In vitro modulation of somatic glycine-like immunoreactivity in presumed glycinergic neurons.
Previous studies indicate that tuberculoventral and cartwheel cells in the dorsal cochlear nucleus as well as a group of stellate cells in the ventral cochlear nucleus are likely to be glycinergic. To test whether these neurons contain higher levels of free glycine than cells that are probably not glycinergic, immunocytochemical studies with antibodies against glycine conjugates were undertaken on slices of the murine cochlear nuclear complex. Present results show that the cell bodies of all three groups of neurons are immunolabeled. However, the somatic labeling of the tuberculoventral and cartwheel cells can be modulated by experimental conditions. In slices fixed immediately after cutting, many cell bodies in the deep layer of the dorsal cochlear nucleus (DCN), presumably tuberculoventral neurons, are labeled. As a slice is incubated in vitro, cell bodies in the deep layer of the DCN lose their glycine-like immunoreactivity. After 7 hours in vitro, labeled cells are absent in the deep DCN, but the immunoreactivity can be regained by electrically stimulating the auditory nerve for 20 minutes. The loss of immunoreactivity is prevented by electrical stimulation, by axotomy, and by inclusion of 0.8 microM tetrodotoxin, or 1 microM strychnine, or 50 microM colchicine or 50 microM beta-lumicolchicine in the bathing saline. Cartwheel cells retain their immunoreactivity during incubation in vitro without electrical stimulation, but lose it under two conditions. One is following a cut across the ventral cochlear nucleus (VCN) that severs most of their granule cell input, and the other is the inclusion of tetrodotoxin in the bathing saline. The labeling of cell bodies in the ventral cochlear nucleus and of puncta and processes is not changed by any of these experimental manipulations.


Antihypertensive and metabolic effects of diltiazem and nifedipine.
The antihypertensive effect of diltiazem (180-270 mg/day) and nifedipine (40-60 mg/day) in slow-release forms was assessed over 8 weeks in a double-blind parallel study in 40 subjects with essential hypertension at rest and during exercise. Blood pressure was comparably reduced in both groups at rest as well as during exercise. The responder rates (greater than or equal to 10% reduction in diastolic blood pressure) after 8 weeks of therapy were 53% at rest and 75% during exercise in the diltiazem group and 78% and 50%, respectively, in the nifedipine group. Diltiazem decreased heart rate by 8% (p less than 0.01), while nifedipine did not affect it. As a consequence, myocardial oxygen consumption, as judged by the pressure-rate product, was reduced by diltiazem. Resting plasma norepinephrine levels were increased significantly after 8 weeks of diltiazem therapy. Plasma epinephrine, renin, aldosterone, glucose, insulin, and lactate and routine laboratory parameters were unchanged at the end of the study. No significant changes in total cholesterol and triglyceride levels were observed after 8 weeks. Whereas therapy with diltiazem resulted in an 8% fall in low density lipoprotein cholesterol after 8 weeks (p less than 0.05), nifedipine induced a drop in very low density lipoprotein cholesterol (p less than 0.05) after 8 weeks of therapy. We conclude that both diltiazem and nifedipine are effective antihypertensive agents lacking undesirable metabolic side effect. Diltiazem, however, had the advantage of lowering heart rate and myocardial oxygen consumption.


Education Differences in the Adverse Impact of PM2.5 on Incident Cognitive Impairment Among U.S. Older Adults.
Air pollution is linked to worse cognitive function in older adults, but whether differences in this relationship exist by education, a key risk factor for cognitive decline, remains unknown. To determine if the association between fine particulate matter air pollution (PM2.5) and incident cognitive impairment varies by level of education in two cohorts assessed a decade apart. We used data on adults ages 60 and older from the nationally representative Health and Retirement Study (HRS) linked with tract-level annual average PM2.5. We used mixed-effects logistic regression models to examine education differences in the association between PM2.5 and incident cognitive impairment in two cohorts: 2004 (n = 9,970) and 2014 (n = 9,185). Cognitive impairment was determined with tests of memory and processing speed for self-respondents and proxy and interviewer assessments of cognitive functioning in non-self-respondents. PM2.5 was unrelated to incident cognitive impairment among those with 13 or more years of education, but the probability of impairment increased with greater concentrations of PM2.5 among those with 8 or fewer years of education. The interaction between education and PM2.5 was only found in 2004, possibly because PM2.5 concentrations were much lower in 2014. Education is a key determinant of cognitive decline and impairment, and in higher pollution contexts may serve as a protective factor against the harms of air pollution on the aging brain. Additionally, because air pollution is ubiquitous, and particularly harmful to vulnerable populations, even small improvements in air quality may have large impacts on population health.


Medroxyprogesterone and paraphiles: do testosterone levels matter?
We examine the associations between pretreatment testosterone (TTS) levels and sociodemographic, clinical, and sexual behavioral characteristics. Two groups, low and normal pretreatment TTS, were treated with medroxyprogesterone acetate (MPA) and compared on clinical response (deviant and nondeviant sexual behaviors; recidivism) and length of time to return to pretreatment TTS after discontinuing MPA. Thirteen paraphilic men who were treated with MPA and had TTS levels monitored at approximately three-month intervals during and after MPA were followed naturalistically. The principal outcome measures pertained to TTS levels and data from a self-report psychosexual inventory, which quantified deviant and nondeviant sexual activities. Time to return to baseline TTS levels were analyzed with Kaplan-Meier survival analysis. Nonparametric methods were used to compare the two groups on other variables. Multiple regression was used to examine the contribution of combinations of variables to TTS outcome. Subjects with low pretreatment TTS received MPA for longer periods of time, and older subjects took longer to return to pretreatment TTS levels despite being treated for shorter periods of time. Although subjects with lower pretreatment TTS levels may be more sensitive to MPA's TTS-suppressive effects, the multiple regression analysis showed that age may be an important determinant of the time it take for TTS levels to return to pretreatment baseline. Sociodemographic, clinical, and self-reported measures of sexual behavior did not distinguish between low and normal TTS level groups. Only one relapse was detected. Further studies with larger samples are required to better understand the role of TTS monitoring of sex offenders treated with MPA, in order to justify its continued use as a measurement of treatment adequacy and to study its potential role as a predictor of treatment outcome.


Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways.
TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κB activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κB activation and that NF-κB may constitute a therapeutic target for the disease.


Oncolytic herpes simplex virus-1 mutant expressing green fluorescent protein can detect and treat peritoneal cancer.
NV1066 is a herpes simplex virus-1 (HSV-1) oncolytic mutant that contains the gene for enhanced green fluorescent protein (EGFP). We sought to determine (1) whether NV1066 is effective against human peritoneal cancer, (2) whether EGFP is detectable in an animal model of gastric cancer, and (3) whether EGFP expression can be used to assess oncolytic therapy in a minimally invasive, laparoscopic system. The current study demonstrates that NV1066 is cytotoxic to OCUM human gastric cancer cells in vitro and in an in vivo model of disseminated peritoneal gastric cancer. In vitro this human gastric cancer cell line is sensitive to NV1066. Lysis occurs in a dose-dependent fashion, achieving near-complete lysis even at multiplicities of infection (MOIs) as low as 0.01 by 7 days. NV1066 also replicates within OCUM cells and induces expression of GFP in a dose-dependent manner. At MOIs of 0.01 to 1, EGFP expression is seen by flow cytometry in 100% of OCUM cells within 5 days after infection. NV1066 effectively treats OCUM carcinomatosis in an in vivo model. After intraperitoneal administration of NV1066, macroscopic tumor foci express EGFP by direct laparoscopy with the appropriate fluorescent filtering. Noncancerous organs are not infected and do not express EGFP. We conclude that NV1066 has significant oncolytic activity in vitro and in vivo and reliably induces EGFP expression in infected tumor cells. Furthermore, EGFP expression in intraperitoneal tumors can be visualized laparoscopically, allowing detection and localization of viral gene therapy.


New perspectives in diabetic neuropathy.
Diabetes prevalence continues to climb with the aging population. Type 2 diabetes (T2D), which constitutes most cases, is metabolically acquired. Diabetic peripheral neuropathy (DPN), the most common microvascular complication, is length-dependent damage to peripheral nerves. DPN pathogenesis is complex, but, at its core, it can be viewed as a state of impaired metabolism and bioenergetics failure operating against the backdrop of long peripheral nerve axons supported by glia. This unique peripheral nerve anatomy and the injury consequent to T2D underpins the distal-to-proximal symptomatology of DPN. Earlier work focused on the impact of hyperglycemia on nerve damage and bioenergetics failure, but recent evidence additionally implicates contributions from obesity and dyslipidemia. This review will cover peripheral nerve anatomy, bioenergetics, and glia-axon interactions, building the framework for understanding how hyperglycemia and dyslipidemia induce bioenergetics failure in DPN. DPN and painful DPN still lack disease-modifying therapies, and research on novel mechanism-based approaches is also covered.


Dietary intervention with an Okinawan-based Nordic diet in type 2 diabetes renders decreased interleukin-18 concentrations and increased neurofilament light concentrations in plasma.
Food may induce inflammation and favor development of metabolic diseases, which have been associated with increased inflammation and potential risk of cognitive impairment. It is customary to know whether food or disease promote inflammation. Our hypothesis was that Okinawan-based Nordic (O-BN) diet leads to decreased circulating concentrations of inflammatory and neural biomarkers. The objectives of this study were to examine the effects of the O-BN diet on inflammatory and neural responses. First, 2 different breakfasts; one standard and another O-BN-based, were given in random order to 19 healthy volunteers. Second, a 12-week O-BN-dietary intervention was performed in type 2 diabetes mellitus (T2DM), where the participants were followed for another 16-weeks, with registration of anthropometry and metabolic parameters. Non-diabetic subjects served as controls at baseline. Plasma was analyzed for cytokines by a 10-plex Luminex assay and neurofilament light (NfL) by an ultrasensitive Single molecule assay. Cytokine levels decreased after a single breakfast intake, independent of diet composition. Cytokine levels were higher in T2DM than in controls. Anthropometric and metabolic parameters were improved by the dietary intervention. In parallel, cytokine levels were lowered, although only significantly for IL-18 (P = .001), with a tendency of significance for IL-12p70 (P = .07). Levels of IL-18 correlated with glucose, HbA1c and lipids, but not with body mass index, insulin or blood pressure. NfL levels increased during the intervention (P = .049). O-BN-based diet does not affect postprandial cytokine levels in health, whereas it renders decreased circulating IL-18 levels along with metabolic biomarkers in T2DM, with no beneficial effect on NfL.


Effect of Fontan geometry on exercise haemodynamics and its potential implications.
Exercise intolerance afflicts Fontan patients with total cavopulmonary connections (TCPCs) causing a reduction in quality of life. Optimising TCPC design is hypothesised to have a beneficial effect on exercise capacity. This study investigates relationships between TCPC geometries and exercise haemodynamics and performance. This study included 47 patients who completed metabolic exercise stress test with cardiac magnetic resonance (CMR). Phase-contrast CMR images were acquired immediately following supine lower limb exercise. Both anatomies and exercise vessel flow rates at ventilatory anaerobic threshold (VAT) were extracted. The vascular modelling toolkits were used to analyse TCPC geometries. Computational simulations were performed to quantify TCPC indexed power loss (iPL) at VAT. A highly significant inverse correlation was found between the TCPC diameter index, which factors in the narrowing of TCPC vessels, with iPL at VAT (r=-0.723, p<0.001) but positive correlations with exercise performance variables, including minute oxygen consumption (VO2) at VAT (r=0.373, p=0.01), VO2 at peak exercise (r=0.485, p=0.001) and work at VAT/weight (r=0.368, p=0.01). iPL at VAT was negatively correlated with VO2 at VAT (r=-0.337, p=0.02), VO2 at peak exercise (r=-0.394, p=0.007) and work at VAT/weight (r=-0.208, p=0.17). Eliminating vessel narrowing in TCPCs and reducing elevated iPL at VAT could enhance exercise tolerance for patients with TCPCs. These findings could help plan surgical or catheter-based strategies to improve patients' exercise capacity.


Incidence and risk factors for cognitive impairment in rural elderly populations in Costa Rica.
Risk factors for the onset of cognitive impairment in Costa Rica are not well understood, despite a substantial elderly population stemming from a higher than average life expectancy for the western hemisphere. To investigate the risk factors that predict the onset of cognitive impairment in the rural elderly of Costa Rica, a modified version of the Mini Mental State Exam-designed for illiterate populations-was administered to 90 elderly inhabitants of San Carlos, Alajuela, Costa Rica between April and May of 2011. Subsequently, each participant took a structured interview assessing viability of risk factors and behaviors potentially contributing to a diagnosis of cognitive impairment. Results showed strong dependencies between age (p = 0.0001), education level (p = 0.0095), the ability to read (p = 0.0001) and write (p = 0.0153), frequency of reading (p = 0.0011), use of puzzles and mind games (p < 0.0001), vocation (p = 0.0225), area of residence (p < 0.0001), comorbid mental dis- eases (p = 0.0005), history of stroke or brain trauma (p = 0.0104), urinary or renal problems (p = 0.0443), consistent cooking practices (p = 0.0262) and number of living companions (p = 0.0299) in susceptibility for developing cognitive impairment. The study concluded that high intellectual use, or lack thereof, during the lifetime of a person was a predictor for cognitive status later in life. In addition, comorbid mental disorders, including neu- rological trauma due to stroke, impeded normal cognitive function. Future research should examine incidence and risk factors of cognitive impairment in urban, more educated populations.


Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches.
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors known to affect humans and carries a dismal prognosis. Our primary aim was to review its epidemiology, biology, risk factors, and prognostic indicators. We also reviewed the individual and combined roles of surgery, radiotherapy, chemotherapy, and newer therapeutic options in the management of ATC. An extensive literature review was conducted to include all published reports on ATC. The changing trends in the management of anaplastic thyroid cancer were analyzed to summarize the current practice of management of ATC. Although ATC is rare, there has been a decline in its incidence worldwide. ATC accounts for more than half of the 1200 deaths per year attributed to thyroid cancer. Long-term survivors are rare, with >75% and 50% of patients harboring cervical nodal disease and metastatic disease, respectively, at presentation. ATC can arise de novo or from preexisting well-differentiated thyroid cancer. Surgical management has shifted from tracheostomy only for palliation to curative resection when possible. Tracheostomy is performed for impending obstruction rather than for prophylaxis. Radiotherapy has evolved from postoperative administration only to preoperative treatment, combining preoperative and postoperative treatment and using higher doses, along with hyperfractionating and accelerating dose schedules. Chemotherapy has changed from monotherapy to combination therapy, and newer drugs such as paclitaxel show promise. Similarly, novel angiogenesis-inhibiting agents are currently being used, with early reports of some benefit. Despite multimodality approaches, ATC still carries a dismal prognosis. This should provoke innovative strategies beyond conventional methods to tackle this uniformly lethal disease.


Identification of Estrogen Signaling in a Prioritization Study of Intraocular Pressure-Associated Genes.
Elevated intraocular pressure (IOP) is the only modifiable risk factor for primary open-angle glaucoma (POAG). Herein we sought to prioritize a set of previously identified IOP-associated genes using novel and previously published datasets. We identified several genes for future study, including several involved in cytoskeletal/extracellular matrix reorganization, cell adhesion, angiogenesis, and TGF-β signaling. Our differential correlation analysis of IOP-associated genes identified 295 pairs of 201 genes with differential correlation. Pathway analysis identified β-estradiol as the top upstream regulator of these genes with ESR1 mediating 25 interactions. Several genes (i.e., EFEMP1, FOXC1, and SPTBN1) regulated by β-estradiol/ESR1 were highly expressed in non-glaucomatous human trabecular meshwork (TM) or Schlemm's canal (SC) cells and specifically expressed in TM/SC cell clusters defined by single-cell RNA-sequencing. We confirmed ESR1 gene and protein expression in human TM cells and TM/SC tissue with quantitative real-time PCR and immunofluorescence, respectively. 17β-estradiol was identified in bovine, porcine, and human aqueous humor (AH) using ELISA. In conclusion, we have identified estrogen receptor signaling as a key modulator of several IOP-associated genes. The expression of ESR1 and these IOP-associated genes in TM/SC tissue and the presence of 17β-estradiol in AH supports a role for estrogen signaling in IOP regulation.


Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells.
Intestinal CD103(+) DC promote the differentiation of Foxp3(+) Treg from naïve CD4(+) T cells through mechanisms involving TGF-beta and the dietary metabolite, retinoic acid (RA). In this study, we have analysed whether the specialised features of CD103(+) DC are conserved in colitis. Our results show that inflammation dampens the tolerogenic properties of MLN CD103(+) DC, which is associated with lower expression of tgfbeta2 and aldh1a2. Accordingly, CD103(+) DC taken from colitic mice are impaired in their ability to induce Foxp3(+) Treg and instead favour the emergence of IFN-gamma-producing CD4(+) T cells compared with their steady-state counterparts. BrdU-labelling studies and analysis of ontogeny markers show that CD103(+) DC from steady-state and colitic settings retain similar subset composition and developmental pathways. These results indicate that MLN CD103(+) DC are not hard-wired to promote tolerance but can adapt to environmental conditions. The inflammatory properties of MLN CD103(+) DC in colitic mice may reflect defective gut tolerogenic conditioning or altered migratory pathways and raise the possibility that migratory DC populations contribute to the pathogenesis of inflammatory bowel disease.


Effects of therapeutic ultrasound on the nucleus and genomic DNA.
In recent years, data have been accumulating on the ability of ultrasound to affect at a distance inside the cell. Previous conceptions about therapeutic ultrasound were mainly based on compromising membrane permeability and triggering some biochemical reactions. However, it was shown that ultrasound can access deep to the nuclear territory resulting in enhanced macromolecular localization as well as alterations in gene and protein expression. Recently, we have reported on the occurrence of DNA double-strand breaks in different human cell lines exposed to ultrasound in vitro with some insight into the subsequent DNA damage response and repair pathways. The impact of these observed effects again sways between extremes. It could be advantageous if employed in gene therapy, wound and bone fracture-accelerated healing to promote cellular proliferation, or in cancer eradication if the DNA lesions would culminate in cell death. However, it could be a worrying sign if they were penultimate to further cellular adaptations to stresses and thus shaking the safety of ultrasound application in diagnosis and therapy. In this review, an overview of the rationale of therapeutic ultrasound and the salient knowledge on ultrasound-induced effects on the nucleus and genomic DNA will be presented. The implications of the findings will be discussed hopefully to provide guidance to future ultrasound research.


Robots mediating interactions between animals for interspecies collective behaviors.
Self-organized collective behavior has been analyzed in diverse types of gregarious animals. Such collective intelligence emerges from the synergy between individuals, which behave at their own time and spatial scales and without global rules. Recently, robots have been developed to collaborate with animal groups in the pursuit of better understanding their decision-making processes. These biohybrid systems make cooperative relationships between artificial systems and animals possible, which can yield new capabilities in the resulting mixed group. However, robots are currently tailor-made to successfully engage with one animal species at a time. This limits the possibilities of introducing distinct species-dependent perceptual capabilities and types of behaviors in the same system. Here, we show that robots socially integrated into animal groups of honeybees and zebrafish, each one located in a different city, allowing these two species to interact. This interspecific information transfer is demonstrated by collective decisions that emerge between the two autonomous robotic systems and the two animal groups. The robots enable this biohybrid system to function at any distance and operates in water and air with multiple sensorimotor properties across species barriers and ecosystems. These results demonstrate the feasibility of generating and controlling behavioral patterns in biohybrid groups of multiple species. Such interspecies connections between diverse robotic systems and animal species may open the door for new forms of artificial collective intelligence, where the unrivaled perceptual capabilities of the animals and their brains can be used to enhance autonomous decision-making, which could find applications in selective "rewiring" of ecosystems.


How often should a port-A-cath be flushed?
While it is important during treatment to flush the port-A-cath (PAC) with heparin regularly, catheter maintenance needs to be evaluated in those patients who, after completion of therapy, retained their ports for extended periods of time. The manufacturer has recommended monthly accession to maintain catheter patency and function. Our objective is to demonstrate that a longer interval between maintenance accessions of PACs still may be medically safe, convenient, and more efficient. We performed a retrospective review of all patients who had undergone PAC insertion from 1988 to 1993 at the Albert Einstein College of Medicine, and from 1997 to 2002 at the New York Hospital Medical Center of Queens. An adequate maintenance time is defined as a period of at least 6 months without chemotherapy or total parenteral nutrition. Data collected included date and location of PAC insertion, date of PAC accessions, PAC complications, and results of attempts at flushing the catheters with no venous blood return. All data were entered into an Excel spreadsheet and analyzed. The difference in interval accessions in patients without any complication to patients with complication was calculated using the Mann-Whitney "U" test. A total of 73 patients were included in the study. Compliance with visits for PAC maintenance varied considerably with the individual median accession times varying between 28 and 262 days with an overall median of 42 days. The individual means ranged from 29.5 to 244 days with an overall mean of 53.6 days. Seven patients in the group had episodes where the provider was unable to draw blood from the port during routine accession. The average intervals between accessions for each of these patients ranged from 38 to 244 days. The average intervals of accession among those patients who had no blood return during PAC accession was 79 days, versus 63 days for those without any difficulty. The difference was not statistically significant (p>0.05). Monthly maintenance of PAC is excessive, inconvenient for the patients, and expensive. Extending the interval of PAC maintenance proves to be medically safe and beneficial to the patients, the physicians and the health care system. Our clinical experience suggests that less frequent accessions of PACs is safe and feasible. We strongly advocate future prospective investigation of alternative PAC maintenance protocols in gynecologic cancer patients.


Case-control study of early-term abortions (early fetal losses) associated with mare reproductive loss syndrome in central Kentucky.
To identify factors associated with abortions during early gestation classified as mare reproductive loss syndrome (MRLS). Case-control study. 324 broodmares from 43 farms in central Kentucky, including 121 mares from 25 farms that had early-term abortions (ETAs) associated with MRLS (case horses), 120 mares from the same farms but that did not abort, and 83 mares from 18 farms that were not severely Impacted by MRLS. Farm managers were interviewed to obtain data on various management practices and environmental exposures for the mares. Data for case and control horses were compared to identify risk factors for mares having MRLS-associated ETAs. Several factors increased the risk of MRLS-associated ETAs, including feeding hay in pasture, greater than usual amounts of white clover in pastures, more eastern tent caterpillars in pastures, abortion during a previous pregnancy, and sighting deer or elk on the premises. Analysis indicates that certain characteristics of pastures predisposed mares to MRLS-associated ETAs. Methods for limiting exposure to pasture (keeping mares in stalls longer) during environmental conditions similar to those of 2001 (ie, sudden freezing in mid-April following warmer-than-usual springtime temperatures and larger-than-usual numbers of eastern tent caterpillars in and around pastures) should reduce the risk of mares having MRLS-associated ETAs. It was not possible to determine whether exposure to white clover or caterpillars were causal factors for MRLS or were merely indicators of unusual environmental conditions that resulted in exposure of mares to a toxic or infectious agent.


Correlation between the preoperative serum prostate specific antigen, Gleason score, and clinical staging with pathological outcome following robot-assisted radical prostatectomy: an Indian experience.
To correlate the preoperative serum prostate specific antigen (PSA), Gleason score, and clinical staging with pathological outcome following robot-assisted radical prostatectomy (RARP) in Indian men with clinically localized cancer prostate. A prospective study analysis was done for 166 consecutive patients of prostate cancer who underwent RARP at our center from June 2006 to October 2009. Preoperative workup included serum PSA, biopsy Gleason score, and clinical staging. The preoperative parameters were correlated with final Gleason score, capsular penetration, seminal vesicle involvement, and lymph node status on final histopathology. The mean age was 64 years (range: 50-76 years) with mean and median PSA of 17.98 ng/ml (range: 0.3-68.3 ng/ml) and 12.1 ng/ml, respectively. With increase in preoperative Gleason score, chance of organ confinement decreases (P=0.002) and capsular penetration increases (P=0.004) linearly. With increasing serum PSA, there is linear decrease in trend of organ-confined disease (P=0.03) and increased chances of seminal vesicle involvement (P=0.02). Patients with higher clinical stage have less probability of localized disease (P=0.007) and more chances of capsular penetration (P=0.04) and seminal vesicle involvement (P=0.004). Our data suggest that patients with higher preoperative serum PSA, Gleason score, and clinical stage have more chances of advanced pathological stage following RARP.


Three red cell sodium transport systems in hypertensive and normotensive Utah adults.
Sodium-lithium countertransport (SLC), sodium-potassium cotransport (CoT), and ouabain binding to sodium-potassium adenosine triphosphatase (Na, K-ATPase) sites were measured on fresh erythrocytes from hypertensive and normotensive Utah subjects with and without a first-degree relative with hypertension. SLC was measured as Li+ efflux into NaCl and MgCl2 media from Li+-loaded cells (5-7 mM). CoT was measured by monitoring Na+ and K+ efflux from cells loaded to 20-30 mM Na+ and 20-30 mMK+. Ouabain binding was determined for fresh cells using 3H-ouabain. Subjects were selected from pedigrees that showed a prevalence of hypertension. SLC was significantly elevated in 26.5% of the hypertensive subjects (p less than 0.001) as well as in 12.8% of the normotensives with a hypertensive first-degree relative (p less than 0.05). Although elevated SLC and decreased CoT have previously been associated with hypertension, no hypertensive subject in this study exhibited both abnormalities. All subjects with elevated SLC had normal CoT. A positive correlation between SLC and CoT was observed. Few hypertensive subjects (11.8%) had decreased CoT. In the majority of subjects studied, both SLC and CoT were normal: hypertensives 61.8%, normotensives with a hypertensive first-degree relative 61.7%, and other normotensives 58.7%. The number of ouabain-binding sites was not significantly altered among hypertensives, or their relatives, even though there was a positive correlation between SLC and the number of ouabain-binding sites.


Helping editors, peer reviewers and authors improve the clarity, completeness and transparency of reporting health research.
Inadequate reporting is problematic for several reasons. If authors do not provide sufficient details concerning the conduct of their study, readers are left with an incomplete picture of what was done. As such, they are not able to judge the merits of the results and interpret them. The EQUATOR Network is a new initiative aimed at improving the clarity and transparency of reporting health research.


Controlling the optical properties of composite multilayered photonic structures: effect of superposition.
Tunability of the optical response of multilayered photonic structures has been compared with sequential (SQ) and superposition (SP) addition of refractive index profile functions. The optical response of the composite multilayered structure, formed after the SP addition of the two Bragg type refractive index profile functions has been studied as a function of percentage overlap and relative shift between the profiles. Apart from the substantial advantage in terms of the reduced physical thickness of the SP composite structures (over the SQ addition), at certain optimum values of relative shift, photonic structures with better quality factor resonant modes or a broader PBG could be designed. Similar analysis has been extended for rugate filters as well. The experimental verification of the optical response, was carried out through multilayered dielectric porous silicon structures fabricated by electrochemical anodization.


Feasibility studies for assaying alpha-fetoprotein using antibody-activated magnetic nanoparticles.
Some previous reports have already shown the characterizations of immunomagnetic reduction (IMR). The assay technology involves the utilities of biofunctionalized magnetic nanoparticles to label target biomolecules. However, the detection threshold and interference tests for IMR have not been investigated in detail. In this study, alpha-fetoprotein (AFP) was used as a target biomolecule. The signals for AFP solutions of various concentrations, or with interfering materials, were detected via IMR. These samples were also used for characterizing the detection threshold and interference with enzyme-linked immunosorbent assay (ELISA). The results of assaying AFP level with IMR and ELISA were compared. The detection threshold for assaying AFP with IMR was found to be 3 ng/mL, which is 15 times lower than that of ELISA, and definitely suppresses false negative. For the interfering materials noted commonly in serum such as hemoglobin, bilirubin, triglyceride, and vascular endothelial growth factor, there was no detectable interfering effect when assaying AFP with IMR. Several serum samples from normal people and liver-tumor-bearing patients were used for the detections of AFP concentration via IMR. These results reveal the feasibilities of assaying AFP in blood using IMR, as well as achieving high-sensitive and high-specific assay for AFP.


Unraveling the principles of auditory cortical processing: can we learn from the visual system?
Studies of auditory cortex are often driven by the assumption, derived from our better understanding of visual cortex, that basic physical properties of sounds are represented there before being used by higher-level areas for determining sound-source identity and location. However, we only have a limited appreciation of what the cortex adds to the extensive subcortical processing of auditory information, which can account for many perceptual abilities. This is partly because of the approaches that have dominated the study of auditory cortical processing to date, and future progress will unquestionably profit from the adoption of methods that have provided valuable insights into the neural basis of visual perception. At the same time, we propose that there are unique operating principles employed by the auditory cortex that relate largely to the simultaneous and sequential processing of previously derived features and that therefore need to be studied and understood in their own right.


Development and myogenesis of the vermiform Buddenbrockia (Myxozoa) and implications for cnidarian body plan evolution.
The enigmatic wormlike parasite Buddenbrockia plumatellae has recently been shown to belong to the Myxozoa, which are now supported as a clade within Cnidaria. Most myxozoans are morphologically extremely simplified, lacking major metazoan features such as epithelial tissue layers, gut, nervous system, body axes and gonads. This hinders comparisons to free-living cnidarians and thus an understanding of myxozoan evolution and identification of their cnidarian sister group. However, B. plumatellae is less simplified than other myxozoans and therefore is of specific significance for such evolutionary considerations. We analyse and describe the development of major body plan features in Buddenbrockia worms using a combination of histology, electron microscopy and confocal microscopy. Early developmental stages develop a primary body axis that shows a polarity, which is manifested as a gradient of tissue development, enabling distinction between the two worm tips. This polarity is maintained in adult worms, which, in addition, often develop a pore at the distal tip. The musculature comprises tetraradially arranged longitudinal muscle blocks consisting of independent myocytes embedded in the extracellular matrix between inner and outer epithelial tissue layers. The muscle fibres are obliquely oriented and in fully grown worms consistently form an angle of 12° with respect to the longitudinal axis of the worm in each muscle block and hence confer chirality. Connecting cells form a link between each muscle block and constitute four rows of cells that run in single file along the length of the worm. These connecting cells are remnants of the inner epithelial tissue layer and are anchored to the extracellular matrix. They are likely to have a biomechanical function. The polarised primary body axis represents an ancient feature present in the last common ancestor of Cnidaria and Bilateria. The tetraradial arrangement of musculature is consistent with a medusozoan affinity for Myxozoa. However, the chiral pattern of muscle fibre orientation is apparently novel within Cnidaria and could thus be a specific adaptation. The presence of independent myocytes instead of Cnidaria-like epitheliomuscular cells can be interpreted as further support for the presence of mesoderm in cnidarians, or it may represent convergent evolution to a bilaterian condition.


Treatment options for Cushing disease after unsuccessful transsphenoidal surgery.
Cushing disease is considered an aggressive pituitary endocrinopathy because of the devastating effects from untreated hypercortisolemia. Although they are histologically benign, these adrenocorticotropic hormone (ACTH)-secreting pituitary tumors are associated with significant morbidity and premature death. Currently, transsphenoidal surgery is the primary treatment of Cushing disease associated with an ACTH-secreting pituitary tumor, resulting in remission rates ranging from about 50 to 90%. Some patients, however, will not achieve sustained remission after transsphenoidal surgery and can exhibit persistent or recurrent Cushing disease that requires multimodal treatment to achieve remission. In these patients, options for treatment include repeat transsphenoidal resection, radiation therapy (including conventional fractionated radiation therapy and stereotactic radiosurgery), and medical therapy. Despite undergoing multiple treatment modalities, some patients may ultimately require bilateral adrenalectomy for definitive treatment to eliminate hypercortisolemia associated with Cushing disease. In this article, the authors review the treatment options for patients who have persistent or recurrent Cushing disease after unsuccessful transsphenoidal surgery. The indications, current results reported in the literature, and complications of each treatment modality are discussed.


The complete genome sequence of Cronobacter sakazakii ATCC 29544T, a food-borne pathogen, isolated from a child's throat.
Cronobacter sakazakii is an emerging opportunistic pathogen that is associated with rare but life-threatening cases of severe diseases: meningitis, necrotizing enterocolitis, and sepsis in premature and full-term infants. However, the pathogenesis mechanism of this pathogen remains largely unknown. To determine its pathogenesis at the genomic level, the genome of C. sakazakii ATCC 29544T was completely sequenced and analyzed. The genomic DNA, containing a circular chromosome and three plasmids, is composed of 4,511,265 bp with a GC content of 56.71%, containing 4380 predicted open reading frames (ORFs), 22 rRNA genes, and 83 tRNA genes. The plasmids, designated pCSK29544_p1, pCSK29544_p2, and pCSK29544_p3, were 93,905-bp, 4938-bp, and 53,457-bp with GC contents of 57.02, 54.88, and 50.07%, respectively. They were also predicted to have 72, 6, and 57 ORFs without RNA genes. The strain ATCC 29544T genome has ompA and ibeB-homologous cusC genes, probably associated with the invasion of human brain microvascular endothelial cells (BMECs). In addition, gene clusters for siderophore production (iucABCD/iutA) and the related transport system (eitCBAD) were detected in pCSK29544_p1 plasmid, indicating better iron uptake ability for survival. Furthermore, to survive under extremely dry condition like milk powder, this genome has gene clusters for biosynthesis of capsular proteins (CSK29544_00281-00284) and cellulose (CSK29544_01124-01127) for biofilm formation and a gene cluster for utilization of sialic acid in the milk (nanKTAR). The genome information of C. sakazakii ATCC 29544T would provide further understanding of its pathogenesis at the molecular level for the regulation of pathogenicity and the development of a rapid detection method using biomarkers.


pvsR: An Open Source Interface to Big Data on the American Political Sphere.
Digital data from the political sphere is abundant, omnipresent, and more and more directly accessible through the Internet. Project Vote Smart (PVS) is a prominent example of this big public data and covers various aspects of U.S. politics in astonishing detail. Despite the vast potential of PVS' data for political science, economics, and sociology, it is hardly used in empirical research. The systematic compilation of semi-structured data can be complicated and time consuming as the data format is not designed for conventional scientific research. This paper presents a new tool that makes the data easily accessible to a broad scientific community. We provide the software called pvsR as an add-on to the R programming environment for statistical computing. This open source interface (OSI) serves as a direct link between a statistical analysis and the large PVS database. The free and open code is expected to substantially reduce the cost of research with PVS' new big public data in a vast variety of possible applications. We discuss its advantages vis-à-vis traditional methods of data generation as well as already existing interfaces. The validity of the library is documented based on an illustration involving female representation in local politics. In addition, pvsR facilitates the replication of research with PVS data at low costs, including the pre-processing of data. Similar OSIs are recommended for other big public databases.


Universal tight binding model for chemical reactions in solution and at surfaces. III. Stoichiometric and reduced surfaces of titania and the adsorption of water.
We demonstrate a model for stoichiometric and reduced titanium dioxide intended for use in molecular dynamics and other atomistic simulations and based in the polarizable ion tight binding theory. This extends the model introduced in two previous papers from molecular and liquid applications into the solid state, thus completing the task of providing a comprehensive and unified scheme for studying chemical reactions, particularly aimed at problems in catalysis and electrochemistry. As before, experimental results are given priority over theoretical ones in selecting targets for model fitting, for which we used crystal parameters and band gaps of titania bulk polymorphs, rutile and anatase. The model is applied to six low index titania surfaces, with and without oxygen vacancies and adsorbed water molecules, both in dissociated and non-dissociated states. Finally, we present the results of molecular dynamics simulation of an anatase cluster with a number of adsorbed water molecules and discuss the role of edge and corner atoms of the cluster.


Second malignancies in Hodgkin's disease: a complication of certain forms of treatment.
A total of 764 patients with Hodgkin's disease treated with radiotherapy (RT) or chemotherapy or both were reviewed 3-186 months (median 43 months) after initial treatment to assess the incidence of second malignancies. Incidence of solid tumours and acute non-lymphoblastic leukaemia (ANLL) were calculated by a life-table method and percentages of patients affected derived from life-table plots. Within 10 years after initial treatment the overall incidence of second solid tumours was 7.3%, and over a comparable period 2.4% of patients developed ANLL. Solid tumours occurred only in patients given RT with or without adjuvant chemotherapy, and ANLL occurred only after treatment with MOPP (mustine, vincristine, procarbazine, and prednisolone) or modified MOPP regimens. Neither solid tumours nor ANLL occurred in patients given ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The highest incidence of leukaemia (5.4%) occurred after treatment with extensive RT plus (5.4%) occurred after treatment with extensive RT plus MOPP; hence the benefits of this approach in Hodgkin's disease must be weighed against its carcinogenic potential.


Relationship of caries and fluorosis in adolescents from high- and low-fluoride areas in Iran.
The main aim of the study was to investigate the association between water fluoride concentration and caries as well as fluorosis occurrence in adolescents in Iran. As a secondary aim we studied the relationship between caries and fluorosis occurrence. We examined 12-16 year-olds (n = 373) in Orumiyeh [0.3 mgF-/l, low-fluoride (LF)] and Pol Dasht [3.2 mgF-/l, high-fluoride (HF)] for caries-status [D3-Level, Pitts & Fyffe (DMFS)] and fluorosis prevalence [Thylstrup & Fejerskov index (TF)]. Children completed questionnaires about several sociodemographic and oral health related factors of the previous years. To adjust for confounding, we used log risk regression and estimated relative risks (RR) and 95% confidence intervals (CI). For 12-13 year-olds mean DMFS were 1.9 (sd 2.5) and 1.1 (2.2) in the LF and the HF-areas, respectively. Prevalence of aesthetically relevant fluorosis (TF > 2) was 1% (LF) and 87% (HF). Water fluoride concentration (adjusted for age and SES) was inversely associated with caries-status [RR: 0.7, (CI 0.6-0.8)]. RR for fluorosis was 17 (CI 8-33). In HF-area, caries scores were significantly higher for children with TF > or = 5 on upper central incisors compared with TF < or = 4 (p < 0.05 Mann-Whitney test). Caries prevalence in the examined areas in Iran is quite low. Above-optimal water fluoride concentration seems to be effective in reducing caries experience, but increases the occurrence of fluorosis. Severe fluorosis seems to be associated with higher caries occurrence in a high-fluoride area.


Influence of fludarabine on pharmacokinetics and pharmacodynamics of cytarabine: implications for a continuous infusion schedule.
Arabinosylcytosine (ara-C) is a cytotoxic agent with major activity against acute leukemias. To exert this effect, it must first be phosphorylated to its active 5'-triphosphate, ara-CTP, which is incorporated into DNA. Our previous studies demonstrated that preincubation with arabinosyl-2-fluoroadenine (F-ara-A) increased the rate of ara-CTP accumulation in leukemia cells when incubated with 10 microM ara-C. Such concentrations of ara-C are readily obtained during intermittent bolus infusions of ara-C, and clinical trials were conducted using fludarabine in combination with 2-h infusions of intermediate-dose ara-C. During continuous infusion of ara-C, however, serum ara-C levels are <10 microM. Because the effectiveness of ara-C depends on the levels of intracellular ara-CTP and its incorporation into DNA, we sought to investigate the influence of fludarabine on pharmacodynamics of ara-C at concentrations of ara-C achieved during continuous infusion. Using the K562 human leukemic cell line, we established that incubation with 30 microM F-ara-A was able to modulate intracellular dNTP pools and achieve maximum enhancement of ara-CTP levels at all concentrations of ara-C tested (0.3-10.0 microM). The relative enhancement of ara-CTP concentrations ranged from 2.2- to 2.8-fold. Combination of F-ara-A with 1.0 and 3.0 microM ara-C also increased the incorporation of ara-CTP into DNA. To model the influence of F-ara-A on continuous infusion ara-C, cells were incubated with 1 microM ara-C alone or in combination with F-ara-A. The F-ara-A-incubated cells accumulated effective intracellular concentrations of F-ara-ATP, which resulted in greatly increased intracellular ara-CTP levels. These studies demonstrate the capacity of clinically attainable concentrations of F-ara-ATP to enhance the formation of ara-CTP at concentrations of ara-C that are achieved during a continuous infusion schedule. Given the important role intracellular ara-CTP concentrations and ara-CMP incorporation into DNA have on the ultimate cytotoxic capacity of ara-C against acute myelogenous leukemia blasts, these studies suggest a promising pharmacological model for improving the efficacy of the continuous infusion ara-C regimen.


Novel cross-stage solitarising effect of gregarious-phase adult desert locust (Schistocerca gregaria (Forskål)) pheromone on hoppers.
Previous studies had demonstrated stage differentiation in the cohesion (aggregation) pheromone systems of the desert locust, Schistocerca gregaria. In laboratory arena, the nymphal and adult stages responded aggregatively to their own pheromone, but dispersed evenly within the arena in the presence of the other. In the present study, we explored the effects of longer-term contact of field gregarious hopper bands and laboratory crowd-reared nymphs with the major constituent of the adult pheromone. During the first few days, hoppers in treated bands became relatively hyperactive. Over the next few days, their movements became random and they stopped marching as coherent groups, they started to roost for longer periods on vegetations, and they fragmented into smaller and smaller groupings and individuals. When attacked by birds, they demonstrated subdued levels of collective defensive behaviour compared to normal hoppers, and there were clear signs of increased predation and cannibalism at the roosting sites. In cage experiments, crowd-reared nymphs treated with the pheromone component became hyperactive, showed abnormal diel patterns and reduced feeding on plants but increased cannibalism. Our observations show that the major adult pheromone constituent has a solitarising effect on gregarious hoppers. The mechanism underlying this effect and the potential of the agent in desert locust control are discussed.


Epidermal growth factor-nanoparticle conjugates change the activity from anti-apoptotic to pro-apoptotic at membrane rafts.
The proliferation epidermal growth factor (EGF) is known to acquire contradictory apoptotic activities upon conjugation with gold nanoparticles (GNPs) through hitherto unknown mechanisms. Here, we identified an essential role of membrane rafts in the drastic activity switching of EGF-GNPs through the following intracellular signaling. (1) In contrast to the rapid diffusion of activated EGF receptor after the soluble EGF stimulation, the receptor is confined within membrane rafts upon binding to the EGF-GNPs. (2) This initial receptor confinements switch its endocytosis process from normal clathrin-mediated endocytosis to caveolin-mediated one, changing the phosphorylation dynamics of essential downstream kinases, i.e., extracellular signal-regulated kinase and AKT. Importantly, the destruction of membrane rafts by β-cyclodextrin reversed this trafficking and signaling, restoring EGF-GNPs to lost anti-apoptotic property. These results reveal the importance of GNP-mediated signal condensation at membrane rafts in conferring the unique apoptotic activity on EGF-nanoparticle conjugates. STATEMENT OF SIGNIFICANCE: Epidermal growth factor (EGF) is a small secretory protein that induces cell proliferation upon binding to its receptor existed on cellular plasma membranes. One interesting feature of the protein in the nanobiology field is, its acquisition of apoptosis-inducing (cellular suicide) activity rather than proliferative one upon conjugation to gold nanoparticles through hitherto unknown mechanisms. Here, we identified the involvement of membrane rafts, plasma membrane nanodomains enriched with cholesterol, in the apoptosis processes by changing the receptor trafficking and downstream signal transduction pathways. Moreover, the destruction of lipid rafts restored the EGF-nanoparticle conjugates with lost anti-apoptotic activity. These finding highlight potential applications of EGF-nanoparticle conjugates to cancer therapy, as the EGF receptor are highly expressed in cancer cells.


Expression of IGF-I and -II mRNA in the brain and craniofacial region of the rat fetus.
Insulin-like growth factors (IGF-I and -II) are present in the brain during development, with high levels of both being also found in the periphery particularly in the embryo. IGFs in the brain are believed to stimulate the proliferation of neuronal and glial precursors and their phenotypic differentiation. Using in situ hybridization, we have investigated the distribution of cells producing IGF-I and -II in the rat fetus during the second half of prenatal development with special emphasis on the peripheral and central nervous system. High levels of IGF-I mRNA were found in the olfactory bulb and in discrete neurons of the cranial sensory ganglia, notably in the trigeminal ganglion, as early as 13 days of gestation, in the pineal primordium of 18 day old fetuses, and in discrete groups of cells in the cochlear epithelium located laterally outside the forming spiral organ, in day 13 to 21 fetuses. High levels of IGF-II mRNA in the brain, besides the choroid plexus and the leptomeninges, were detected in hypothalamus, in the floor of the 3rd ventricle at all stages studied, in the pineal primordium at 18 days and in the pars intermedia of the pituitary or in the Rathke's pouch epithelium from which it is derived, with progressive fading towards the end of the gestation. In the peripheral nervous system the IGF-II mRNA was only found in association with the vascular endothelia of the ganglia. IGF-II mRNA in the nervous system was found in highly vascularized areas, meninges, blood vessels and choroid plexuses. It is thus associated with structures involved in the production of extracellular fluids and/or substrate transport and supply in the nervous tissues. A more specific role in the differentiation or fetal endocrine function should be considered for IGF-II in cells producing melatonin and melanocyte stimulating hormone (MSH) in the pineal and pituitary glands, respectively. The presence of IGF-I mRNA in the nervous system could be associated with fiber outgrowth and synaptogenesis in the cases of olfactory bulb and developing iris. The role of IGF-I in restricted populations of cells of the cochlear epithelium and in the pineal gland is unclear and requires further investigations including a search for IGF-I receptors in possible target cells. In the sensory ganglia, the presence of high levels of IGF-I mRNA eventually corresponds to the production, by post-translational processing, of the amino-terminal tripeptide of IGF-I, which might represent a neurotransmitter for these sensory neurons.


The Global Synanthrome Project: A Call for an Exhaustive Study of Human Associates.
Here we coin the term synanthrome to describe all of the species we interact with. We propose that the time is now here for The Global Synanthrome Project to describe all of our interacting species and how they have changed through time and across space. This effort must involve natural history, ecology, and evolutionary biology in addition to genomics studies that are already underway.


Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs oxphos and prostate cancer metastatic spread.
Cancer associated fibroblasts (CAFs) are key determinants of cancer progression. In prostate carcinoma (PCa), CAFs induce epithelial-mesenchymal transition (EMT) and metabolic reprogramming of PCa cells towards oxidative phosphorylation (OXPHOS), promoting tumor growth and metastatic dissemination. We herein establish a novel role for pyruvate kinase M2 (PKM2), an established effector of Warburg-like glycolytic behavior, in OXPHOS metabolism induced by CAFs. Indeed, CAFs promote PKM2 post-translational modifications, such as cysteine oxidation and Src-dependent tyrosine phosphorylation, allowing nuclear migration of PKM2 and the formation of a trimeric complex with hypoxia inducible factor-1α (HIF-1α) and the transcriptional repressor Differentially Expressed in Chondrocytes-1 (DEC1). DEC1 recruitment is mandatory for downregulating miR205 expression, thereby fostering EMT execution and metabolic switch toward OXPHOS. Furthermore, the analysis of a cohort of PCa patients reveals a significant positive correlation between PKM2 nuclear localization and cancer aggressiveness, thereby validating our in vitro observations. Crucially, in vitro and in vivo pharmacological targeting of PKM2 nuclear translocation using DASA-58, as well as metformin, impairs metastatic dissemination of PCa cells in SCID mice. Our study indicates that impairing the metabolic tumor:stroma interplay by targeting the PKM2/OXPHOS axis, may be a valuable novel therapeutic approach in aggressive prostate carcinoma.


Mutating RBF can enhance its pro-apoptotic activity and uncovers a new role in tissue homeostasis.
The tumor suppressor retinoblastoma protein (pRb) is inactivated in a wide variety of cancers. While its role during cell cycle is well characterized, little is known about its properties on apoptosis regulation and apoptosis-induced cell responses. pRb shorter forms that can modulate pRB apoptotic properties, resulting from cleavages at caspase specific sites are observed in several cellular contexts. A bioinformatics analysis showed that a putative caspase cleavage site (TELD) is found in the Drosophila homologue of pRb(RBF) at a position similar to the site generating the p76Rb form in mammals. Thus, we generated a punctual mutant form of RBF in which the aspartate of the TELD site is replaced by an alanine. This mutant form, RBFD253A, conserved the JNK-dependent pro-apoptotic properties of RBF but gained the ability of inducing overgrowth phenotypes in adult wings. We show that this overgrowth is a consequence of an abnormal proliferation in wing imaginal discs, which depends on the JNK pathway activation but not on wingless (wg) ectopic expression. These results show for the first time that the TELD site of RBF could be important to control the function of RBF in tissue homeostasis in vivo.


IL-18 enhances immunosuppressive responses by promoting differentiation into monocytic myeloid-derived suppressor cells.
Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that lead to T cell defects in cancer. IL-18 is important in inflammatory and immune responses. IL-18 has been reported to have a dual effect on tumor progression, as it not only stimulates host immune responses, but also exerts procancer effects by inducing immune escape and angiogenesis. In the present study, we investigated the effect of IL-18 on MDSCs and found that IL-18 treatment significantly increased the percentage and the absolute number of monocytic MDSCs (M-MDSCs) via differentiation of CD11b(-) bone marrow progenitor cells. IL-18-induced MDSCs showed enhanced suppression of T cell proliferation and IFN-γ production along with a dramatic increase of M-MDSC suppressive function, including NO production and arginase 1 expression. Although IL-18 decreased the number of granulocytic MDSCs (G-MDSCs) in a concentration-dependent manner, we found that the absolute number of G-MDSCs and their reactive oxygen species production remained unchanged. Additionally, we demonstrated that IL-18-induced M-MDSCs have a more potent suppressive effect on T cell responses with lower IFN-γ production than do G-MDSCs, suggesting that the increased suppressive effect observed in our study resulted from M-MDSCs. Furthermore, in vivo administration of IL-18 significantly increased the accumulation of M-MDSCs in the tumor microenvironment. Taken together, our findings indicate that IL-18 specifically enhances the differentiation and function of M-MDSCs, leading to immunosuppression.


Effects of chromatic adaptation on phase-dependent sensitivity to heterochromatic flicker.
Temporal modulation sensitivity was measured as a function of the relative phase of two equiluminous chromatic sources (564 and 625 nm) for temporal frequencies from 6 to 20 Hz. The difference between 180 degrees and the phase of least sensitivity was computed as the measured phase shift. A 2 degree test field was superimposed upon 8 degrees chromatic adapting fields with luminances from 100 to 3000 Td and chromaticities of 500, 600, and 650 nm. For each adapting field, the 564-nm source was set to 175 Td, and the 625-nm source was matched to it with heterochromatic flicker photometry (giving an effective mean luminance of 350 Td). The 650-nm adapting fields produced large changes in photometric setting but only small changes in the measured phase shift. The 600- and 500-nm adapting fields produced smaller changes in photometric setting but larger changes in the measured phase shift. In general, increased adapting luminance resulted in an increase in the measured phase shift for 600-nm adaptation and a decrease in the measured phase shift for 500-nm adaptation.


Dynamics theory for molecular liquids based on an interaction site model.
Dynamics theories for molecular liquids based on an interaction site model have been developed over the past few decades and proved to be powerful tools to investigate various dynamical phenomena. In many of these theories, equations of time correlation functions are formulated by using the Zwanzig-Mori projection operator. Since algebriac equations are directly treated in these statistical mechanical approaches, the obtained dynamical properties are essentially free from statistical error. This perspective presents the theoretical framework of such theories and their applications, including visualization of diffusion processes, collective excitations, solvation dynamics, transport properties, and diffusion controlled reactions.


[Characteristics of Patients with Breathlessness].
Background Breathlessness is a common and distressing symptom in patients with advanced life-limiting disease. The aim of this study was to describe demographical and clinical characteristics of patients with breathlessness in Germany. Methods We conducted a secondary analysis of hospice and palliative care inpatient data from 2006 to 2008. The Hospice and Palliative Care Evaluation (HOPE) is an annual prospective German survey, that includes a validated 16-item symptom-and-problem checklist (severity score 0 - 3). Characteristics of patients with or without breathlessness were compared in a pure descriptive manner. Interpretation of given p-values takes the error inflation due to multiple testing into account. Results Breathlessness was recorded in 2860/5320 (53.8 %) patients (mean age 67.2 years (SD 12.4), 51.4 % female, 93.6 % malignant disease (female/male lung cancer 15.7/29.5 %, breast cancer 20.3/0.3 %, colon 10.3/8.7 %). Breathless patients compared with those without breathless ness had a significantly worse functional status (ECOG 3 - 4: 78.4 % vs. 70.8 %, p < 0.001), suffered from a larger number (11.1 vs. 9.5, p < 0.001) of symptoms and the symptoms were of higher intensity (except confusion). Breathless patients had a higher risk to die during inpatient stay (43.5 % vs. 32.4 %, p < 0.001). Conclusion Based on this large sample of hospice and palliative care inpatients, breathlessness is associated with a high symptom burden and shortened survival. Breathless patients need more attention in health care.


Protein aggregates and dementia: is there a common toxicity?
This review considers some of the recent advances made in the understanding of the pathogenic proteins known to aggregate and be implicated in neurodegenerative dementing disorders. It concentrates on the two most obvious candidates for the role of toxic protein in Alzheimer's disease (AD)--beta-amyloid peptide and tau--but also considers other proteins in this disorder and in less common but equally devastating diseases.


Thyroxine-induced hypertrophy of the rabbit heart. Effect on regional oxygen extraction, flow, and oxygen consumption.
The effects of the administration of 0.5 or 1 mg/kg of 1-thyroxine for 3 or 16 days were studied in 55 New Zealand white rabbits. Heart size was 29% above control after 16 days of 1-thyroxine, despite lower body weights. In an anesthetized open-chest animal, regional microspectro-photometric observations of small arteries and veins to determine oxygen extraction were combined with regional blood flow measurements using radioactive microspheres to determine regional oxygen consumption by the Fick principle. Vascular flow reserves were studied through measurement of blood flow after the administration of chromonar HCl, 10 mg/kg. Myocardial oxygen consumption was, respectively, 2.4 and 3.8 times control after 3 and 16 days of 1-thyroxine. This was accompanied by significant increases in both coronary blood flow and oxygen extraction. In control, oxygen extraction and consumption were higher in the subendocardial region compared to the subepicardial area. No significant regional differences were found in flow, oxygen extraction, or consumption after 1-thyroxine administration. Chromonar increased coronary blood flow 2.8 times in the control animals, but did not significantly increase flow or decrease vascular resistance in the rabbits given 1-thyroxine. Adenosine increased coronary blood flow 3.5 times in the control animals but only 2.2 times in animals given 1-thyroxine for 3 days. Animals given 1-thyroxine had hypertrophied hearts with increased oxygen consumption, markedly increased flow, and increased oxygen extraction but without regional left ventricular differences.


Life-long epigenetic programming of cortical architecture by maternal 'Western' diet during pregnancy.
The evolution of human diets led to preferences toward polyunsaturated fatty acid (PUFA) content with 'Western' diets enriched in ω-6 PUFAs. Mounting evidence points to ω-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans. When chosen during pregnancy, ω-6 PUFA-enriched 'Western' diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine ω-6 PUFA excess, cellular underpinnings of life-long modifications to brain architecture remain unknown. Here, we show that nutritional ω-6 PUFA-derived endocannabinoids desensitize CB1 cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity when mouse fetuses are exposed to excess ω-6 PUFAs in utero. Conversion of ω-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB1 cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates, with DNA methylation and chromatin accessibility profiling uncovering epigenetic reprogramming at >1400 sites in neurons after prolonged cannabinoid exposure. We found anxiety and depression-like behavioral traits to manifest in adult offspring, which is consistent with genetic models of reduced IgCAM expression, to suggest causality for cortical wiring defects. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit an offspring's brain function for life.


Strategies for long-term expression of transgenes in the respiratory epithelium.
Lung gene therapy is being developed to treat acute and chronic airway diseases, and many viral and non-viral gene transfer vectors have been evaluated in the airway epithelium lining the nose and lung. Stem cells have not been clearly defined in the airways and, currently, it is only possible to target progenitor cells to proliferate and repair the epithelium after inducing epithelial damage. However, the majority of airway epithelial cells are slowly dividing or terminally differentiated, thus necessitating repeated administration of gene transfer vectors for life-long transgene expression. Many improvements to adeno-associated virus and lentivirus vectors have led to increased airway transduction efficiencies, although achieving consistent repeated administration remains problematic because of immune system activation. Non-viral vectors appear to be less efficient, but can be successfully re-administered. The modification of plasmid sequences also offers maximum flexibility in increasing and extending the duration of transgene expression in the airways. This review describes recent developments in achieving persistent transgene expression in the airways by specifically targeting the cells of the respiratory epithelium lining the nose and lung.


Antivirals for the common cold.
The common cold is a ubiquitous short and usually mild illness for which preventive and treatment interventions have been under development since the mid-40s. As our understanding of the disease has increased, more experimental antivirals have been developed. This review attempts to draw together experimental evidence of the effects of these compounds. To identify, assemble, evaluate and (if possible) synthesise the results of published and unpublished randomised controlled trials of the effects of antivirals to prevent or minimise the impact of the common cold. We searched electronic databases, corresponded with researchers and handsearched the archives of the MRC's Common Cold Unit (CCU). We included original reports of randomised and quasi-randomised trials assessing the effects of antivirals on volunteers artificially infected and in individuals exposed to colds in the community. We included 241 studies assessing the effects of Interferons, interferon-inducers and other antivirals on experimental and naturally occurring common colds, contained in 230 reports. We structured our comparisons by experimental or community setting. Although intranasal interferons have high preventive efficacy against experimental colds (protective efficacy 46%, 37% to 54%) and to a lesser extent against natural colds (protective efficacy 24%, 21% to 27%) and are also significantly more effective than placebo in attenuating the course of experimental colds (WMD 15.90, 13.42 to 18.38), their safety profile makes compliance with their use difficult. For example, prolonged prevention of community colds with interferons causes blood-tinged nasal discharge (OR 4.52, 3.78 to 5.41). Dipyridamole (protective efficacy against natural colds 49%, 30% to 62%), ICI 130, 685 (protective efficacy against experimental colds 58%, 35% to 74% ), Impulsin (palmitate) (protective efficacy against natural colds 44%, CI 35% to 52% ) and Pleconaril (protective efficacy against experimental colds 71%, 15% to 90% ) appear to have important antiviral properties and are well-tolerated. The evidence of effectiveness of other compounds in the treatment of experimental or natural colds is sparse. There are no licensed effective antivirals for the common cold. Because prolonged intranasal administration causes a clinical picture which is not distinguishable from the common cold, interferons have no place in everyday use. Further assessment of the effects of dipyridamole, palmitate, ICI 130, 685, Impulsin and Pleconaril in preventing the common cold should be carried out. Given the multi-agent nature of the causes of the common cold, future research efforts should focus on non virus-specific compounds.


Coronavirus Disease (COVID-19) Outbreak and Its Impact on Spinal Daily Practice : Preliminary Report from a Single (Regional) University Hospital in Republic of Korea.
Since the first discovery of the 2019 novel coronavirus (COVID-19), rapid and wide spread of the disease has been reported and the World Health Organization announced that a 'pandemic' has started. Up to date there is little known regarding the impact of this outbreak on spinal specialists' daily clinical practice. We intended to evaluate how COVID-19 has affected the number of spinal disease patients we meet and operate in daily practice. The de-identified data regarding number of patients visiting the spine clinic at a tertiary referral hospital and a secondary level hospital from January, February and March of 2017 to 2020 were retrospectively reviewed. The number of out-patient department (OPD) visits, number of emergency room (ER) visits as well as number of surgeries performed during the reviewed period were collected and analyzed, comparing 2020 to the previous 3 years. The number of daily OPD visits showed a steady decrease starting from January, and presented a statistically significant decrease by early March 2020, compared to the previous 3 years. During the same period, decrease in number of daily ER visits was statistically significant as well. The number of elective surgeries or number of surgeries for patients admitted via ER during COVID-19 outbreak remained similar to that of 2017-2019 suggesting, despite the decrease of patients visiting the hospital for spinal diseases, those whom required surgery still visited the hospital. The results were consistant among other hospital level. The outbreak of COVID-19 affected our daily practice as OPD and ER visits reduced but did not affect the number of surgeries. We believe that this report will be informative to spinal specialists worldwide fighting the COVID-19 pandemic.


Profiles of Stimulus-Frequency Otoacoustic Emissions from 0.5 to 20 kHz in Humans.
The characteristics of human otoacoustic emissions (OAEs) have not been thoroughly examined above the standard audiometric frequency range (>8 kHz). This is despite the fact that deterioration of cochlear function often starts at the basal, high-frequency end of the cochlea before progressing apically. Here, stimulus-frequency OAEs (SFOAEs) were obtained from 0.5 to 20 kHz in 23 young, audiometrically normal female adults and three individuals with abnormal audiograms, using a low-to-moderate probe level of 36 dB forward pressure level (FPL). In audiometrically normal ears, SFOAEs were measurable at frequencies approaching the start of the steeply sloping high-frequency portion of the audiogram (∼12-15 kHz), though their amplitudes often declined substantially above ∼7 kHz, rarely exceeding 0 dB SPL above 8 kHz. This amplitude decline was typically abrupt and occurred at a frequency that was variable across subjects and not strongly related to the audiogram. In contrast, certain ears with elevated mid-frequency thresholds but regions of normal high-frequency sensitivity could possess surprisingly large SFOAEs (>10 dB SPL) above 7 kHz. When also measured, distortion-product OAEs (DPOAEs) usually remained stronger at higher stimulus frequencies and mirrored the audiogram more closely than SFOAEs. However, the high-frequency extent of SFOAE and DPOAE responses was similar when compared as a function of the response frequency, suggesting that middle ear transmission may be a common limiting factor at high frequencies. Nevertheless, cochlear factors are more likely responsible for complexities observed in high-frequency SFOAE spectra, such as abrupt amplitude changes and narrowly defined response peaks above 10 kHz, as well as the large responses in abnormal ears. These factors may include altered cochlear reflectivity due to subtle damage or the reduced spatial extent of the SFOAE generation region at the cochlear base. The use of higher probe levels is necessary to further evaluate the characteristics and potential utility of high-frequency SFOAE measurements.


Improved overall survival in melanoma with combined dabrafenib and trametinib.
The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).


DNA damage-induced cytotoxicity is dissociated from BRCA1's DNA repair function but is dependent on its cytosolic accumulation.
The tumor suppressor BRCA1 is a nuclear shuttling protein. However, the role of BRCA1 localization in the control of its functions remains to be elucidated. Given the central role of BRCA1 in DNA damage repair, we hypothesized that depletion of nuclear BRCA1 would compromise its nuclear function in DNA repair and thereby result in enhanced cytotoxic response to DNA damage. In this study, we showed that repair of DNA double-strand breaks required BRCA1 in the nucleus. In addition, sequestering BRCA1 in the cytosol enhanced the cytotoxic response to ionizing radiation or cisplatin in human breast and colon cancer cells. However, further genetic dissection of the mechanism of this enhanced cytotoxicity using BRCA1 mutants deficient in double-strand break repair unexpectedly revealed a dissociation of BRCA1's function in DNA repair from its effects on cellular sensitivity to DNA damage. Interestingly, we observed a dependence of the DNA damage-induced cell killing on the translocation and accumulation of BRCA1 in the cytosol. Together, these data suggest a novel role of cytoplasmic translocation of BRCA1, not only in controlling its DNA repair functions, but also in the regulation of cell death processes following DNA damage. Further dissection of the mechanism of cytotoxicity induced by BRCA1 cytoplasmic translocation revealed the involvement of the apoptotic pathway. We propose that the status of BRCA1 nuclear/cytoplasmic shuttling might provide a molecular marker to predict tumor response and a potential novel target to sensitize cancer cells to DNA damage-based therapy.


Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signaling pathways that regulate transcription factor activity.
The type 1 TNFR (TNFR1) contains a death domain through which it interacts with other death-domain proteins to promote cellular responses. However, signaling through death-domain proteins does not explain how TNFR1 induces the tyrosine phosphorylation of intracellular proteins, which are important to cellular responses induced by TNFR1. In this study, we show that TNFR1 associates with Jak2, c-Src, and PI3K in various cell types. Jak2 and c-Src constitutively associate with and are constitutively active in the TNFR1 complex. Stimulation with TNF induces a time-dependent change in the level of Jak2, c-Src, and PI3K associated with TNFR1. The tyrosine kinase activity of the complex varies with the level of tyrosine kinase associated with TNFR1. TNFR1/c-Src plays a role in activating Akt, but not JNK or p38 MAPK, whereas TNFR1/Jak2 plays a role in activating p38 MAPK, JNK, and Akt. TNFR1/c-Src, but not TNFR1/Jak2, plays an obligate role in the activation of NF-kappaB by TNF, whereas TNFR1/Jak2, but not TNFR1/c-Src, plays an obligate role in the activation of STAT3. Activation of TNFR1 increased the expression of vascular endothelial growth factor, p21(WAF1/CIP1), and manganese superoxide dismutase in MCF7 breast cancer cells, and increased the expression of CCl2/MCP-1 and IL-1beta in THP-1 macrophages. Inhibitors of Jak2 and c-Src impaired the induction of each of these target proteins. These observations show that TNFR1 associates with and uses nonreceptor tyrosine kinases to engage signaling pathways, activate transcription factors, and modulate gene expression in cells.


Associations of Polyethylenimine-Coated AN69ST Membrane in Continuous Renal Replacement Therapy with the Intensive Care Outcomes: Observations from a Claims Database from Japan.
Polyethylenimine-coated polyacrylonitrile (AN69ST) membrane is expected to improve the outcomes of critically ill patients treated by continuous renal replacement therapy (CRRT). Using a Japanese health insurance claim database, we identified adult patients receiving CRRT in intensive care units (ICUs) from April 2014 to October 2015. We used a multivariable logistic regression model to assess in-hospital mortality and Fine and Gray's proportional subhazards model to assess the ICU length of stay (ICU-LOS) accounting for the competing risks. Of 2,469 ICU patients, 156 were treated by AN69ST membrane. Crude in-hospital mortality was 50.0% in the AN69ST group and 54.0% in the non-AN69ST group. Adjusted odds ratio (OR) of AN69ST membrane use for in-hospital mortality was 0.65 (95% CI 0.45-0.93). The use of AN69ST membrane was also independently associated with shorter ICU-LOS. This retrospective observational study suggested that CRRT with AN69ST membrane might be associated with better in-hospital outcomes.


Is intimate partner violence associated with the use of alcohol treatment services? Results from the National Survey on Drug Use and Health.
The purpose of this study was to examine (1) the prevalence of alcohol treatment use by intimate partner violence (IPV) type (any IPV, victimization, and perpetration) among problem drinkers and (2) the relationship between alcohol treatment use and IPV, by IPV type, in the general population. The sample was drawn from the 2002 National Survey on Drug Use and Health. Black, Hispanic, and non-Hispanic white cohabiting respondents 18-49 years of age and who reported one or more alcohol problems in the past year are included in the analysis. Logistic regression was used to examine the relationship between alcohol treatment use and IPV. The prevalence of alcohol treatment use was significantly greater among individuals exposed to IPV, regardless of IPV type (7.4%, 7.8%, and 6.9% among those with any IPV, victimization, and perpetration, respectively) compared with those without reported IPV (2.8%, 2.8%, and 3.0%, respectively). Any IPV (adjusted odds ratio [AOR] = 1.97, 95% confidence interval [CI]: 1.06-3.65) and IPV victimization (AOR = 1.93, CI: 1.00-3.73), but not perpetration, were associated with alcohol treatment use. Male gender, alcohol abuse/dependence, illicit drug abuse/dependence, and serious mental illness were positively and significantly associated with alcohol treatment in all three models. IPV, especially victimization, may have a substantial impact on alcohol treatment services. Findings highlight the potential to identify IPV in alcohol treatment settings and provide referral and intervention services.


Role of food preoccupation and current dieting in the associations of parental feeding practices to emotional eating in young adults: A moderated mediation study.
Parental feeding practices reflecting coercive control are related to children's later eating behaviors, but the mechanisms underlying these effects remain poorly understood. This study examined the relationships between recalled childhood experiences of parental pressure to eat and restriction and current food preoccupation, dieting, and emotional eating in a racially diverse sample of college students (N = 711). Results revealed that parental restriction, but not pressure to eat, was associated with more emotional eating (r = 0.18, p < 0.0001). Food preoccupation mediated the association between restriction and emotional eating (95% CI [3.6495-7.2231]); however, a moderated mediation model revealed that the strength of the indirect effect of restrictive feeding on emotional eating through food preoccupation was significantly different for dieters and non-dieters (index of moderated mediation = 1.79, Boot SE = 0.79; 95% bias-corrected bootstrap CI [-3.5490 to -0.4515]). These findings provide unique insight into the mechanisms linking parental feeding practices with emotional eating in young adulthood. Future studies attempting to clarify the processes through which child feeding practices impact later eating behaviors should consider the role of current dieting.


Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer.
Aberrant promoter hypermethylation is frequently observed in cancer. The potential for this mechanism to contribute to tumor development depends on whether the genes affected are repressed because of their methylation. Many aberrantly methylated genes play important roles in development and are bivalently marked in ES cells, suggesting that their aberrant methylation may reflect developmental processes. We investigated this possibility by analyzing promoter methylation in 19 breast cancer cell lines and 47 primary breast tumors. In cell lines, we defined 120 genes that were significantly repressed in association with methylation (SRAM). These genes allowed the unsupervised segregation of cell lines into epithelial (EPCAM+ve) and mesenchymal (EPCAM-ve) lineages. However, the methylated genes were already repressed in normal cells of the same lineage, and >90% could not be derepressed by treatment with 5-aza-2'-deoxycytidine. The tumor suppressor genes APC and CDH1 were among those methylated in a lineage-specific fashion. As predicted by the epithelial nature of most breast tumors, SRAM genes that were methylated in epithelial cell lines were frequently aberrantly methylated in primary tumors, as were genes specifically repressed in normal epithelial cells. An SRAM gene expression signature also correctly identified the rare claudin-low and metaplastic tumors as having mesenchymal characteristics. Our findings implicate aberrant DNA methylation as a marker of cell lineage rather than tumor progression and suggest that, in most cases, it does not cause the repression with which it is associated.


Glycomic characterization of respiratory tract tissues of ferrets: implications for its use in influenza virus infection studies.
The initial recognition between influenza virus and the host cell is mediated by interactions between the viral surface protein hemagglutinin and sialic acid-terminated glycoconjugates on the host cell surface. The sialic acid residues can be linked to the adjacent monosaccharide by α2-3- or α2-6-type glycosidic bonds. It is this linkage difference that primarily defines the species barrier of the influenza virus infection with α2-3 binding being associated with avian influenza viruses and α2-6 binding being associated with human strains. The ferret has been extensively used as an animal model to study the transmission of influenza. To better understand the validity of this model system, we undertook glycomic characterization of respiratory tissues of ferret, which allows a comparison of potential viral receptors to be made between humans and ferrets. To complement the structural analysis, lectin staining experiments were performed to characterize the regional distributions of glycans along the respiratory tract of ferrets. Finally, the binding between the glycans identified and the hemagglutinins of different strains of influenza viruses was assessed by glycan array experiments. Our data indicated that the respiratory tissues of ferret heterogeneously express both α2-3- and α2-6-linked sialic acids. However, the respiratory tissues of ferret also expressed the Sda epitope (NeuAcα2-3(GalNAcβ1-4)Galβ1-4GlcNAc) and sialylated N,N'-diacetyllactosamine (NeuAcα2-6GalNAcβ1-4GlcNAc), which have not been observed in the human respiratory tract surface epithelium. The presence of the Sda epitope reduces potential binding sites for avian viruses and thus may have implications for the usefulness of the ferret in the study of influenza virus infection.


The pressure difference between eye and brain changes with posture.
The discovery of a posture-dependent effect on the difference between intraocular pressure (IOP) and intracranial pressure (ICP) at the level of lamina cribrosa could have important implications for understanding glaucoma and idiopathic intracranial hypertension and could help explain visual impairments in astronauts exposed to microgravity. The aim of this study was to determine the postural influence on the difference between simultaneously measured ICP and IOP. Eleven healthy adult volunteers (age = 46 ± 10 years) were investigated with simultaneous ICP, assessed through lumbar puncture, and IOP measurements when supine, sitting, and in 9° head-down tilt (HDT). The trans-lamina cribrosa pressure difference (TLCPD) was calculated as the difference between the IOP and ICP. To estimate the pressures at the lamina cribrosa, geometrical distances were estimated from magnetic resonance imaging and used to adjust for hydrostatic effects. The TLCPD (in millimeters of mercury) between IOP and ICP was 12.3 ± 2.2 for supine, 19.8 ± 4.6 for sitting, and 6.6 ± 2.5 for HDT. The expected 24-hour average TLCPD on earth-assuming 8 hours supine and 16 hours upright-was estimated to be 17.3mmHg. By removing the hydrostatic effects on pressure, a corresponding 24-hour average TLCPD in microgravity environment was simulated to be 6.7mmHg. We provide a possible physiological explanation for how microgravity can cause symptoms similar to those seen in patients with elevated ICP. The observed posture dependency of TLCPD also implies that assessment of the difference between IOP and ICP in upright position may offer new understanding of the pathophysiology of idiopathic intracranial hypertension and glaucoma. Ann Neurol 2016;80:269-276.


Coupled mode theory analysis of mode-splitting in coupled cavity system.
We analyze transmission characteristics of two coupled identical cavities, of either standing-wave (SW) or traveling-wave (TW) type, based on temporal coupled mode theory.Mode splitting is observed for both directly (cavity-cavity) and indirectly (cavity-waveguide-cavity) coupled cavity systems. The effects of direct and indirect couplings, if coexisting in one system, can offset each other such that no mode splitting occurs and the original single-cavity resonant frequency is retained. By tuning the configuration of the coupled cavity system, one can obtain different characteristics in transmission spectra, including splitting in transmission, zero transmission, Fano-type transmission, electromagnetically-induced-transparency (EIT)-like transmission, and electromagnetically-induced-absorption (EIA)-like transmission. It is also interesting to notice that a side-coupled SW cavity system performs similarly to an under-coupled TW cavity. The results are useful for the design of cavity-based devices for integration in nanophotonics.


Discordance in variation of the ITS region and the mitochondrial COI gene in the subterranean amphipod Crangonyx islandicus.
The amphipod Crangonyx islandicus is a recently discovered species endemic to Iceland. Populations of C. islandicus are highly structured geographically and genetically. The COI and 16S mitochondrial genes confine six monophyletic groups which have diverged for up to 5 million years within Iceland, and may present two cryptic species. To investigate the potential cryptic species status we analyse here the internal transcribed spacers (ITS1 and ITS2) and compare its variation with the patterns obtained with the mtDNA. The ITS regions present much less divergence among the geographic regions in comparison with the mtDNA, distances based on ITS1 are correlated with the COI distances as well as with geographic distances, but most of the variation is observed within individuals. The variation in the ITS region appears to have been shaped both by homogenization effect of concerted evolution and divergent evolution. A duplication of 269 base pairs is found in the ITS1 of all individuals from the southern populations, its divergence from its paralog appears to predate the split of the different groups within Iceland but some evidence point to rapid diversification after the split. This duplication does not affect the secondary structures found in the 3' and 5' ends of the sequence, suggested to have a role in the excision of the ITS1. Compensatory base changes within the ITS2 sequences which have been suggested to be a species indicator were not detected.


Organic chemistry as a language and the implications of chemical linguistics for structural and retrosynthetic analyses.
Methods of computational linguistics are used to demonstrate that a natural language such as English and organic chemistry have the same structure in terms of the frequency of, respectively, text fragments and molecular fragments. This quantitative correspondence suggests that it is possible to extend the methods of computational corpus linguistics to the analysis of organic molecules. It is shown that within organic molecules bonds that have highest information content are the ones that 1) define repeat/symmetry subunits and 2) in asymmetric molecules, define the loci of potential retrosynthetic disconnections. Linguistics-based analysis appears well-suited to the analysis of complex structural and reactivity patterns within organic molecules.


Preterm birth is associated with epigenetic programming of transgenerational hypertension in mice.
Renal and cardiovascular complications of prematurity are well established, notably the development of hypertension in adulthood. However, the underlying molecular mechanisms remain poorly understood. Our objective was to investigate the impact of prematurity on the ontogenesis of renal corticosteroid pathways, to evaluate its implication in perinatal renal complications and in the emergence of hypertension in adulthood. Swiss CD1 pregnant mice were injected with lipopolysaccharides at 18 days of gestation (E18) to induce prematurity at E18.5. Pups were sacrificed at birth, 7 days and 6 months of life. Second (F2) and third (F3) generations, established by mating prematurely born adult females with wild-type males, were also analyzed. Former preterm males developed hypertension at M6 (P < 0.0001). We found robust activation of renal corticosteroid target gene transcription at birth in preterm mice (αENaC (+45%), Gilz (+85%)), independent of any change in mineralocorticoid or glucocorticoid receptor expression. The offspring of the preterm group displayed increased blood pressure in F2 and F3, associated with increased renal Gilz mRNA expression, despite similar MR or GR expression and plasma corticosteroid levels measured by LC-MS/MS. Gilz promoter methylation measured by methylated DNA immunoprecipitation-qPCR was reduced with a negative correlation between methylation and expression (P = 0.0106). Our study demonstrates prematurity-related alterations in renal corticosteroid signaling pathways, with transgenerational inheritance of blood pressure dysregulation and epigenetic Gilz regulation up to the third generation. This study provides a better understanding of the molecular mechanisms involved in essential hypertension, which could partly be due to perinatal epigenetic programming from previous generations.