studying the dependence on the buffer pH, we show that the increased noise cannot be explained by charge fluctuations of chemical groups on the pore rim. Finally, we compare single and bilayer graphene to few-layer and multi-layer graphene and boron nitride (h-BN), and we find that the noise reduces with layer thickness for both materials, which suggests that mechanical fluctuations may be the underlying cause of the high 1/f noise levels in monolayer graphene nanopore devices.


Defining hormesis.
Much confusion surrounds the concept of hormesis and what its biological meaning represents. This paper provides a definition of hormesis that addresses its historical foundations, quantitative features, and underlying evolutionary and toxicologically based mechanistic strategies. Hormesis should be considered an adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis. Given the limited magnitude of the stimulatory response (i.e., usually 30-60% greater than controls at maximum), heightened study design and replication requirements are often necessary to ensure reliable judgments on causality. Even though hormesis is considered an adaptive response, the issue of beneficial/harmful effects should not be part of the definition of hormesis, but reserved to a subsequent evaluation of the biological and ecological context of the response.


Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study.
Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical loss of at least 1 MMR protein. Molecular biomarkers of pembrolizumab activity were also analyzed. Consecutive patients with recurrent HGG and partial or complete loss of MMR protein expression were prospectively enrolled; they received pembrolizumab 200 mg once every 3 weeks until disease progression. The primary endpoint was disease control rate (DCR). Post hoc exploratory analyses included next-generation sequencing to assess tumor mutational burden (TMB), and immunostaining for CD8+ T-cells and CD68+ macrophages. Among 310 HGG patients screened, 13 cases with MMR loss were enrolled: eight glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31%: four patients had stable disease and no patient had complete or partial response. TMB ranged between 6.8 and 23.4 mutations/megabase. Neither TMB nor gene mutations, nor CD8+ T-cell and CD68+ macrophage content, were associated with pembrolizumab activity. pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity.


The emerging roles of m6A modification in liver carcinogenesis.
The 'epitranscriptome', a collective term for chemical modifications that influence the structure, metabolism, and functions of RNA, has recently emerged as vitally important for the regulation of gene expression. N6-methyladenosine (m6A), the most prevalent mammalian mRNA internal modification, has been demonstrated to have a pivotal role in almost all vital bioprocesses, such as stem cell self-renewal and differentiation, heat shock or DNA damage response, tissue development, and maternal-to-zygotic transition. Hepatocellular carcinoma (HCC) is prevalent worldwide with high morbidity and mortality because of late diagnosis at an advanced stage and lack of effective treatment strategies. Epigenetic modifications including DNA methylation and histone modification have been demonstrated to be crucial for liver carcinogenesis. However, the role and underlying molecular mechanism of m6A in liver carcinogenesis are mostly unknown. In this review, we summarize recent advances in the m6A region and how these new findings remodel our understanding of m6A regulation of gene expression. We also describe the influence of m6A modification on liver carcinoma and lipid metabolism to instigate further investigations of the role of m6A in liver biological diseases and its potential application in the development of therapeutic strategies.


Molecular aspects of immune recognition of cytomegalovirus.
The studies discussed in this presentation have shown that CD8 T lymphocytes have a primary role in conferring resistance to MCMV in the immunocompetent BALB/c mouse. In the presence of selective CD8 deficiency, however, other mechanisms, apparently mediated by the CD4 T-cell subset, contribute in a compensatory fashion to antiviral immunity. The protective CTL response to MCMV, at least in BALB/c mice, is elicited by a single epitope encoded by the major ie 1 and expressed in protein pp89. The epitope itself contains 18 amino acids, only five of which are the minimum for CTL recognition. Substitutions within a nonapeptide sequence that is part of the pp89 epitope identified two positions that are critical for TCR binding by clone IE1 CTLs. Polyclonal CTLs, in contrast, respond to either the native nonapeptide or any of the substituted variants that were tested, which suggests a certain degree of degeneracy in the specificity of the physiologic immune response.