Normal metallic point contacts.
The measured voltage derivative of the nonlinear resistance of tiny point contacts can be separated into a phonon-emission effect (alpha(2)F) and an analytic functional form (background effect). The alpha(2)F's show structure coincident with bulk phonon densities of states. Values of the integral of 2 alpha(2)F/omega are closely related to literature values. The background effect is related to the impurity concentration of the materials.


Expression of leukocyte adhesion-related glycosyltransferase genes in acute coronary syndrome patients.
Acute coronary syndrome (ACS) is caused by destabilization and rupture of atherosclerotic plaque in the coronary artery via mechanisms affecting leukocyte signaling, rolling, adhesion, extravasation and inflammation-promoting factors. The majority of cellular communication takes place on the membrane surface that is covered with glycoproteins and glycolipids synthesized by glycosyltransferases. The aim of this study was to determine the mRNA expression of leukocyte adhesion-related glycosyltransferases in patients during the onset and the chronic phase of ACS and to compare the expression with matching subjects without coronary disease. The study included 26 ACS patients and 26 ACS-free matched-pair controls. Blood samples were collected at the time of hospital admittance and 8 days later. Expression analysis of six fucosyltransferases and six sialyltransferases was performed by a real-time polymerase chain reaction. At the time of admittance ACS subjects had lower expression levels of FUT4, ST6GalNac4, ST6Gal1 and GM3 synthase (p < 0.05) than the control subjects, and moreover, after 8 days down-regulation of FUT7 and ST6GalNac3 was also observed (p < 0.05). When compared to the initial gene expression, after treatment and stabilization of ACS subjects, FUT7, ST6GalNac2 and ST6GalNac3 were down-regulated, whereas ST6GalNac1 was up-regulated. Expression levels of FUT7, ST6GalNac1, ST6GalNac2 and ST6GalNac3 were predicted by several drugs and medical history. Expression of glycosyltransferase genes differs in ACS and control subjects. During the course of the ACS study we established further changes in gene expression levels. Medical history was predictive of gene expression levels while drugs were shown to modulate expression levels.


Exercise and exposure to heat following bovine colostrum supplementation: a review of gastrointestinal and immune function.
Colostrum is the first milk produced by mammalian mothers and is essential for the health and survival of the newborn. Bovine colostrum (BC) has greater concentrations of the bioactive components (i.e. immune and growth factors) than those found in human colostrum. As a result, BC supplementation has been recently adopted by many sport competitors as a means of enhancing immune function as well as improving performance. Improvements in physical performance associated with BC supplementation may stem from the ability of BC to maintain gastrointestinal (GI) integrity by decreasing GI permeability. During exercise in the heat, blood flow to the GI tract is reduced that leads to endotoxin leakage into circulation. Endotoxins, such as lipopolysaccharide, can trigger an inflammatory cascade leading to physiological strain that, in turn, increases heat storage and decreases time to exhaustion. GI permeability is lessened during passive heat stress following BC supplementation, but the influence of BC supplementation on GI function during exercise heat stress remains to be determined. The implications of endotoxemia during exercise in the heat is a matter of growing importance and warrants further study given the global increase in ambient temperatures during sport competitions.


Core circadian clock genes Per1 and Per2 regulate the rhythm in photoreceptor outer segment phagocytosis.
Retinal photoreceptors undergo daily renewal of their distal outer segments, a process indispensable for maintaining retinal health. Photoreceptor outer segment (POS) phagocytosis occurs as a daily peak, roughly about 1 hour after light onset. However, the underlying cellular and molecular mechanisms which initiate this process are still unknown. Here we show that, under constant darkness, mice deficient for core circadian clock genes (Per1 and Per2) lack a daily peak in POS phagocytosis. By qPCR analysis, we found that core clock genes were rhythmic over 24 hours in both WT and Per1, Per2 double mutant whole retinas. More precise transcriptomics analysis of laser capture microdissected WT photoreceptors revealed no differentially expressed genes between time points preceding and during the peak of POS phagocytosis. In contrast, we found that microdissected WT retinal pigment epithelium (RPE) had a number of genes that were differentially expressed at the peak phagocytic time point compared to adjacent ones. We also found a number of differentially expressed genes in Per1, Per2 double mutant RPE compared to WT ones at the peak phagocytic time point. Finally, based on STRING analysis, we found a group of interacting genes that potentially drive POS phagocytosis in the RPE. This potential pathway consists of genes such as: Pacsin1, Syp, Camk2b, and Camk2d among others. Our findings indicate that Per1 and Per2 are necessary clock components for driving POS phagocytosis and suggest that this process is transcriptionally driven by the RPE.


Chemically amplified photoresist for high resolution autoradiography in targeted radiotherapy.
Evaluation of the intracellular distribution of radionuclides used for targeted radiotherapy (tRT) is essential for accurate dosimetry. Therefore, a direct and quantitative method for subcellular micro-autoradiography using radiation sensitive polymers (PMMA, UV1116 and AZ40XT) was developed. The electron exposure dose in radio-labelled cells due to Auger and internal conversion (IC) electron emissions of indium (¹¹¹In), a radionuclide currently used for tRT, was calculated using Monte Carlo (MC) simulation. Electron beam lithography using pre-defined exposure doses was used to calibrate the resist response. The topography of the exposed and developed resists was analysed with atomic force microscopy (AFM) and the resulting pattern depth was related to a specific exposure dose. UV1116 exhibited the best contrast as compared to AZ40XT and PMMA, while AZ40XT exhibited the highest sensitivity at low doses (<10 μC/cm²). AFM analysis of the exposure pattern from radio-labelled cells and nuclei in UV1116 revealed a non-uniform distribution of ¹¹¹In-EGF in the cell and nucleus, consistent with less well-resolved data from confocal microscopy and micro-autoradiography.


Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia.
Chronic inflammation contributes to the pathogenesis of gastric tumorigenesis. The aurora kinase A (AURKA) gene is frequently amplified and overexpressed in gastrointestinal cancers. We investigated the roles of AURKA in inflammation and gastric tumorigenesis. We used quantitative real-time reverse transcription polymerase chain reaction, immunofluorescence, immunohistochemistry, luciferase reporter, immunoblot, co-immunoprecipitation, and in vitro kinase assays to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1(-/-) mice, growth of tumor xenografts, and human tissues. We correlated increased expression of AURKA with increased levels of tumor necrosis factor-α and inflammation in the gastric mucosa of Tff1(-/-) mice (r = 0.62; P = .0001). MLN8237, an investigational small-molecule selective inhibitor of AURKA, reduced nuclear staining of nuclear factor-κB (NF-κB) p65 in human gastric cancer samples and mouse epithelial cells, suppressed NF-κB reporter activity, and reduced expression of NF-κB target genes that regulate inflammation and cell survival. Inhibition of AURKA also reduced growth of xenograft tumors from human gastric cancer cells in mice and reversed the development of gastric tumors in Tff1(-/-) mice. AURKA was found to regulate NF-κB activity by binding directly and phosphorylating IκBα in cells. Premalignant and malignant lesions from the gastric mucosa of patients had increased levels of AURKA protein and nuclear NF-κB, compared with healthy gastric tissue. In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be up-regulated during chronic inflammation to promote activation of NF-κB and tumorigenesis. AURKA inhibitors might be developed as therapeutic agents for gastric cancer.


Financial crisis and income-related inequalities in the universal provision of a public service: the case of healthcare in Spain.
The objective of this paper is to analyse whether the recent recession has altered health care utilisation patterns of different income groups in Spain. Based on information concerning individuals 'income and health care use, along with health need indicators and demographic characteristics (provided by the Spanish National Health Surveys from 2006/07 and 2011/12), econometric models are estimated in two parts (mixed logistic regressions and truncated negative binominal regressions) for each of the public health services studied (family doctor appointments, appointments with specialists, hospitalisations, emergencies and prescription drug use). The results show that the principle of universal access to public health provision does not in fact prevent a financial crisis from affecting certain income groups more than others in their utilisation of public health services. Specifically, in relative terms the recession has been more detrimental to low-income groups in the cases of specialist appointments and hospitalisations, whereas it has worked to their advantage in the cases of emergency services and family doctor appointments.


Transforming growth factor (TGF)-beta stimulates hepatic jun-B and fos-B proto-oncogenes and decreases albumin mRNA.
Transforming growth factor-beta (TGF-beta) modulates some components of the acute phase response in hepatic cells. The mechanisms for these actions of TGF-beta are largely unknown. The authors recently found that the decrease in albumin mRNA after TGF-beta 1 treatment required de novo RNA and protein synthesis, suggesting that TGF-beta acts through induction of another gene. The purpose of the current study was to determine whether TGF-beta 1 could regulate the expression of both the jun and fos genes that encode transcriptional regulatory proteins that constitute the AP-1 complex, and to determine whether expression of these genes may be coordinated with the decrease in albumin mRNA. Northern blot hybridization was used to determine levels of specific mRNAs. Transforming growth factor-beta 1 increased the levels of both jun-B and fos-B mRNA by 60 minutes after treatment of mouse hepatoma (BWTG3) cells. When TGF-beta 1 was removed from the media after 4 hours, there was a sustained effect of increased jun-B and decreased albumin mRNA (greater than 48 hours), and the subsequent decrease in jun-B levels coincided with the increase in albumin mRNA. The tumor-promoting phorbol ester (phorbol 12-myristate 13-acetate [PMA]), known to induce jun and fos gene expression, caused increases in jun-B and fos-B that preceded the decrease in albumin mRNA levels at 24 hours. These observations are consistent with our hypothesis that jun-B and fos-B induction may participate in downregulation of albumin synthesis as well as other hepatic responses to TGF-beta.


Long-term consequences of foodborne infections.
Foodborne infections with Campylobacter, E. coli O157:H7, Listeria monocytogenes, Salmonella, Shigella, Toxoplasma gondii, and other pathogens can result in long-term sequelae to numerous organ systems. These include irritable bowel syndrome, inflammatory bowel disease, reactive arthritis, hemolytic uremic syndrome, chronic kidney disease, Guillain-Barré Syndrome, neurological disorders from acquired and congenital listeriosis and toxoplasmosis, and cognitive and developmental deficits due to diarrheal malnutrition or severe acute illness. A full understanding of the long-term sequelae of foodborne infection is important both for individual patient management by clinicians, as well as to inform food safety and public health decision making.


The cannabinoid acids, analogs and endogenous counterparts.
The cannabinoid acids are a structurally heterogeneous group of compounds some of which are endogenous molecules and others that are metabolites of phytocannabinoids. The prototypic endogenous substance is N-arachidonoyl glycine (NAgly) that is closely related in structure to the cannabinoid agonist anandamide. The most studied phytocannabinoid is Δ(9)-THC-11-oic acid, the principal metabolite of Δ(9)-THC. Both types of acids have in common several biological actions such as low affinity for CB1 anti-inflammatory activity and analgesic properties. This suggests that there may be similarities in their mechanism of action, a point that is discussed in this review. Also presented are reports on analogs of the acids that provide opportunities for the development of novel therapeutic agents, such as ajulemic acid.


Responses of the hypothalamic-pituitary-adrenal and renin-angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress.
We studied the responses of plasma CRH, ACTH, cortisol, norepinephrine, epinephrine, and renin activity in 11 patients undergoing parathyroid or thyroid surgery after identical preoperative sedation and during isoflurane (Forane) anesthesia. During surgical exploration, plasma CRH levels [10 +/- 2 (+/- SEM) pg/mL] remained at basal (unstimulated) levels, and plasma ACTH (11.5 +/- 1.4 pg/mL), cortisol (24 +/- 4 micrograms/dL), and epinephrine (35 +/- 10 pg/mL) concentrations remained within their normal morning ranges. The majority of the patients had no evidence of pulsatile ACTH secretion during the operation, but, rather, secreted ACTH and cortisol continuously. There was a small elevation of plasma norepinephrine and PRA which was associated with a small increase in heart rate and decrease in blood pressure. Anesthesia reversal, endotrachial extubation, and the early recovery period were associated with marked mean peak increases in plasma ACTH (173 +/- 45 pg/mL), cortisol (35 +/- 6 micrograms/dL), and epinephrine (220 +/- 56 pg/mL) and the return of plasma norepinephrine and PRA to basal levels. All hormones returned to basal levels by the first post-operative day. The data suggest that with modern anesthetic techniques patients undergoing neck surgery had mildly elevated plasma ACTH, cortisol, and epinephrine levels. Glucocorticoid secretion during the operation was maintained primarily by continuous rather than pulsatile ACTH secretion. The immediate postoperative period was associated with profound elevations of plasma ACTH, cortisol, and epinephrine. The major determinant of ACTH, cortisol, and epinephrine secretion was anesthesia reversal and recovery and not surgical trauma.


Production and characterization of soluble and transmembrane murine CD2. Demonstration that CD48 is a ligand for CD2 and that CD48 adhesion is regulated by CD2.
The baculovirus expression vector was used to produce full length, two amino-terminal Ig-like extracellular domains, and one amino-terminal Ig-like extracellular domain soluble murine CD2 products. The products were monomeric, glycosylated, and of the correct predicted m.w. Sf9 insect cells infected with recombinant baculovirus encoding the full length construct display cell surface CD2 by flow cytometry and rosette with murine cell lines that express the ligand for CD2. Uninfected Sf9, wild-type baculovirus-infected Sf9, and Sf9 expressing truncated products do not display cell surface CD2 nor do these latter Sf9 bind to murine cell lines. Cell binding is inhibited by anti-CD2 mAb. All CD2 products possess ligand binding activity since purified preparations of these block cell adhesion. All CD2 antigenic epitopes are close to the ligand binding site because all mAb tested can inhibit cell adhesion. The ligand for CD2 is shown to be CD48. Only CD48+ cell lines can bind CD2+ Sf9 and this is inhibited by anti-CD48 mAb. Antibodies against the closely related cell surface Ag Ly-6A.2 and Ly-9.2 do not inhibit binding. Purified, soluble CD2 also inhibits the binding of anti-CD48 mAb to the cell surface. Unexpectedly, additional mAb blocking studies show that CD2 on the surface of CD48+ cell lines influences adhesion to CD2+ binding partners. The use of cells expressing CD2 and/or CD48 provides evidence for a cis CD2-CD48 interaction on the cell surface in which CD2 negatively regulates CD48 adhesion properties.


Cre-dependent Cas9-expressing pigs enable efficient in vivo genome editing.
Despite being time-consuming and costly, generating genome-edited pigs holds great promise for agricultural, biomedical, and pharmaceutical applications. To further facilitate genome editing in pigs, we report here establishment of a pig line with Cre-inducible Cas9 expression that allows a variety of ex vivo genome editing in fibroblast cells including single- and multigene modifications, chromosome rearrangements, and efficient in vivo genetic modifications. As a proof of principle, we were able to simultaneously inactivate five tumor suppressor genes (TP53, PTEN, APC, BRCA1, and BRCA2) and activate one oncogene (KRAS), achieved by delivering Cre recombinase and sgRNAs, which caused rapid lung tumor development. The efficient genome editing shown here demonstrates that these pigs can serve as a powerful tool for dissecting in vivo gene functions and biological processes in a temporal manner and for streamlining the production of genome-edited pigs for disease modeling.


White matter fiber tract segmentation in DT-MRI using geometric flows.
In this paper, we present a 3D geometric flow designed to segment the main core of fiber tracts in diffusion tensor magnetic resonance images. The fundamental assumption of our fiber segmentation technique is that adjacent voxels in a tract have similar properties of diffusion. The fiber segmentation is carried out with a front propagation algorithm constructed to fill the whole fiber tract. The front is a 3D surface that evolves with a propagation speed proportional to a measure indicating the similarity of diffusion between the tensors lying on the surface and their neighbors in the direction of propagation. We use a level set implementation to assure a stable and accurate evolution of the surface and to handle changes of topology of the surface during the evolution process. The fiber tract segmentation method does not need a regularized tensor field since the surface is automatically smoothed as it propagates. The smoothing is done by an intrinsic surface force, based on the minimal principal curvature. This segmentation can be used for obtaining quantitative measures of the diffusion in the fiber tracts and it can also be used for white matter registration and for surgical planning.


Extreme aggression in male squid induced by a β-MSP-like pheromone.
Male-male aggression is widespread in the animal kingdom and subserves many functions related to the acquisition or retention of resources such as shelter, food, and mates. These functions have been studied widely in the context of sexual selection, yet the proximate mechanisms that trigger or strengthen aggression are not well known for many taxa. Various external sensory cues (visual, audio, chemical) acting alone or in combination stimulate the complex behavioral interactions of fighting behaviors. Here we report the discovery of a 10 kDa protein, termed Loligo β-microseminoprotein (Loligo β-MSP), that immediately and dramatically changes the behavior of male squid from calm swimming and schooling to extreme fighting, even in the absence of females. Females synthesize Loligo β-MSP in their reproductive exocrine glands and embed the protein in the outer tunic of egg capsules, which are deposited on the open sea floor. Males are attracted to the eggs visually, but upon touching them and contacting Loligo β-MSP, they immediately escalate into intense physical fighting with any nearby males. Loligo β-MSP is a distant member of the chordate β-microseminoprotein family found in mammalian reproductive secretions, suggesting that this gene family may have taxonomically widespread roles in sexual competition.


Attentional bias in eating disorders.
To examine the relationship between eating disorders and attentional biases. The first study comprised 23 female patients with clinical eating disorders, women with high levels of anxiety (n = 19), and three female normal control groups comprising low (n = 31), moderate (n = 21), or high levels of shape concern (n = 23). The second study comprised 82 women with clinical eating disorders and 44 healthy controls. All participants completed measures of eating disorder psychopathology and completed a modified pictorial dot-probe task. In the first study, biases were found for negative eating and neutral weight pictures, and for positive eating pictures in women with eating disorders; these biases were greater than those found in anxious and normal controls. The second study replicated these findings and biases were also found for negative and neutral shape stimuli. It is concluded that future research should establish whether such biases warrant specific therapeutic interventions.


Spatial Control of Biological Ligands on Surfaces Applied to T Cell Activation.
In this chapter, we present techniques, based on molecular-scale nanofabrication and selective self-assembly, for the presentation of biomolecules of interest (ligands, receptors, etc.) on a surface with precise spatial control and arbitrary geometry at the single-molecule level. Metallic nanodot arrays are created on glass coverslips and are then used as anchors for the immobilization of biological ligands via thiol linking chemistry. The nanodot size is controlled by both lithography and metallization. The reagent concentration in self-assembly can be adjusted to ensure single-molecule occupancy for a given dot size. The surrounding glass is backfilled by a protein-repellent layer to prevent nonspecific adsorption. Moreover, bifunctional surfaces are created, whereby a second ligand is presented on the background, which is frequently a requirement for simulating complex cellular functions involving more than one key ligand. This platform serves as a novel and powerful tool for molecular and cellular biology, e.g., to study the fundamental mechanisms of receptor-mediated signaling.


An integrated transcriptome and expressed variant analysis of sepsis survival and death.
Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes. The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies. ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.


Long-term follow-up of older patients with Mobitz type I second degree atrioventricular block.
To examine the long-term survival of older patients with Mobitz I second degree atrioventricular (AV) block. Retrospective cohort study. Propensity score adjustment for requiring a cardiac implantable electronic device (CIED) was performed. Multivariable Cox regression analysis was used. Tertiary care referral centre. We examined 299 older patients (age >45 years) with Mobitz I second degree AV block on ECG at the Minneapolis Veterans Affairs Medical Center from 1992 to 2010. Survival. The average age of patients was 75±9 years; 99% were male; 59% had coronary heart disease; 44% had heart failure. 141 (47%) patients required CIED, of which 17 were implantable cardioverter-defibrillators (ICDs). CIEDs were implanted a median of 110 days after the ECG for symptomatic bradycardia, high-degree AV block or prevention of sudden cardiac death. Patients with CIED had greater cardiac co-morbidity than those without CIED. After a median 3.3 years of follow-up (range 3 days to 19 years), 190 (64%) patients died. Patients with CIED had longer survival than those without CIED (p=0.001). In propensity-adjusted multivariable Cox regression analysis, CIED implantation was associated with a 46% reduction in mortality (HR 0.54, 95% CI 0.35 to 0.82; p=0.004). Excluding 17 patients with ICDs did not alter the results. In this retrospective cohort study of older male patients with Mobitz I AV block on ECG, CIED implantation was associated with longer survival.


A protocol of dual prophylaxis for venous thromboembolism prevention in gynecologic cancer patients.
To evaluate a quality improvement protocol for venous thromboembolism prevention in postoperative gynecologic cancer patients. On January 1, 2006, we initiated a universal protocol of dual prophylaxis with sequential compression devices and three times daily heparin (or daily low molecular weight heparin) until discharge in gynecologic cancer patients having major surgery. Patients with both malignancy and age over 60 years (or history of prior clot) were discharged on 2 weeks of anticoagulant. Before January 2006, all patients were given sequential compression devices starting before the induction of anesthesia, continuing until discharge from the hospital. Records of gynecologic cancer service patients admitted in 2005 and 2006 were reviewed, excluding patients with a history of heparin-induced thrombocytopenia or those admitted on an anticoagulant. Any pulmonary embolism or deep vein thrombosis diagnosed within 6 weeks of surgery was identified. We performed chi2 and Wilcoxon rank sum tests as well as multivariable regression analysis for confounders. Six of the 311 women meeting inclusion criteria in 2006 (1.9%) and 19 of 294 (6.5%) in 2005 had venous thromboembolism (odds ratio 0.33, 95% confidence interval 0.12-0.88, multivariable analysis adjusting for baseline differences between the groups). Heparin was given to 98.1% of patients in the hospital in 2006, and 91.1% of those meeting high-risk criteria were discharged on an anticoagulant. No differences in major bleeding complications were seen between years. A protocol of dual prophylaxis with prolonged prophylaxis in high-risk patients was successfully implemented and was associated with a significant reduction in the rate of venous thromboembolism without increasing bleeding complications. II.


Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status.
Macrophages play a dual role in multiple sclerosis (MS) pathology. They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators. The effector function of macrophages is determined by the way they are activated. Stimulation of monocyte-derived macrophages in vitro with interferon-γ and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages. For this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry. This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively. Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples. Our data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions. M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages. Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status. Our findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status.


Human immunodeficiency virus type 1-infected HL-60 cells are capable of both monocytic and granulocytic differentiation.
We have used the human myelomonocytic cell line HL-60 as a model system to determine whether human immunodeficiency virus type 1 (HIV-1) infection affects differentiation of myeloid progenitor cells. HL-60 cells were infected with three HIV-1 isolates (IIIB, NL4-3 and PM213). HIV-1 antigen expression and cytopathicity in HL-60 cells infected with each of the three isolates was delayed by approximately 15 days as compared to those in the prototypic T cell line, H9. Chronically infected HL-60 cells and clonal lines derived from them were treated with dimethyl formamide (DMF) and induced to differentiate into granulocytes. Approximately the same percentage of these cells as of DMF-treated, uninfected HL-60 cells differentiated. Superoxide production by infected and uninfected DMF-induced cells was similar. Likewise, approximately the same percentage of cells in infected and uninfected cultures became adherent and were positive for non-specific esterase when monocytic differentiation was induced. The data demonstrate that HL-60 cells infected with HIV-1 are capable of morphological and functional granulocytic and monocytic differentiation.


Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.
Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non-small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described. Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses. EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P < .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy-treated patients. EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.


Alzheimer disease versus mixed dementias: an EEG perspective.
To examine differences between patients with AD (n=54) and mixed (vascular Alzheimer) dementia (n=24), and controls (n=66), with respect to clinic, neuropsychology, neuroradiology and quantitative EEG (QEEG). We used CAMDEX, CT and QEEG. Patients with mixed dementia had more subcortical lesions. Increased slow frequency EEG power was observed in mixed dementia compared to AD, whereas the level of high frequency power was nearly normal in mixed dementia, but decreased in pure AD. Topography of slow band power was unaltered in both groups, but was changed for fast bands. The Hachinski score and neuropsychological tests showed small differences between mixed dementia and pure AD. Neuroimaging and QEEG made a greater differential diagnostic contribution than clinical symptoms and neuropsychology. An alteration of slow frequency power with nearly normal high frequency power in mixed dementia may reflect subcortical pathology, whereas cortical pathology in pure AD may relate to decreased fast frequency power. With vascular pathology, less AD pathology is needed for a similar severity of dementia. In dementia of the Alzheimer type a vascular component is often found - especially at an older age. The quantitative EEG can contribute to a better understanding of the interaction of the two components.


Healthcare disparities among anticoagulation therapies for severe COVID-19 patients in the multi-site VIRUS registry.
Here we analyze hospitalized andintensive care unit coronavirus disease 2019 (COVID-19) patient outcomes from the international VIRUS registry (https://clinicaltrials.gov/ct2/show/NCT04323787). We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have a higher mortality-rate (390 of 1012 = 39%) compared to patients administered enoxaparin but not unfractionated heparin (270 of 1939 = 14%), presenting a risk ratio of 2.79 (95% confidence interval [CI]: [2.42, 3.16]; p = 4.45e-52). This difference persists even after balancing on a number of covariates including demographics, comorbidities, admission diagnoses, and method of oxygenation, with an increased mortality rate on discharge from the hospital of 37% (268 of 733) for unfractionated heparin versus 22% (154 of 711) for enoxaparin, presenting a risk ratio of 1.69 (95% CI: [1.42, 2.00]; p = 1.5e-8). In these balanced cohorts, a number of complications occurred at an elevated rate for patients administered unfractionated heparin compared to patients administered enoxaparin, including acute kidney injury, acute cardiac injury, septic shock, and anemia. Furthermore, a higher percentage of Black/African American COVID patients (414 of 1294 [32%]) were noted to receive unfractionated heparin compared to White/Caucasian COVID patients (671 of 2644 [25%]), risk ratio 1.26 (95% CI: [1.14, 1.40]; p = 7.5e-5). After balancing upon available clinical covariates, this difference in anticoagulant use remained statistically significant (311 of 1047 [30%] for Black/African American vs. 263 of 1047 [25%] for White/Caucasian, p = .02, risk ratio 1.18; 95% CI: [1.03, 1.36]). While retrospective studies cannot suggest any causality, these findings motivate the need for follow-up prospective research into the observed racial disparity in anticoagulant use and outcomes for severe COVID-19 patients.


Dietary patterns, physical activity, body mass index, weight-related behaviours and their interrelationship among Romanian university students-trends from 2003 to 2016.
promotion of a healthy diet and involvement in physical activity among young people has an important impact on their actual and future lifestyle, health and well being. this study investigates dietary patterns, physical activity, body mass index (BMI) and weight-related behaviours as well as their interrelationship among Romanian university students. the study used anonymous questionnaires and was performed in Cluj-Napoca, Romania in 2003 (n = 320) and 2016 (n = 320). the factor analyse revealed three main dietary structures which were similar at both waves. The first one describes a varied diet. The second one shows a diet rich in white meat, dietary fibres and varied sources of carbohydrates. The last one refers to a diet containing red meat, fat, potatoes, sugar. The first dietary structure protects against overweight and it correlates positively with daily physical activity, while has a negative correlation with using several methods for losing weight. The second dietary factor is also protective for overweight, but has a positive correlation with using several methods for losing weight. It has a negative association with eating frequently in fast food restaurants and with daily physical activity. The last dietary structure is negatively associated with daily physical activity, while being positively associated with eating frequently in fast-food restaurants and with a higher BMI. the study presents trends in dietary patterns, physical activity, BMI and weight related behaviours among Romanian university students between 2003 and 2016 and highlights the existence of several main dietary structures, which seems stable over time.


Optics of water cloud droplets mixed with black-carbon aerosols.
We use the recently extended superposition T-matrix method to calculate scattering and absorption properties of micrometer-sized water droplets contaminated by black carbon. Our numerically exact results reveal that, depending on the mode of soot-water mixing, the soot specific absorption can vary by a factor exceeding 6.5. The specific absorption is maximized when the soot material is quasi-uniformly distributed throughout the droplet interior in the form of numerous small monomers. The range of mixing scenarios captured by our computations implies a wide range of remote sensing and radiation budget implications of the presence of black carbon in liquid-water clouds. We show that the popular Maxwell-Garnett effective-medium approximation can be used to calculate the optical cross sections, single-scattering albedo, and asymmetry parameter for the quasi-uniform mixing scenario, but is likely to fail in application to other mixing scenarios and in computations of the elements of the scattering matrix.


Expression of an antisense dihydrofolate reductase transcript in transfected mosquito cells: effects on growth and plating efficiency.
Novel approaches to control of vector-borne disease include potential use of transgenic insects, in which molecular mechanisms will be induced to prevent transmission of pathogenic organisms. The infrastructure essential to this technology includes the cloning of essential genes from vector insects, and the development of efficient transformation strategies. In this study, we use a continuous mosquito (Aedes albopictus) cell line and a cloned mosquito dihydrofolate reductase gene to demonstrate a transgenic approach that may be used to select for the presence or absence of particular gene functions in transfected cells. Plasmids containing the dihydrofolate reductase gene in sense and antisense orientation, under the regulation of a temperature-inducible promoter, were expressed in stably transfected mosquito cells. At the normal growth temperature of 28 degrees C, or after mild heat induction at 34 degrees C, expression of the dihydrofolate reductase construct in sense orientation had little effect on cell growth. In contrast, recovery of clones transfected with the antisense construct was reduced, and induction of antisense transcripts at 34 degrees C further compromised cell growth and viability. Clones transfected with the sense construct retained significantly higher copy numbers of foreign DNA than did cells transfected with the antisense construct. These studies provide a basis for use of sense and antisense dihydrofolate reductase constructs to recover transfected mosquito cells with specific desired phenotypes, based on the relative expression of cloned genes of interest.


Infected Dentine Revisited.
Dentine becomes infected as a result of caries lesion formation on root surfaces and when lesions progress following cavitation of enamel lesions. However, this infection is unimportant because the driving force for lesion formation and progression is the overlying biofilm. This explains why root surface caries can be controlled by mechanical plaque control and fluoride, and restorations are not needed to arrest these lesions. Similarly, the infected dentine in cavitated coronal lesions does not have to be removed to arrest the lesion. If the lesion is either accessible or opened for cleaning by the patient or parent, the lesion can be arrested. Sealing of infected dentine within the tooth, either by a Hall crown in the primary dentition or by partial caries removal prior to placing a well-sealed filling, will also arrest the lesion. When restoring deep lesions in symptomless, vital teeth, vigorous excavation of infected dentine is likely to expose the pulp and make root canal treatment necessary. Thus complete excavation'is not needed and should be avoided. CPD/CLINICAL RELEVANCE: Root surface caries can be arrested by cleaning and fluoride application. Restorations are not essential. Vigorous excavation of softened dentine in deep cavities of symptomless, vital teeth is contra-indicated. It is not needed and increases the risk of pulp exposure.


Perceptions about the Federally Mandated Smoke-Free Housing Policy among Residents Living in Public Housing in New York City.
Background: To assess residents' attitudes towards the United States (U.S.) Department of Housing and Urban Development's new smoke-free public housing policy, perceptions about barriers to policy implementation, and suggestions for optimizing implementation. Methods: In 2017, we conducted 10 focus groups among 91 residents (smokers and nonsmokers) living in New York City public housing. Results: Smokers and nonsmokers expressed skepticism about the public housing authority's capacity to enforce the policy due to widespread violations of the current smoke-free policy in common areas and pervasive use of marijuana in buildings. Most believed that resident engagement in the roll-out and providing smoking cessation services was important for compliance. Resident expressed concerns about evictions and worried that other building priorities (i.e., repairs, drug use) would be ignored with the focus now on smoke-free housing. Conclusions: Resident-endorsed strategies to optimize implementation effectiveness include improving the access to cessation services, ongoing resident engagement, education and communication to address misconceptions and concerns about enforcement, and placing smoke-free homes in a larger public housing authority healthy housing agenda.


The racial integration of health facilities.
No published measures of racial integration in health facilities in the United States exist. This article reviews the problems with possible sources of data. It then derives estimates of the degree of integration in nursing homes and hospitals from the 1985 National Nursing Home and National Hospital Discharge surveys. Nursing homes were less racially integrated than hospitals. Health facilities in the South were more integrated than in any other region of the country. There was little difference in the degree of racial segregation of publicly financed patients and those whose care was financed from private sources. Data on nursing homes in Pennsylvania illustrate in more detail some of the consequences of such patterns of segregation. The article discusses some of the reasons for the lack of easy access to such information and makes recommendations for addressing it.


Association of Bone Mineral Density with Lean Mass, Fat Mass, and Physical Activity in Young Overweight and Obese Women.
To examine the associations between bone mineral density (BMD), body composition and habitual physical activity in women who are overweight/obese. We measured whole-body bone, and body composition (lean mass, fat mass, and total fat percent) via dual-energy x-ray absorptiometry (model General Electric Lunar whole-body scanner) in a diverse group of women (N=48, age 26.6+/-4.7 years, 63% Black) living in an urban setting. The relations between BMD with total fat percent [%]), lean mass (kg), fat mass (kg), and physical activity were examined using Pearson correlations and multiple linear regression models, adjusted for race, age, and dietary calcium. BMD was positively correlated with lean mass (r=0.43, p=0.002) and negatively correlated with total fat percentage (r=-0.31, p=0.03). Multiple linear regression models indicated BMD was positively associated with lean mass (β: 0.007, p<0.001), and negatively associated with fat mass (kg) and total fat percentage (β: -0.003, p=0.03; β: -0.004, p=0.03, respectively). When stratified by race, these relations were maintained in white women but only lean mass in Black women. When stratified by age, the positive correlation between BMD and lean mass was significant in younger women (<30y) only. There were no significant relationships between BMD and any physical activity measures. Our results indicate that in young women who are overweight/obese BMD is significantly associated with body composition, both lean mass and total fat percentage, but not habitual physical activity. An emphasis on lean mass accrual may be valuable for young women, particularly Black women, to improve bone health.


Global Approaches to the Role of miRNAs in Drug-Induced Changes in Gene Expression.
Neurons modulate gene expression with subcellular precision through excitation-coupled local protein synthesis, a process that is regulated in part through the involvement of microRNAs (miRNAs), a class of small non-coding RNAs. The biosynthesis of miRNAs is reviewed, with special emphasis on miRNA families, the subcellular localization of specific miRNAs in neurons, and their potential roles in the response to drugs of abuse. For over a decade, DNA microarrays have dominated genome-wide gene expression studies, revealing widespread effects of drug exposure on neuronal gene expression. We review a number of recent studies that explore the emerging role of miRNAs in the biochemical and behavioral responses to cocaine. The more powerful next-generation sequencing technology offers certain advantages and is supplanting microarrays for the analysis of complex transcriptomes. Next-generation sequencing is unparalleled in its ability to identify and quantify low-abundance transcripts without prior sequence knowledge, facilitating the accurate detection and quantification of miRNAs expressed in total tissue and miRNAs localized to postsynaptic densities (PSDs). We previously identified cocaine-responsive miRNAs, synaptically enriched and depleted miRNA families, and confirmed cocaine-induced changes in protein expression for several bioinformatically predicted target genes. The miR-8 family was found to be highly enriched and cocaine-regulated at the PSD, where its members may modulate expression of cell adhesion molecules. An integrative approach that combines mRNA, miRNA, and protein expression profiling in combination with focused single gene studies and innovative behavioral paradigms should facilitate the development of more effective therapeutic approaches to treat addiction.


A review of esomeprazole in the treatment of gastroesophageal reflux disease (GERD).
Proton-pump inhibitors (PPIs) are the drugs of choice for the treatment of gastroesophageal reflux disease (GERD). Esomeprazole is the latest PPI and was developed as the S-isomer of omeprazole as an attempt to improve its pharmacokinetic properties. Esomeprazole has been reported to have a somewhat higher potency in acid inhibition than other PPIs. Despite some controversy, data from clinical trials and meta-analyses indicate that esomeprazole 40 mg od for up to 8 weeks provided higher rates of healing of erosive GERD and a greater proportion of patients with sustained resolution of heartburn, than omeprazole 20 mg, lansoprazole 30 mg, or pantoprazole 40 mg od. Esomeprazole 20 mg od has also been shown to be more effective in maintaining healing of erosive GERD compared with lansoprazole 15 mg od or pantoprazole 20 mg od. However, it is not clear whether these statistically significant differences are of major clinical importance. Esomeprazole 20 mg od is superior to placebo for treatment of non-erosive reflux disease (NERD) but clinical trials have not shown any significant differences in efficacy between esomeprazole 20 mg and omeprazole 20 mg or pantoprazole 20 mg od. Lastly, although esomeprazole treatment in GERD has been reported to result in improvement of health-related quality of life (QoL) indices, no clinical trials have evaluated the possible differential effects of different PPIs on QoL in GERD.


An epidemiological profile of in-patient workload in dermatology.
Trends in admission rates, patterns of readmission, lengths of stay and clinical caseload for in-patient dermatology from 1976 to 1985 are described using data from the Oxford record-linkage study. Age-specific admission rates were considerably higher in people aged 50 years and over than in younger people. Admission rates declined over time in most age-sex groups below the age of 70 years, but increased over time for the over 70s. In dermatology, unlike most other specialties, the length of patients' stay did not decrease substantially over the 10 years. In-patient workload consisted predominantly of leg ulcers, psoriasis, and eczema. This did not change appreciably over time. New out-patients at dermatology clinics rose by 41% from 1976 to 1985, and all out-patient visits rose by 20% during the 10-year period. Because the profile of in-patient workload changed relatively little over time, we speculate that the impact of innovations in dermatological practice has been much greater in the ambulatory setting than in the management of those patients requiring prolonged in-patient care. Future routine measures of workload in dermatology should include demographic and clinical data on out-patients.


The transformation behaviour of "alucones", deposited by molecular layer deposition, in nanoporous Al2O3 layers.
Nanoporous alumina films can be synthesized from hybrid organic-inorganic "alucone" films deposited by molecular layer deposition (MLD) by wet etching in deionized water or calcination in air at 500 °C. This transformation process was systematically investigated for two alucone chemistries based on ethylene glycol (EG) and glycerol (GL). Ellipsometric porosimetry (EP) was used for the characterization of the porous alumina structures that are formed as a result of the treatments. Etching in deionized water transforms both EG- and GL-alucones into porous alumina with a porosity of about 40%, albeit with a different pore structure: cylindrical pores for EG-alucones and ink-bottle structures for GL-alucones. Calcination in air up to 500 °C only successfully transformed EG-alucones into porous alumina if the chosen heating and cooling rate was lower than 200 °C h-1. Below this ramp rate, a relationship between the resulting porosity and the ramp rate was found. At the lowest investigated ramp rate of 20 °C h-1, the highest porosity of 36% was achieved. For this treatment type, the pore shape was of the ink-bottle type for all investigated ramp rates with narrow 1 nm-sized pores. Infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy revealed that the final chemistry of the porous structures was slightly different for both treatments due to trace amounts of carbon left behind by water etching. This suggests that the internal surface of the porous structure has a different termination depending on the chosen treatment. The precise thickness control and conformal nature inherent to MLD combined with the wet and heat treatments enables the coating of complex 3D structures with a porous alumina film with a well-defined thickness and pore structure.


The etiology and management of cystic adventitial disease.
Cystic adventitial disease (CAD) is a rare condition that affects arteries and veins. The etiology remains controversial and several treatment methods have been described. By understanding the pathogenesis of CAD, we can improve the surgical treatment, reduce recurrence rates, and improve patient outcomes. The objective of this study was to perform a systematic review of the world's literature. We searched across multiple scientific databases and cross-referenced each article to collect the world's literature on CAD. Studies included were those that reported a case or case series of CAD. Each article was analyzed for site of CAD, patient demographic data, type of imaging, surgical management, presence of a joint connection on imaging or at surgery, and recurrences. A regression analysis was used to identify risk factors for cyst recurrence. We identified 503 reports (724 patients), which were included in our analysis. The most common vessel affected was the popliteal artery with 587 cysts. The mean age was 46 (range, 5-80) years with a male-to-female ratio of approximately 4:1. Magnetic resonance imaging (MRI) or angiography was performed for 182 cysts and conventional angiography was the most advanced imaging modality used in 355 patients who did not receive a MRI or computed tomography scan as part of their assessment. Multiple types of surgical interventions were reported with the most common being cyst resection and saphenous vein graft reconstruction (204 cases). There were 122 joint connections (17%) identified. Sixty-five patients (9%) developed at least one cyst recurrence or persistence. Percutaneous surgery (aspiration or angioplasty) was found to be a risk factor for cyst recurrence (odds ratio, 13.7; 95% confidence interval, 6.5-29.0; P < .0001). Because of the rarity of this condition, publications were limited to level IV evidence consisting of case series and case reports. Several reports had short or no follow-up and few patients had postoperative MRI. These limitations likely underestimate the true rate of cyst recurrence or persistence. This article provides a comprehensive review of the world's literature on CAD, which can serve as a baseline for future studies. When analyzed in the context of the literature, this systematic review supplies further evidence that CAD adheres to the articular (synovial) theory. We believe that knowledge of these joint connections can simplify treatment, reduce recurrence rates, and improve patient outcomes.


Dinuclear magnesium, zinc and aluminum complexes supported by bis(iminopyrrolide) ligands: synthesis, structures, and catalysis toward the ring-opening polymerization of ε-caprolactone and rac-lactide.
Synthesis and characterization of novel dinuclear magnesium, zinc and aluminum complexes supported by bis(iminopyrrolide) ligands and their catalysis toward the ring-opening polymerization (ROP) of ε-caprolactone (ε-CL) and rac-lactide (rac-LA) were carried out. The ligand precursors [(5-Bu(t)-2-C4H2NH)CH=N(CH2)2]2NH (H2L(Bu), 1) and [(2-C4H3NH)CH=N(CH2)2]2NH (H2L(H), 2) were prepared by condensation of diethylene triamine with 5-tert-butyl-1H-pyrrole-2-carbaldehyde and 1H-pyrrole-2-carbaldehyde, respectively. Treatment of 1 with 2 equiv. of Bu(n)MgOBn in toluene at 70 °C produced dinuclear magnesium complex [(μ-OBn)2Mg2L(Bu)] (3). Similar treatment of 1 with EtZnOBn generated [(μ-OBn)2Zn2L(Bu)] (4). Reaction of 2 with 2 equiv. of Me2AlOBn in toluene at 70 °C afforded aluminum complex [Me2Al(μ-OBn)2AlL(H)] (5). Complexes 3-5 were characterized by (1)H and (13)C NMR spectroscopy, elemental analyses, and single crystal X-ray diffraction techniques. Each of complexes 3-5 is active for the ROP of ε-CL and rac-LA. Kinetic studies of the polymerization reactions were performed.


The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients.
To evaluate the efficacy and safety of high-dose therapy with the human immunodeficiency virus (HIV) protease inhibitor saquinavir and to establish the duration of the effect of this therapy. Open-label study. Clinical research referral center. 40 adults with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ T-cell counts of 200 to 500 cells/mm3. Monotherapy with 3600 mg or 7200 mg of saquinavir per day, in six divided doses, for 24 weeks. Patients were monitored for adverse events and were evaluated monthly for CD4+ T-cell count, HIV-1 viral load (as measured by reverse transcriptase polymerase chain reaction [PCR] for plasma HIV RNA levels), immune-complex-disassociated p24 antigen levels, peripheral blood mononuclear cell viral DNA levels (as measured by PCR), and resistance mutations to saquinavir. Quantitative peripheral blood mononuclear cell cultures were also done every 2 months. The low-dose saquinavir regimen (3600 mg/d) resulted in a maximal mean decrease in plasma HIV RNA levels of 1.06 log RNA copies/mL of plasma and a mean maximal increase in CD4 counts of 72 cells/mm3. At week 24, the plasma HIV RNA level remained 0.48 log RNA copies/mL of plasma lower than baseline (P < 0.001) and the CD4 count remained 31 cells/mm3 higher than baseline (P = 0.165). The high-dose saquinavir regimen (7200 mg/d) produced a mean maximal decrease in the plasma HIV RNA level of 1.34 log RNA copies/mL of plasma and a mean maximal increase in CD4 count of 121 cells/mm3. At week 24, the plasma HIV RNA level remained 0.85 log RNA copies/mL of plasma lower than baseline (P < 0.001) and the CD4 count remained 82 cells/mm3 higher than baseline (P = 0.002). The high-dose regimen produced a greater reduction in plasma HIV RNA level (P = 0.08), a greater reduction in peripheral blood mononuclear cell cultures (P = 0.008), and a greater increase in CD4 count (P = 0.002) than did the low-dose regimen. Higher plasma drug concentrations in individual patients correlated with greater reductions in plasma HIV RNA levels over the two doses. Nine patients receiving the low-dose regimen and four patients receiving the high-dose regimen developed key saquinavir resistance mutations. Adverse reactions, most commonly gastrointestinal problems and elevated serum aminotransferase levels, were more common in patients receiving the high-dose regimen, but most adverse events were mild and all were reversible. Saquinavir is a potent antiviral agent that has a favorable toxicity profile at high doses. Higher doses produce a greater and more durable suppression of viral load and elevation in CD4+ T-cell counts and may delay the development of resistance mutations. Therapy with high-dose saquinavir alone or in combination with other antiretroviral agents should be investigated further.


Effects of continuous erythropoietin receptor activator in sepsis-induced acute kidney injury and multi-organ dysfunction.
Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-κB)--and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1β, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.


Transforming Data into Knowledge: How to Improve the Efficiency of Clinical Care?
Objectives: To provide an introduction to the 2017 IMIA Yearbook of Medical Informatics by the editors. Methods: We present a brief overview of the 2017 special topic "Learning from experience: Secondary use of patient data". We review our choice of special topic section editors, present the new section "Health Information Management", and discuss transitions in the editorial team. Results: In this edition of the Yearbook, we focused on one of the most important issues for the medical informatics community: The secondary use of clinical data. With the ubiquitous adoption of electronic health records (EHRs) and the increasing availability of genomic and environmental data, as well as the accessibility of unstructured data in social media, issues related to data integration, storage, and management, as well as the need for novel analytic approaches are clear challenges. The paradigm of Learning Health Systems (LHSs) is presented in the keynote paper and survey papers review the significant developments in allied fields such as clinical research, clinical systems, translational informatics, and public health over the past two years. IMIA Working Groups also contributed to this topic. Conclusion: The 2017 issue of the IMIA yearbook focuses on the secondary use of patient data and presents the difficulties that still need to be solved before witnessing the actual development of LHSs.


Inability to process and store proinsulin in transdifferentiated pancreatic acinar cells lacking the regulated secretory pathway.
Generation of new beta-cells from the adult pancreas or the embryonic stem cells is being pursued by research groups worldwide. Success will be dependent on confirmation of true beta-cell phenotype evidenced by capacity to process and store proinsulin. The aim of these studies was to robustly determine endocrine characteristics of the AR42J rat pancreatic acinar cell line before and after in vitro transdifferentiation. beta-cell phenotypic marker expression was characterised by RT-PCR, immunostaining, western blotting, ELISA and in human preproinsulin transgene over-expression studies in wild-type AR42J cells and after culture on Matrigel basement membrane matrix with and without growth/differentiation factor supplementation. Pancreatic duodenal homeobox 1 (PDX1), forkhead box transcription factor a2 (Foxa2), glucokinase, pancreatic polypeptide and low-level insulin gene transcription in wild-type AR42J cells were confirmed by RT-PCR. Culture on Matrigel-coated plates and supplementation of medium with glucagon-like peptide 1 induced expression of the beta-cell Glut 2 with maintained expression of insulin and PDX1. Increased biosynthesis and secretion of proinsulin were confirmed by immunocytochemical staining and sensitive ELISA. Absence of the regulated secretory pathway was demonstrated by undetectable prohormone convertase expression. In addition, inability to process and store endogenous proinsulin or human proinsulin translated from a constitutively over-expressed preproinsulin transgene was confirmed. The importance of robust phenotypic characterisation at the protein level in attempted beta-cell transdifferentiation studies has been confirmed. Rodent and human sensitive/specific differential proinsulin/insulin ELISA in combination with human preproinsulin over-expression enables detailed elucidatation of core endocrine functions of proinsulin processing and storage in putative new beta-cells.


Gut Microbiome and the Development of Food Allergy and Allergic Disease.
The impact of gut microbiome on human development, nutritional needs, and disease has become evident with advances in the ability to study these complex communities of microorganisms, and there is growing appreciation for the role of the microbiome in immune regulation. Several studies have examined associations between changes in the commensal microbiota and the development of asthma, allergic rhinitis, and asthma, but far less have evaluated the impact of the microbiome on the development of food allergy. This article reviews the human gastrointestinal microbiome, focusing on the theory and evidence for its role in the development of IgE-mediated food allergy and other allergic diseases.


Children with asthma and their caregivers help improve written asthma action plans: A pilot mixed-method study.
The objectives of this study were to (a) qualitatively examine caregiver and child feedback about a gold standard written asthma action plan (WAAP), and (b) determine whether having an asthma action plan was associated with child and caregiver self-efficacy in managing an exacerbation. This was a cross-sectional analysis of structured interviews with 22 children with persistent asthma that collected feedback about the WAAP as well as self-efficacy. An analysis of interviews used the constant comparative method to identify themes of child and caregiver statements. Caregivers completed a questionnaire that measured asthma management self-efficacy, barriers to managing asthma, and belief in the treatment efficacy using validated scales. Approximately 36% of the caregivers reported having a WAAP for their child from their child's pediatrician. Most caregivers stated that having pictures would improve the WAAP, while most children stated that the layout needed to be improved by adding more space between the sections. Caregivers who reported knowing what the asthma action plan was had greater self-efficacy than caregivers who did not (z = -1.99, p = 0.047). Re-designing the current WAAP layout and including pictures of inhalers may promote patient understanding. Future research needs to examine if a re-designed WAAP improves asthma management of children with asthma and their caregivers.


Addressing passive smoking in children.
A significant number of parents are unaware or unconvinced of the health consequences of passive smoking (PS) in children. Physicians could increase parental awareness by giving personal advice. To evaluate the current practices of three Dutch health professions (paediatricians, youth health care physicians, and family physicians) regarding parental counselling for passive smoking (PS) in children. All physicians (n = 720) representing the three health professions in Limburg, The Netherlands, received an invitation to complete a self-administered electronic questionnaire including questions on their: sex, work experience, personal smoking habits, counselling practices and education regarding PS in children. The response rate was 34%. One tenth (11%) of the responding physicians always addressed PS in children, 32% often, 54% occasionally and 4% reported to never attend to it. The three health professions appeared comparable regarding their frequency of parental counselling for PS in children. Addressing PS was more likely when children had respiratory problems. Lack of time was the most frequently mentioned barrier, being very and somewhat applicable for respectively 14% and 43% of the physicians. One fourth of the responders had received postgraduate education about PS. Additionally, 49% of the responders who did not have any education about PS were interested in receiving it. Physicians working in the paediatric field in Limburg, The Netherlands, could more frequently address PS in children with parents. Lack of time appeared to be the most mentioned barrier and physicians were more likely to counsel parents for PS in children with respiratory complaints/diseases. Finally, a need for more education on parental counselling for PS was expressed.


Differential polarization imaging. III. Theory confirmation. Patterns of polymerization of hemoglobin S in red blood sickle cells.
In this paper we test the predictions of the differential polarization imaging theory developed in the previous two papers. A characterization of the patterns of polymerization of hemoglobin in red blood cells from patients with sickle cell anemia is presented. This system was chosen because it is relatively easy to handle and because previous studies have been done on it. A differential polarization microscope designed and built in our laboratory was used to carry out this study. This microscope uses an image dissector camera, a photoelastic modulator, and a phase-lock amplifier. This design represents a substantial modification with respect to the instrumentation used in the previous results communicated on this system. Therefore, the results presented here also permit us to confirm the validity of our conclusions. On the basis of the differential polarization images obtained, models of the patterns of polymerization of the hemoglobin S inside the sickle cells are proposed and their M12 and regular images are calculated by the theory. Good agreement between those models and the experimental systems is found, as well as with the results previously reported.


The magnitude of and health system responses to the mental health treatment gap in adults in India and China.
This Series paper describes the first systematic effort to review the unmet mental health needs of adults in China and India. The evidence shows that contact coverage for the most common mental and substance use disorders is very low. Effective coverage is even lower, even for severe disorders such as psychotic disorders and epilepsy. There are vast variations across the regions of both countries, with the highest treatment gaps in rural regions because of inequities in the distribution of mental health resources, and variable implementation of mental health policies across states and provinces. Human and financial resources for mental health are grossly inadequate with less than 1% of the national health-care budget allocated to mental health in either country. Although China and India have both shown renewed commitment through national programmes for community-oriented mental health care, progress in achieving coverage is far more substantial in China. Improvement of coverage will need to address both supply-side barriers and demand-side barriers related to stigma and varying explanatory models of mental disorders. Sharing tasks with community-based workers in a collaborative stepped-care framework is an approach that is ripe to be scaled up, in particular through integration within national priority health programmes. India and China need to invest in increasing demand for services through active engagement with the community, to strengthen service user leadership and ensure that the content and delivery of mental health programmes are culturally and contextually appropriate.


Antigen-reactive T cell clones. I. Transcomplementing hybrid I-A-region gene products function effectively in antigen presentation.
Studies in our laboratory and elsewhere have shown that it is possible to propagate antigen-specific murine T cells in vitro with resultant specific stepwise enrichment of antigen-induced proliferative cells. The proliferative responses of these T cells are antigen specific and dependent upon the presence of antigen-presenting cells (spleen cells) that share the I-A subregion with the proliferating T cell. Using techniques of soft-agar cloning, it has been further possible to isolate clones of antigen-reactive T lymphocytes from such long-term cultures. Data suggesting that these were clones of antigen-reactive T cells were obtained by studying the recognition of antigen in association with antigen-presenting cells with a panel of such clones of antigen-reactive T cells. Proof of clonality was obtained by subcloning. Clones derived from F1-immune mice can be divided into three separate categories: one clone recognizes antigen in association with antigen-presenting determinants of parent A and the F1; the second type recognizes antigen in association with antigen-presenting determinants of parent B and the F1; and the third type recognizes antigen only in association with antigen-presenting determinants of the F1 mouse. Genetic studies on the major histocompatibility complex requirements for antigen presentation to such F1-reactive T cell clones suggests that the hybrid antigen-presenting determinant in this system results from transcomplementation of products of the I-A region of haplotypes a and b. These studies support the concept developed in our laboratory that there exist unique F1 hybrid determinants on (A/J X C57BL/6) F1 cells and suggest that these determinants can be utilized physiologically by hybrid mice in immunocompetent cellular interactions.


Prenatal exposure to the 1944-45 Dutch 'hunger winter' and addiction later in life.
Prenatal exposure to severe famine has been associated with an increased risk of schizophrenia and affective disorders. We studied the relationship between prenatal exposure to famine during the Dutch hunger winter of 1944-45 and addiction later in life. A case-control study. The Rotterdam city area during the Dutch hunger winter lasting from mid-October 1944 to mid-May 1945. From February 1945 to mid-May 1945 the hunger winter was characterized by a famine peak. Patients are native Dutch addicted patients from the Rotterdam Addiction Treatment Program and controls are native Dutch inhabitants of Rotterdam, born between 1944 and 1947. Exposure to the whole hunger winter (< 1400 kcal/day) and the peak of the hunger winter (< 1000 kcal/day) was determined for each trimester of gestation. For each trimester the exposed/unexposed ratios were compared between patients and controls and quantified as odds ratios (OR). The odds of first-trimester gestational exposure to famine during the total hunger winter was significantly higher among patients receiving treatment for an addictive disorder [OR = 1.34, 95% confidence interval (CI) 1.10-1.64]. Stratification by sex shows that the odds of exposure during the first trimester was significantly higher only among men (OR = 1.34, 95% CI 1.05-1.72), but not among women (OR = 1.26, 95% CI 0.88-1.81). The odds of exposure to the peak of the hunger winter during the first trimester of gestation were also significantly higher among addiction treatment patients (OR = 1.61, 95% CI 1.22-2.12). We did not find any significant differences for the second and third trimesters of gestation. First-trimester prenatal exposure to famine appears to be associated with addiction later in life. The study confirms the adverse influence of severe malnutrition on brain development and maturation, confirms the influence of perinatal insults on mental health in later life and gives rise to great concern about the possible future consequences for the hunger regions in our world.


Head injury mechanisms in FIS World Cup alpine and freestyle skiers and snowboarders.
Head injuries represent a concern in skiing and snowboarding, with traumatic brain injuries being the most common cause of death. To describe the mechanisms of head and face injuries among World Cup alpine and freestyle skiers and snowboarders. We performed a qualitative analysis of videos obtained of head and face injuries reported through the International Ski Federation Injury Surveillance System during 10 World Cup seasons (2006-2016). We analysed 57 head impact injury videos (alpine n=29, snowboard n=13, freestyle n=15), first independently and subsequently in a consensus meeting. During the crash sequence, most athletes (84%) impacted the snow with the skis or board first, followed by the upper or lower extremities, buttocks/pelvis, back and, finally, the head. Alpine skiers had sideways (45%) and backwards pitching falls (35%), with impacts to the rear (38%) and side (35%) of the helmet. Freestyle skiers and snowboarders had backwards pitching falls (snowboard 77%, freestyle 53%), mainly with impacts to the rear of the helmet (snowboard 69%, freestyle 40%). There were three helmet ejections among alpine skiers (10% of cases), and 41% of alpine skiing injuries occurred due to inappropriate gate contact prior to falling. Athletes had one (47%) or two (28%) head impacts, and the first impact was the most severe (71%). Head impacts were mainly on snow (83%) on a downward slope (63%). This study has identified several characteristics of the mechanisms of head injuries, which may be addressed to reduce risk.


Construction of iron oxide nanoparticle-based hybrid platforms for tumor imaging and therapy.
The aim of this original review is to highlight and analyze the most recent progress and challenges in the synthesis and surface modifications of superparamagnetic iron oxide (Fe3O4) nanoparticles (NPs) for multimodal imaging and therapy applications, which represent important fields in medicine in general and cancer in particular. Thus, the oncology domain is rapidly moving to a more personalized medicine including precision imaging and theranostic approaches. Novel biocompatible Fe3O4 nanoparticulate systems have been designed for enhanced and targeted cellular uptake by surface layer coating modifications, to have improved r2 relaxivity for sensitive magnetic resonance (MR) imaging applications, to have the ability to be used for dual mode imaging, and to be used for imaging-guided cancer therapy. In this review, we analyzed in depth the new strategies for generating biocompatible multifunctional Fe3O4 nanoplatforms for both the diagnosis and therapy of cancer.


Nuclear receptor and transcriptional complex cycles.
Transcriptional regulation by ligand-activated nuclear receptors, also known as steroid receptors, is a highly dynamic process. Nuclear receptors are intracellular proteins that reside in either the cytoplasm or nucleus in the inactive state. The interaction of this family of receptors with the promoters of target genes and with various proteins involved in stimulating gene expression is governed by binding to lipid soluble ligands. The animation, based on experiments following the dynamic interactions of the glucocorticoid receptor or the estrogen receptor with DNA, shows nuclear estrogen receptor and its interaction with a short two-nucleosome fragment of chromatin in the absence and presence of estrogen. The events that occur on the DNA are represented by the ordered recruitment of protein components to a larger macromolecular complex. The associated table describes the proteins and multimolecular complexes that participate in the nuclear receptor-chromatin cycles.


The Bipolar Illness Onset study: research protocol for the BIO cohort study.
Bipolar disorder is an often disabling mental illness with a lifetime prevalence of 1%-2%, a high risk of recurrence of manic and depressive episodes, a lifelong elevated risk of suicide and a substantial heritability. The course of illness is frequently characterised by progressive shortening of interepisode intervals with each recurrence and increasing cognitive dysfunction in a subset of individuals with this condition. Clinically, diagnostic boundaries between bipolar disorder and other psychiatric disorders such as unipolar depression are unclear although pharmacological and psychological treatment strategies differ substantially. Patients with bipolar disorder are often misdiagnosed and the mean delay between onset and diagnosis is 5-10 years. Although the risk of relapse of depression and mania is high it is for most patients impossible to predict and consequently prevent upcoming episodes in an individual tailored way. The identification of objective biomarkers can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Accurate diagnosis of bipolar disorder in its early stages could help prevent the long-term detrimental effects of the illness.The present Bipolar Illness Onset study aims to identify (1) a composite blood-based biomarker, (2) a composite electronic smartphone-based biomarker and (3) a neurocognitive and neuroimaging-based signature for bipolar disorder. The study will include 300 patients with newly diagnosed/first-episode bipolar disorder, 200 of their healthy siblings or offspring and 100 healthy individuals without a family history of affective disorder. All participants will be followed longitudinally with repeated blood samples and other biological tissues, self-monitored and automatically generated smartphone data, neuropsychological tests and a subset of the cohort with neuroimaging during a 5 to 10-year study period. The study has been approved by the Local Ethical Committee (H-7-2014-007) and the data agency, Capital Region of Copenhagen (RHP-2015-023), and the findings will be widely disseminated at international conferences and meetings including conferences for the International Society for Bipolar Disorders and the World Federation of Societies for Biological Psychiatry and in scientific peer-reviewed papers. NCT02888262.


Chemically driven surface effects in polar intermetallic topological insulators A3Bi.
Surface electronic spectra, surface and bulk properties as well as the underlying chemical bonding characteristics in topological insulators with complex bonding patterns are considered for the example of cubic, polar intermetallics KNa2Bi, K3Bi and Rb3Bi (with the general formula A3Bi, A - alkali metal). Chemical bonding in A3Bi has a delocalized, polar character as elucidated by the Bader charge analysis in bulk and at the surface, by real-space bonding indicators and by the maximally localized-Wannier-function technique. We underpin emergent surface features in the electronic spectra that are driven by chemical bonding. The organization of these trivial and topological surface states is juxtaposed with the trends in the Bader charges at the surface and surface contributions to the on-site matrix elements of the ab initio Hamiltonian in the localized basis. The surface states are essentially affected by a large positive or negative on-site contribution induced near the vacuum boundary, where the sign of the contribution depends on the surface termination. Based on our findings, the experimentally observed surface features in the related Na3Bi compound can be correctly interpreted. The listed aspects distinguish the title compounds from the HgX (X - chalcogen) series with the same fingerprint bulk-band dispersion near the Fermi level and similar symmetries, but with covalent bonding character. Surface effects investigated for A3Bi also can be expected for a wide range of compounds of various topological classes with a similar bonding type, and will define their surface reactivity.


The production of a new MAGE-3 peptide presented to cytolytic T lymphocytes by HLA-B40 requires the immunoproteasome.
By stimulating human CD8(+) T lymphocytes with autologous dendritic cells infected with an adenovirus encoding MAGE-3, we obtained a cytotoxic T lymphocyte (CTL) clone that recognized a new MAGE-3 antigenic peptide, AELVHFLLL, which is presented by HLA-B40. This peptide is also encoded by MAGE-12. The CTL clone recognized MAGE-3--expressing tumor cells only when they were first treated with IFN-gamma. Since this treatment is known to induce the exchange of the three catalytic subunits of the proteasome to form the immunoproteasome, this result suggested that the processing of this MAGE-3 peptide required the immunoproteasome. Transfection experiments showed that the substitution of beta5i (LMP7) for beta5 is necessary and sufficient for producing the peptide, whereas a mutated form of beta5i (LMP7) lacking the catalytically active site was ineffective. Mass spectrometric analyses of in vitro digestions of a long precursor peptide with either proteasome type showed that the immunoproteasome produced the antigenic peptide more efficiently, whereas the standard proteasome more efficiently introduced cleavages destroying the antigenic peptide. This is the first example of a tumor-specific antigen exclusively presented by tumor cells expressing the immunoproteasome.


Two new species of Quasithelazia Maplestone, 1932 (Nematoda: Acuariidae) from Malaysia, with an amended diagnosis and review of the genus.
Quazithelazia rostrata n. sp. from Ceyx erithaca (L.) (type-host) and Alcedo euryzona Temminck (Coraciiformes, Alcedinidae) and Q. alata n. sp. from Enicurus ruficapillus Temminck (Passeriformes, Muscicapidae) are described from vicinities of Gombak Biological Station, Selangor, Malaysia; both species are parasitic under the koilin lining of the gizzard. Paratypes of Schistogendra pelargopsis Nandi, De & Majumdar, 1985, a parasite of Pelargopsis capensis (L.) (Alcedinidae) from India, are redescribed and the species is recognised as a junior synonym of the type-species of Quasithelazia, Q. tenuis Maplestone, 1932 (new synonymy), a species originally described from Halcyon smyrnensis (L.) (Alcedinidae) in India. An amended diagnosis of the genus Quasithelazia Maplestone, 1932 is proposed. Currently, this genus includes eight species occurring in the Old World, six of them parasitic in kingfishers (Alcedinidae) and two species parasitic in flycatchers (Muscicapidae). These include, inter alia, Q. halcyoni n. comb. for Viktorocara halcyoni Ryzhikov & Khokhlova, 1964 from Halcyon smyrnensis and H. pileata (Boddaert) in Vietnam and the Russian Far East, Q. microcordonis n. comb. for Rusguniella microcordonis Schmidt & Kuntz, 1971 from Halcyon coromanda major (Temminck & Schlegel) in Taiwan and Q. multipapillata n. comb. for Schistogendra multipapillata Zhang, 1993 from Tarsiger cyanurus (Pallas) (Muscicapidae) in China. Comparative morphological data for Quasithelazia spp. are presented. Schistogendra oligopapillata Zhang & An, 2002 from domestic ducks in China is considered a species incertae sedis.


PAR proteins diffuse freely across the anterior-posterior boundary in polarized C. elegans embryos.
Polarization of cells by PAR proteins requires the segregation of antagonistic sets of proteins into two mutually exclusive membrane-associated domains. Understanding how nanometer scale interactions between individual PAR proteins allow spatial organization across cellular length scales requires determining the kinetic properties of PAR proteins and how they are modified in space. We find that PAR-2 and PAR-6, which localize to opposing PAR domains, undergo exchange between well mixed cytoplasmic populations and laterally diffusing membrane-associated states. Domain maintenance does not involve diffusion barriers, lateral sorting, or active transport. Rather, both PAR proteins are free to diffuse between domains, giving rise to a continuous boundary flux because of lateral diffusion of molecules down the concentration gradients that exist across the embryo. Our results suggest that the equalizing effects of lateral diffusion are countered by actin-independent differences in the effective membrane affinities of PAR proteins between the two domains, which likely depend on the ability of each PAR species to locally modulate the membrane affinity of opposing PAR species within its domain. We propose that the stably polarized embryo reflects a dynamic steady state in which molecules undergo continuous diffusion between regions of net association and dissociation.


TIGAR: transcript isoform abundance estimation method with gapped alignment of RNA-Seq data by variational Bayesian inference.
Many human genes express multiple transcript isoforms through alternative splicing, which greatly increases diversity of protein function. Although RNA sequencing (RNA-Seq) technologies have been widely used in measuring amounts of transcribed mRNA, accurate estimation of transcript isoform abundances from RNA-Seq data is challenging because reads often map to more than one transcript isoforms or paralogs whose sequences are similar to each other. We propose a statistical method to estimate transcript isoform abundances from RNA-Seq data. Our method can handle gapped alignments of reads against reference sequences so that it allows insertion or deletion errors within reads. The proposed method optimizes the number of transcript isoforms by variational Bayesian inference through an iterative procedure, and its convergence is guaranteed under a stopping criterion. On simulated datasets, our method outperformed the comparable quantification methods in inferring transcript isoform abundances, and at the same time its rate of convergence was faster than that of the expectation maximization algorithm. We also applied our method to RNA-Seq data of human cell line samples, and showed that our prediction result was more consistent among technical replicates than those of other methods. An implementation of our method is available at http://github.com/nariai/tigar email@example.com Supplementary data are available at Bioinformatics online.


Quantitative mass spectrometry reveals plasticity of metabolic networks in Mycobacterium smegmatis.
Mycobacterium tuberculosis has a remarkable ability to persist within the human host as a clinically inapparent or chronically active infection. Fatty acids are thought to be an important carbon source used by the bacteria during long term infection. Catabolism of fatty acids requires reprogramming of metabolic networks, and enzymes central to this reprogramming have been targeted for drug discovery. Mycobacterium smegmatis, a nonpathogenic relative of M. tuberculosis, is often used as a model system because of the similarity of basic cellular processes in these two species. Here, we take a quantitative proteomics-based approach to achieve a global view of how the M. smegmatis metabolic network adjusts to utilization of fatty acids as a carbon source. Two-dimensional liquid chromatography and mass spectrometry of isotopically labeled proteins identified a total of 3,067 proteins with high confidence. This number corresponds to 44% of the predicted M. smegmatis proteome and includes most of the predicted metabolic enzymes. Compared with glucose-grown cells, 162 proteins showed differential abundance in acetate- or propionate-grown cells. Among these, acetate-grown cells showed a higher abundance of proteins that could constitute a functional glycerate pathway. Gene inactivation experiments confirmed that both the glyoxylate shunt and the glycerate pathway are operational in M. smegmatis. In addition to proteins with annotated functions, we demonstrate carbon source-dependent differential abundance of proteins that have not been functionally characterized. These proteins might play as-yet-unidentified roles in mycobacterial carbon metabolism. This study reveals several novel features of carbon assimilation in M. smegmatis, which suggests significant functional plasticity of metabolic networks in this organism.


Test-retest reliability of a questionnaire measuring perceptions of neighborhood food environment.
There is a lack of validated and reliable instruments on perception of the food environment, in particular for rural environments. We estimated the test-retest reliability of a questionnaire assessing perceptions of the food environment. A total of 101 primary food shoppers in South Carolina were interviewed by phone to assess their perceptions of the food environment and presence of different food outlet types in their neighborhood. The survey was repeated approximately one month after the initial administration. The intra-class correlation (ICC) and Phi coefficient are reported as measures of reliability. The majority of questions on perceptions of the neighborhood food environment appear highly reliable (ICCs range from 0.55 to 0.71), including the 3-item scale on healthy food availability (ICC 0.71). Compared to participants in rural areas, those in urban areas demonstrated better reliability for questions on opportunities to purchase fast food and perceived presence of a supercenter. More research is needed to evaluate potential rural-urban differences in reliability.


Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS.
Mechanisms underlying motor neuron subtype-selective endoplasmic reticulum (ER) stress and associated axonal pathology in amyotrophic lateral sclerosis (ALS) remain unclear. Here we show that the molecular environment of the ER between motor neuron subtypes is distinct, with characteristic signatures. We identify cochaperone SIL1, mutated in Marinesco-Sjögren syndrome (MSS), as being robustly expressed in disease-resistant slow motor neurons but not in ER stress-prone fast-fatigable motor neurons. In a mouse model of MSS, we demonstrate impaired ER homeostasis in motor neurons in response to loss of SIL1 function. Loss of a single functional Sil1 allele in an ALS mouse model (SOD1-G93A) enhanced ER stress and exacerbated ALS pathology. In SOD1-G93A mice, SIL1 levels were progressively and selectively reduced in vulnerable fast-fatigable motor neurons. Mechanistically, reduction in SIL1 levels was associated with lowered excitability of fast-fatigable motor neurons, further influencing expression of specific ER chaperones. Adeno-associated virus-mediated delivery of SIL1 to familial ALS motor neurons restored ER homeostasis, delayed muscle denervation and prolonged survival.


4-Aminoquinoline derivatives: Synthesis, in vitro and in vivo antiplasmodial activity against chloroquine-resistant parasites.
Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential against Plasmodium berghei in vivo. These 4-aminoquinolines cured BALB/c mice infected with P. berghei. The ED50 values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18 mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500 mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax.


Multistability, chains, and cycles in optical multiwave mixing processes.
We exhibit the information processing capabilities of the first few terms that arise in the amplitude expansion for resonant scattering in a medium with a delay nonlinearity (generalized volume hologram). We begin by showing how the physics of intensity dependent charge transport near a two-photon resonance gives both delayed quadratic and quartic nonlinearities. After reviewing the utility for matrix associative memories exhibited by the delayed quadratic nonlinearity (the ordinary Gabor hologram), we examine the role of the quartic nonlinearity, which is a fourth rank tensor. The symmetries of this tensor determine the information processing capabilities (via multilinear correlations) of the medium in an optical computing paradigm. We find multiple basins of stability, Jordan strings, and cycles as possible dynamic behaviors for the medium. We indicate how each corresponds to an information processing task: multiple basins to multiassociative memory, Jordan strings and cycles to chain and sequence memory and to group-invariant pattern recognition. We briefly indicate how branching processes may be implemented by the fourth rank mode-coupling tensor.


Difficulty in learning similar-sounding words: A developmental stage or a general property of learning?
How are languages learned, and to what extent are learning mechanisms similar in infant native-language (L1) and adult second-language (L2) acquisition? In terms of vocabulary acquisition, we know from the infant literature that the ability to discriminate similar-sounding words at a particular age does not guarantee successful word-meaning mapping at that age (Stager & Werker, 1997). However, it is unclear whether this difficulty arises from developmental limitations of young infants (e.g., poorer working memory) or whether it is an intrinsic part of the initial word learning, L1 and L2 alike. In this study, we show that adults of particular L1 backgrounds-just like young infants-have difficulty learning similar-sounding L2 words that they can nevertheless discriminate perceptually. This suggests that the early stages of word learning, whether L1 or L2, intrinsically involve difficulty in mapping similar-sounding words onto referents. We argue that this is due to an interaction between 2 main factors: (a) memory limitations that pose particular challenges for highly similar-sounding words, and (b) uncertainty regarding the language's phonetic categories, because the categories are being learned concurrently with words. Overall, our results show that vocabulary acquisition in infancy and adulthood shares more similarities than previously thought, thus supporting the existence of common learning mechanisms that operate throughout the life span. (PsycINFO Database Record