Osteopontin is proteolytically processed by matrix metalloproteinase 9.
Osteopontin is robustly upregulated following myocardial infarction (MI), which suggests that it has an important role in post-MI remodeling of the left ventricle (LV). Osteopontin deletion results in increased LV dilation and worsened cardiac function. Thus, osteopontin exerts protective effects post-MI, but the mechanisms have yet to be defined. Matrix metalloproteinases (MMPs) regulate LV remodeling post-MI, and osteopontin is a known substrate for MMP-2, -3, -7, and -9, although the cleavage sites have not been mapped. Osteopontin-derived peptides can exert distinct biological functions that may depend on their cleavage sites. We mapped the MMP-9 cleavage sites via LC-MS/MS analysis using label-free and N-terminal labeling methods, and compared them with those of MMP-2, -3, and -7. Each MMP yielded a unique cleavage profile with few overlapping cleavage sites. Using synthetic peptides, we validated 3 sites for MMP-9 cleavage at amino acid positions 151-152, 193-194, and 195-196. Four peptides were synthesized based on the upstream- and downstream-generated fragments and were tested for biological activity in isolated cardiac fibroblasts. Two peptides increased cardiac fibroblast migration rates post-wounding (p < 0.05 compared with the negative control). Our study highlights the importance of osteopontin processing, and confirms that different cleavage sites generate osteopontin peptides with distinct biological functions.


Does facial expression affect attention orienting by gaze direction cues?
In 6 experiments, the authors investigated whether attention orienting by gaze direction is modulated by the emotional expression (neutral, happy, angry, or fearful) on the face. The results showed a clear spatial cuing effect by gaze direction but no effect by facial expression. In addition, it was shown that the cuing effect was stronger with schematic faces than with real faces, that gaze cuing could be achieved at very short stimulus onset asynchronies (14 ms), and that there was no evidence for a difference in the strength of cuing triggered by static gaze cues and by cues involving apparent motion of the pupils. In sum, the results suggest that in normal, healthy adults, eye direction processing for attention shifts is independent of facial expression analysis.


Examine the public health impacts of functional somatic disorders using the DanFunD study.
Background: Persistent physical symptoms (e.g. pain, fatigue) are prevalent in the population and some persons may develop a functional somatic disorder (FSD). We still need to explore the limits between general bodily sensations and FSD, and great controversies exist as regard delimitation, occurrence, risk factors, prognosis, and costs of FSD in the general population. This is mainly due to the lack of focused, sufficient powered, population-based epidemiological studies. Material and Methods: The DanFunD study is the largest focused population-based study on FSD and has the potential to answer these crucial questions regarding the FSD disorders. DanFunD has its origin in the Copenhagen area of Denmark and was initiated in 2009 by an interdisciplinary team of researchers including basic scientists, clinical researchers, epidemiologists, and public health researchers. A population-based cohort of nearly 10,000 people have filled in detailed questionnaires, gone through a thorough health examination, and a biobank is established. The cohort was re-examined after five years. Results:The prevalence of FSD in the Danish population is about 10-15% and is twice as common in women as in men. Persons with FSD report impaired daily activities and low self-perceived health, which qualifies FSD as a major public health problem. The research plan to unravel the risk factors for FSD employs a bio-psycho-social approach according to a detailed plan. Preliminary results are presented, and work is in progress. Likewise, plans for assessing prognosis and health care costs are provided. Conclusion: We invite researchers in the field to collaborate on this unique data material.


Comprehensive primary health care under neo-liberalism in Australia.
This paper applies a critical analysis of the impact of neo-liberal driven management reform to examine changes in Australian primary health care (PHC) services over five years. The implementation of comprehensive approaches to primary health care (PHC) in seven services: five state-managed and two non-government organisations (NGOs) was tracked from 2009 to 2014. Two questions are addressed: 1) How did the ability of Australian PHC services to implement comprehensive PHC change over the period 2009-2014? 2) To what extent is the ability of the PHC services to implement comprehensive PHC shaped by neo-liberal health sector reform processes? The study reports on detailed tracking and observations of the changes and in-depth interviews with 63 health service managers and practitioners, and regional and central health executives. The documented changes were: in the state-managed services (although not the NGOs) less comprehensive service coverage and more focus on clinical services and integration with hospitals and much less development activity including community development, advocacy, intersectoral collaboration and attention to the social determinants. These changes were found to be associated with practices typical of neo-liberal health sector reform: considerable uncertainty, more directive managerial control, budget reductions and competitive tendering and an emphasis on outputs rather than health outcomes. We conclude that a focus on clinical service provision, while highly compatible with neo-liberal reforms, will not on its own produce the shifts in population disease patterns that would be required to reduce demand for health services and promote health. Comprehensive PHC is much better suited to that task.


Treatment of IgA nephropathy with nephrotic syndrome using pulse doses of IgG.
This paper presents the preliminary results of the treatment of nephrotic syndrome in IgA nephropathy (IgAN) using pulse doses of IgG. Diagnosis was established only by percutaneous ultrasonically-guided renal biopsy, as well as on the basis of typical immunofluorescence and light microscopy findings. Histopathologic changes were classified according to the World Health Organization classification for IgAN, by determination of average glomerular, vascular and interstitial fibrosis indices and the degree of tubular atrophy. IgG therapy was administered in three patients with nephrotic syndrome associated with IgAN characterized by minimal histological changes, i.e., by diffuse mesangioproliferative glomerulonephritis. Initial IgG pulse dose was 0.4 g/kg, given as slow intravenous infusion during three consecutive days in the course of the three-month period. Maintenance therapy consisted of intramuscular IgG in the doses of 2.5 g twice a month, for the next three months. After a six-month treatment, clinical and biochemical remission was achieved in patients with minimal histologic changes, but in other two patients with diffuse mesangioproliferative glomerulonephritis, the effect of the therapy consisted of reduced proteinuria by more than 50%, with the renal function restored to the level before therapy. Transient increase in the serum creatinine level was found in two patients. These preliminary results with IgG pulse therapy, although obtained on a small number of patients, suggest the drug's potent immunomodulatory properties, but its complexity and levels of actions should be further investigated.


The Content and Nature of Narrative Comments on Swiss Physician Rating Websites: Analysis of 849 Comments.
The majority of physician rating websites (PRWs) provide users the option to leave narrative comments about their physicians. Narrative comments potentially provide richer insights into patients' experiences and feelings that cannot be fully captured in predefined quantitative rating scales and are increasingly being examined. However, the content and nature of narrative comments on Swiss PRWs has not been examined to date. This study aimed to examine (1) the types of issues raised in narrative comments on Swiss PRWs and (2) the evaluation tendencies of the narrative comments. A random stratified sample of 966 physicians was generated from the regions of Zürich and Geneva. Every selected physician was searched for on 3 PRWs (OkDoc, DocApp, and Medicosearch) and Google, and narrative comments were collected. Narrative comments were analyzed and classified according to a theoretical categorization framework of physician-, staff-, and practice-related issues. The selected physicians had a total of 849 comments. In total, 43 subcategories addressing the physician (n=21), staff (n=8), and practice (n=14) were identified. None of the PRWs' comments covered all 43 subcategories of the categorization framework; comments on Google covered 86% (37/43) of the subcategories, Medicosearch covered 72% (31/43), DocApp covered 60% (26/43), and OkDoc covered 56% (24/43). In total, 2441 distinct issues were identified within the 43 subcategories of the categorization framework; 83.65% (2042/2441) of the issues related to the physician, 6.63% (162/2441) related to the staff, and 9.70% (237/2441) related to the practice. Overall, 95% (41/43) of the subcategories of the categorization framework and 81.60% (1992/2441) of the distinct issues identified were concerning aspects of performance (interpersonal skills of the physician and staff, infrastructure, and organization and management of the practice) that are considered assessable by patients. Overall, 83.0% (705/849) of comments were classified as positive, 2.5% (21/849) as neutral, and 14.5% (123/849) as negative. However, there were significant differences between PRWs, regions, and specialty regarding negative comments: 90.2% (111/123) of negative comments were on Google, 74.7% (92/123) were regarding physicians in Zurich, and 73.2% (90/123) were from specialists. From the narrative comments analyzed, it can be reported that interpersonal issues make up nearly half of all negative issues identified, and it is recommended that physicians should focus on improving these issues. The current suppression of negative comments by Swiss PRWs is concerning, and there is a need for a consensus-based criterion to be developed to determine which comments should be published publicly. Finally, it would be helpful if Swiss patients are made aware of the current large differences between Swiss PRWs regarding the frequency and nature of ratings to help them determine which PRW will provide them with the most useful information.


The dilemma of isolated systolic hypertension.
Isolated systolic hypertension, characterized by elevated systolic blood pressure (greater than 150 to 165 mm Hg), normal diastolic blood pressure (less than 90 to 95 mm Hg) and, often, atherosclerosis, is now recognized as an important risk factor for cardiovascular disease. When the systolic pressure is 200 mm Hg or greater, or when it is 180 mm Hg or greater and accompanied by target organ damage, therapeutic intervention may be of value in patients under the age of 80 years. Low doses of thiazide diuretics have been shown to be safe and effective in lowering the systolic pressure. If the blood pressure remains high, treatment with methyldopa may be added.


HLA amino acid residue matching.
1. HLA amino acid sequences have been defined for 77 A- and 176 B-locus antigens. Amino acid polymorphisms occurred at 80 A- and 74 B- sequence positions. 2. The majority of amino acid substitutions occurred in regions involved with peptide binding. A surprisingly large number of substitutions were in the alpha-3 regions of the molecule. 3. Graft outcome in cadaveric and living donor transplants was calculated for mismatches for every possible amino acid allele. 4. Two-thirds of the HLA-A and -B locus antigens used for solid organ allocation had disparate frequencies in White and Black recipients. Only 6 antigens were found in over 20% of White recipients. 5. Five-year survival for first transplants was 66% for zero-DR, zero-residue mismatched kidneys compared to 59% for kidneys with mismatches. Half-life for residue matched kidneys was 11 years compared with 8 years for kidneys with mismatches. 6. Mismatches for all of the A-locus residues and the majority of B-locus residues were correlated with positive crossmatches. 7. None of the crossmatches for highly sensitized patients with zero-A,B,DR mismatches were positive; 30% of zero-residue mismatched patients had a positive crossmatch compared to 70% of cases with mismatches.


Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298.
Bisphosphonates are the important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Although their molecular mechanism of action has not been fully elucidated, recent studies have shown that the nitrogen-containing bisphosphonates can inhibit protein prenylation in macrophages in vitro. In this study, we show that the nitrogen-containing bisphosphonates risedronate, zoledronate, ibandronate, alendronate, and pamidronate (but not the non nitrogen-containing bisphosphonates clodronate, etidronate, and tiludronate) prevent the incorporation of [14C]mevalonate into prenylated (farnesylated and geranylgeranylated) proteins in purified rabbit osteoclasts. The inhibitory effect of nitrogen-containing bisphosphonates on bone resorption is likely to result largely from the loss of geranylgeranylated proteins rather than loss of farnesylated proteins in osteoclasts, because concentrations of GGTI-298 (a specific inhibitor of geranylgeranyl transferase I) that inhibited protein geranylgeranylation in purified rabbit osteoclasts prevented osteoclast formation in murine bone marrow cultures, disrupted the osteoclast cytoskeleton, inhibited bone resorption, and induced apoptosis in isolated chick and rabbit osteoclasts in vitro. By contrast, concentrations of FTI-277 (a specific inhibitor of farnesyl transferase) that prevented protein farnesylation in purified rabbit osteoclasts had little effect on osteoclast morphology or apoptosis and did not inhibit bone resorption. These results therefore show the molecular mechanism of action of nitrogen-containing bisphosphonate drugs in osteoclasts and highlight the fundamental importance of geranylgeranylated proteins in osteoclast formation and function.


Focused ultrasound activates voltage-gated calcium channels through depolarizing TRPC1 sodium currents in kidney and skeletal muscle.
Pulsed focused ultrasound (pFUS) technology is being developed for clinical neuro/immune modulation and regenerative medicine. Biological signal transduction of pFUS forces can require mechanosensitive or voltage-gated plasma membrane ion channels. Previous studies suggested pFUS is capable of activating either channel type, but their mechanistic relationship remains ambiguous. We demonstrated pFUS bioeffects increased mesenchymal stem cell tropism (MSC) by altering molecular microenvironments through cyclooxygenase-2 (COX2)-dependent pathways. This study explored specific relationships between mechanosensitive and voltage-gated Ca2+ channels (VGCC) to initiate pFUS bioeffects that increase stem cell tropism. Methods: Murine kidneys and hamstring were given pFUS (1.15 or 1.125 MHz; 4MPa peak rarefactional pressure) under ultrasound or magnetic resonance imaging guidance. Cavitation and tissue displacement were measure by hydrophone and ultrasound radiofrequency data, respectively. Elastic modeling was performed from displacement measurements. COX2 expression and MSC tropism were evaluated in the presence of pharmacological ion channel inhibitors or in transient-receptor-potential-channel-1 (TRPC1)-deficient mice. Immunohistochemistry and co-immunoprecipitation examined physical channel relationships. Fluorescent ionophore imaging of cultured C2C12 muscle cells or TCMK1 kidney cells probed physiological interactions. Results: pFUS induced tissue deformations resulting in kPa-scale forces suggesting mechanical activation of pFUS-induced bioeffects. Inhibiting VGCC or TRPC1 in vivo blocked pFUS-induced COX2 upregulation and MSC tropism to kidneys and muscle. A TRPC1/VGCC complex was observed in plasma membranes. VGCC or TRPC1 suppression blocked pFUS-induced Ca2+ transients in TCMK1 and C2C12 cells. Additionally, Ca2+ transients were blocked by reducing transmembrane Na+ potentials and observed Na+ transients were diminished by genetic TRPC1 suppression. Conclusion: This study suggests that pFUS acoustic radiation forces mechanically activate a Na+-containing TRPC1 current upstream of VGCC rather than directly opening VGCC. The electrogenic function of TRPC1 provides potential mechanistic insight into other pFUS techniques for physiological modulation and optimization strategies for clinical implementation.


The role of procalcitonin in community-acquired pneumonia: a literature review.
Community-acquired pneumonia (CAP) is a significant clinical and public health problem. Recently, attention has been paid to the potential for procalcitonin (PCT) both to differentiate the diagnosis and to indicate the prognosis of pneumonia. The purpose of this literature review was to evaluate the eligibility of PCT for defining typical bacterial infections and for predicting severity and mortality in trials for CAP. The literature review suggests that PCT has the ability to supplement clinical information to determine whether or not the cause of the infection is likely to be bacterial. In addition, PCT seems to be superior to the most prevalent inflammatory biomarker C-reactive protein and also demonstrates a significant correlation between the current clinical scoring systems and actual mortality.


An efficient fluorescent protein-based multifunctional affinity purification approach in mammalian cells.
Knowledge of an individual protein's modifications, binding partners, and localization is essential for understanding complex biological networks. We recently described a fluorescent protein-based (mVenus) multifunctional affinity purification (MAP) tag that can be used both to purify a given protein and determine its localization (Ma et al., Mol Cell Proteomics 11:501-511, 2012). MAP purified protein complexes can be further analyzed to identify binding partners and posttranslational modifications by LC-MS/MS. The MAP approach offers rapid FACS-selection of stable clonal cell lines based on the expression level/fluorescence of the MAP-protein fusion. The MAP tag is highly efficient and shows little variability between proteins. Here we describe the general MAP purification method in detail, and show how it can be applied to a specific protein using the human Cdc14B phosphatase as an example.


Computational Analysis of Chemical Space of Natural Compounds Interacting with Sulfotransferases.
The aim of this study was to investigate the chemical space and interactions of natural compounds with sulfotransferases (SULTs) using ligand- and structure-based in silico methods. An in-house library of natural ligands (hormones, neurotransmitters, plant-derived compounds and their metabolites) reported to interact with SULTs was created. Their chemical structures and properties were compared to those of compounds of non-natural (synthetic) origin, known to interact with SULTs. The natural ligands interacting with SULTs were further compared to other natural products for which interactions with SULTs were not known. Various descriptors of the molecular structures were calculated and analyzed. Statistical methods (ANOVA, PCA, and clustering) were used to explore the chemical space of the studied compounds. Similarity search between the compounds in the different groups was performed with the ROCS software. The interactions with SULTs were additionally analyzed by docking into different experimental and modeled conformations of SULT1A1. Natural products with potentially strong interactions with SULTs were outlined. Our results contribute to a better understanding of chemical space and interactions of natural compounds with SULT enzymes and help to outline new potential ligands of these enzymes.


Robotic sacrocolpopexy for the management of pelvic organ prolapse: quality of life outcomes.
Our aim was to investigate longer-term surgical and quality of life (QOL) outcomes in a cohort of women undergoing robotic-assisted laparoscopic sacrocolpopexy (RALS) for pelvic organ prolapse (POP). We performed a retrospective cohort study at a single institution of female patients undergoing RALS with and without concomitant robotic-assisted laparoscopic hysterectomy, urethral sling, and rectocele repair. Scores from the Pelvic Floor Distress Inventory (PFDI) and Pelvic Floor Impact Questionnaire (PFIQ) surveys were used to evaluate QOL outcomes. Clinical improvement was defined by a decrease in a patient's PFDI and PFIQ postoperative score by ⩾70%. Clinical improvement was seen in 62.6% by the PFIQ and in 64% by the PFDI survey. Younger patient age (OR 0.92, p = 0.011) and worse preoperative American Urological Association (AUA) Quality of Life score (OR 1.42, p = 0.046) were associated with clinical improvement. Within the PFIQ, 35.6% of patients saw clinical improvement with their bowel symptoms, compared with bladder (54.1%, p < 0.001) and prolapse (45.6%, p = 0.053) symptoms. Within the PFDI, 45.5% of patients reached clinical improvement with their bowel symptoms, compared with bladder (56.7%, p = 0.035) and prolapse (62.6%, p < 0.001) symptoms. Of the patients who had a rectocele repair, 46.3% reached clinical improvement in their CRADI-8 score, and 51% saw clinical improvement in the bowel portion of the PDFI. Significantly fewer patients reached clinical improvement within the portions of the surveys that focus on bowel symptoms, compared with symptoms related to urination and POP. Of those that had a concomitant rectocele repair, approximately half reached clinical improvement with their bowel symptoms.


Anomalies of the fingers and toes associated with Klippel-Trenaunay syndrome.
Klippel-Trenaunay syndrome is a rare congenital malformation characterized by a large angiomatous nevus; hypertrophy of soft tissue or overgrowth of bone, or both; and venous varicosities. The cases of 108 patients who had a diagnosis of this syndrome between 1956 and 1990 were reviewed. One hundred and twenty-six anomalies were found in twenty-nine patients, each of whom had one to thirteen malformations of the fingers or toes, or both. The ratio of female patients to male patients was approximately two to one. Twenty-six patients had macrodactyly affecting one to six digits; nine, syndactyly involving two or more digits; five, metatarsus primus varus; two, clinodacytly; two, polydactyly; one, camptodactyly; and one, a congenital trigger finger. Thirty-three of the 126 anomalies were in extremities that had no nevi, varicose veins, or generalized hypertrophy.


Xyloglucan endotransglycosylase: evidence for the existence of a relatively stable glycosyl-enzyme intermediate.
Xyloglucan endotransglycosylases (XETs) catalyse the breakdown of xyloglucan molecules predominantly by transglycosylation. In this process, fragments of cleaved polysaccharide are preferentially transferred to other xyloglucan molecules or their oligosaccharide subunits, with overall retention of the anomeric configuration of the glycosidic bond. In accordance with the theory, we propose that the cleavage and re-formation of the glycosidic bond in xyloglucan involves the formation of a glycosyl-enzyme intermediate which decomposes by transfer of the glycosyl moiety to a suitable carbohydrate acceptor. XETs from nasturtium seed cotyledons, mung bean hypocotyls and cauliflower florets interacted with xyloglucan to form complexes of high Mr as judged by gel-permeation chromatography. The nasturtium enzyme also showed evidence of XET-xyloglucan complex-formation according to anion-exchange chromatography and adsorption of the complex to filter paper on the basis of affinity of its xyloglucan moiety for cellulose. The XET-xyloglucan complex was stable in water, 6 M urea and acidic and alkaline buffers (pH 2.5-9.5), but readily decomposed by transferring its glycosyl moiety to xyloglucan-derived oligosaccharides or by incubation with the strong nucleophile imidazole at pH 3.8-9.6. These results strongly support the assumption that XET forms a relatively stable covalently linked glycosyl-enzyme intermediate.


Predictors of bone mineral density in human immunodeficiency virus-1 infected children.
To compare bone mineral density (BMD) among human immunodeficiency virus (HIV)-infected children with population norms and to determine predictors of BMD in HIV-infected children. Total body BMD was measured by dual energy x-ray absorptiometry in 37 HIV-infected children and nine sibling controls at baseline. Clinical, dietary and anthropometric data were obtained at the time of the dual energy x-ray absorptiometry examination. Age- and gender-adjusted z scores were calculated for BMD, body mass index, weight and height from population standards. Age-adjusted percentiles were determined for dietary intake of calcium and vitamin D. Differences in BMD z scores between HIV-infected children and sibling controls were determined and adjusted for height and weight, as were independent risk factors for lower BMD among infected children. Eighteen HIV-infected children and 5 controls had serial BMD measures. Compared with population norms, HIV-infected children had significantly lower BMD z scores (-0.51 SD, P = 0.004), in contrast with controls who had normal z scores (0.38 SD, P = 1.0). However, there was no difference in BMD z scores between HIV-infected children and the small number of sibling controls, adjusted for height and weight. Among HIV-infected children, lower BMD z scores were independently associated with lower weight z scores (P < 0.0001), lower height z scores (P = 0.01), advanced (stage B or C) HIV stage (P = 0.01) and age greater than 8 years (P < 0.0001). In the same model, multivitamin use (P = 0.009) and African American race (P = 0.001) were associated with better BMD z scores, with nevirapine use showing borderline positive effect (P = 0.06). All results were adjusted for Tanner stage. Change in BMD z score over time showed that there was no change or an increase in BMD in 100% of controls but in only 44% of the HIV-infected children (P = 0.09). When compared with population norms, HIV-infected children had lower than expected bone mass for their age and gender that may be attributable to delays in growth, sexual maturity, time (length of HIV infection), ethnicity and disease severity. Dietary intake of calcium and vitamin D were not associated with bone loss, but most children had suboptimal intake. However, multivitamin use was strongly associated with better bone mineral density.


Lidocaine for pain relief in burn injured patients.
Pain is a major issue for patients suffering from many different types of wounds in particular those with burn injuries. Prompt, aggressive use of opioid analgesics such as morphine has been suggested as critical to avert the cycle of pain and anxiety, but side effects are encountered. It is proposed that newer agents such as lidocaine could be effective in reducing pain and alleviating the escalating opioid dosage requirements in patients with burn injury. To assess the safety and effectiveness of intravenous lidocaine as a means of pain relief versus no therapy, placebo, other drugs or two or more of the above therapies in combination in patients exposed to burn injury. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2007), MEDLINE (1966 to March 2007), EMBASE (1980 to 2007), CINAHL (1982 to March 2007). Those trials that were considered were: randomised controlled trials (RCTs) and controlled clinical trials (CCTs), both published and unpublished studies, which assessed the efficacy of intravenous lidocaine varying doses as a single-agent therapy with no therapy, placebo, other analgesics such as opioids, lidocaine plus another drug, or two or more of the above therapies as a means of pain relief in patients exposed to burn injury. The two review authors applied the entry criteria to identified studies. No clinically relevant RCTs or CCTs were identified through the above searches. No information is available from the published RCTs or CCTs on clinically relevant primary outcome measures which can influence current burns care practice and management. Therefore, since current clinical evidence is subject to the inherent weaknesses of case series or reports, intravenous lidocaine must be considered a pharmacological agent under investigation in burns care whose effectiveness is yet to be determined in well-designed and conducted clinical trials.


Bio-assembling Macro-Scale, Lumenized Airway Tubes of Defined Shape via Multi-Organoid Patterning and Fusion.
Epithelial, stem-cell derived organoids are ideal building blocks for tissue engineering, however, scalable and shape-controlled bio-assembly of epithelial organoids into larger and anatomical structures is yet to be achieved. Here, a robust organoid engineering approach, Multi-Organoid Patterning and Fusion (MOrPF), is presented to assemble individual airway organoids of different sizes into upscaled, scaffold-free airway tubes with predefined shapes. Multi-Organoid Aggregates (MOAs) undergo accelerated fusion in a matrix-depleted, free-floating environment, possess a continuous lumen, and maintain prescribed shapes without an exogenous scaffold interface. MOAs in the floating culture exhibit a well-defined three-stage process of inter-organoid surface integration, luminal material clearance, and lumina connection. The observed shape stability of patterned MOAs is confirmed by theoretical modelling based on organoid morphology and the physical forces involved in organoid fusion. Immunofluorescent characterization shows that fused MOA tubes possess an unstratified epithelium consisting mainly of tracheal basal stem cells. By generating large, shape-controllable organ tubes, MOrPF enables upscaled organoid engineering towards integrated organoid devices and structurally complex organ tubes.


Do not overlook Weismann-Netter syndrome in differential diagnosis of skeletal dysplasias.
Weismann-Netter syndrome (WNS), a rare condition, is characterized by an anterior curvature of the bones of the lower limbs, usually bilateral and symmetrical. It was first described in 1954 by Weismann-Netter and Stuhl. We report a 2-year-old girl with typical findings of WNS who was misdiagnosed as having rickets. Our purpose is to draw attention to the WNS in the differential diagnosis of skeletal dysplasias. We think that the true incidence of WNS is probably higher than previously reported; therefore, we would like to emphasize that WNS should be considered in patients who have bowed lower extremities and have been diagnosed as having syphilis or healed rickets.


Psychrobacter oceani sp. nov., isolated from marine sediment.
A novel marine bacterium, designated strain 4k5(T), was isolated from a sediment sample of the Pacific Ocean. The strain was Gram-stain-negative, strictly aerobic, non-motile, oxidase-positive and catalase-positive and required Na(+) for growth. Its major isoprenoid quinone was ubiquinone 8 (Q-8), and its cellular fatty acid profile consisted mainly of C18 : 1v9c (71.4%), C16 : 1v7c (9.1%) and C18 : 0. The DNA G+C content was 45.3 mol%. 16S rRNA gene sequence analysis suggested that strain 4k5(T) is a member of the genus Psychrobacter . Strain 4k5(T) exhibited the closely phylogenetic affinity to Psychrobacter pacificensis IFO 16270(T) (99.4% 16S rRNA gene sequence similarity), P. piscatorii T-3-2(T) (97.7%), P. nivimaris 88/2-7(T) (97.7%), P. celer SW-238(T) (97.7%), P. aestuarii SC35(T) (97.6%) and P. vallis CMS39(T) (97.6%). DNA-DNA hybridization between strain 4k5(T) and P. pacificensis NBRC 103191(T), P. piscatorii JCM 15603(T). P. nivimaris DSM 16093(T), P. celer JCM 12601(T), P. aestuarii JCM 16343(T) and P. vallis DSM 15337(T) was 42.5, 47.0, 38.1, 23.7, 9.0 and 27.4%, respectively. Owing to the significant differences in phenotypic and chemotaxonomic characteristics, phylogenetic analysis based on the 16S rRNA gene sequence and DNA-DNA relatedness data, the isolate merits classification within a novel species, for which the name Psychrobacter oceani sp. nov. is proposed. The type strain is 4k5(T) ( = JCM 30235(T) =NCIMB 14948(T)).


Curriculum infusion to promote nursing student well-being.
This paper is a report of a study of baccalaureate nursing students' experiences with curriculum infusion of college health issues into academic courses and students' well-being. Bringing Theory to Practice is an ongoing project at a number of colleges in the United States of America. Its goal is to use the academic classroom and campus community to engage students actively in self-reflection on a variety of common college student health and well-being issues. This qualitative study was based on 159 students' experiences with curriculum infusion in two undergraduate nursing courses at a university in the United States of America over a 2-year period from 2006 to 2008. Student reflection papers, photo-essays, narrative course evaluations, classroom engagement with educators and peers and student use of campus health resources were the data examined. As a result of the integration of personal wellness concepts into classroom pedagogy, students experienced a variety of feelings and needs including isolation, shock and anger, taking time, awareness and valuing. In light of the increasing rigour of baccalaureate nursing programmes, it is important for educators to be aware of the health-related effects of stress and isolation on students. By increasing student self-awareness and changing relational dynamics in the classroom, student well-being can be supported.


Role of saliva in oral dryness, oral feel and oral malodour.
Patients who believe they have oral malodour often have a dry mouth condition instead. Here we have examined its relation to oral malodour, real or perceived. A direct relationship between the thickness of the film of residual saliva on mucosal surfaces throughout the mouth and perception of a dry mouth was observed. On the hard palate, the thickness of this film proved to be diagnostic for a dry mouth and corresponded to lower resting saliva flow and pH levels (P< 0.001). Intra-muscular administration of the anti-sialogogue, Robinul, accurately produced the dry mouth condition. Using a sulphide monitor, loss of volatile sulphur compounds into mouth air progressively occurred as the mouth became drier. Mouth pH and Eh on the dorsum of the tongue correspondingly fell. Mouth breathing led to tongue and palate moisture loss thus enabling escape of malodour volatiles into mouth air. Measurement of oral dryness should make it possible to differentiate genuine malodour from dry mouth related pseudo-malodour subjects, and in turn, the latter from patients that are halitophobic. This should facilitate identification of such patients and avoid error in their clinical management.


Excitatory effects of ACPD receptor activation in the hippocampus are mediated by direct effects on pyramidal cells and blockade of synaptic inhibition.
1. Phosphoinositide hydrolysis-linked excitatory amino acid (EAA) receptors (ACPD receptors) are selectively activated by the glutamate analogue trans-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD). Regional analysis of trans-ACPD-induced phosphoinositide hydrolysis indicates that this response is greater in the hippocampus than in other brain regions. Therefore we designed a series of studies aimed at testing the hypothesis that activation of this receptor modulates synaptic function in the hippocampal region. 2. We report that trans-ACPD dramatically altered field population spikes at each of the three major synapses in the hippocampal trisynaptic circuit at concentrations that are effective in activating phosphoinositide hydrolysis. At the perforant path-dentate gyrus synapse, bath application of trans-ACPD resulted in a decrease in the amplitude of field population spikes. In contrast, trans-ACPD markedly enhanced field population spike amplitude at the mossy fiber-CA3 synapse and the Schaffer collateral-CA1 synapse. In area CA1, but not area CA3, trans-ACPD also induced generation of multiple population spikes. 3. Simultaneous field potential recordings from the s. pyramidale and s. radiatum in area CA1 revealed that the effect of trans-ACPD on population spikes in this region was not accompanied by an increase in the initial slope of the field EPSP. This suggests that the effect of trans-ACPD was not mediated by a presynaptic action but must be mediated by direct effects on CA1 pyramidal cells or by a decrease in synaptic inhibition. 4. trans-ACPD had a number of direct excitatory effects on CA1 pyramidal cells. These included 1) cell depolarization (with an increase in input resistance), 2) inhibition of the slow afterhyperpolarization, and 3) blockade of spike frequency adaptation. trans-ACPD also had effects on CA1 pyramidal cells that were not excitatory in nature. These included an increase in the threshold for initiation of calcium spikes and an increase in interspike interval during prolonged current injection. None of these effects were mimicked by an ACPD analogue that does not activate the ACPD receptor (trans-methanoglutamate), nor were they blocked by kynurenate, a nonselective EAA receptor antagonist that does not block the ACPD receptor.(ABSTRACT TRUNCATED AT 400 WORDS)


Biogenic synthesis and thermo-magnetic study of highly porous carbon nanotubes.
Nanomaterials synthesis using natural sources is the technology to up come with advanced materials through extracts of plant, microorganisms, poultry waste etc. In this study, the authors report the synthesis of porous carbon nanotubes using high-temperature decomposition technique facilitated by cobalt salt using chicken fats, a poultry waste as a precursor. Since chicken fats contain fatty acids which can decompose into short hydrocarbon chains and cobalt can act as the catalyst. The formation of carbon nanotubes was confirmed by Raman spectra, peaks at 1580 and 1350.46 cm-1 confirmed the graphite mode G-band and structural imperfections defect mode D-band, respectively. Transmission electron microscopy showed the formation of tube-like structures. Nitrogen adsorption-desorption studies showed the high-surface area of 418.1 m2g-1 with an estimated pore diameter of 8.1 nm. Thermogravimetry analysis-derivative thermogravimetric analysis-differential thermal analysis showed the instant weight loss at 517°C attributed to the rapid combustion of nanotubes. A vibrating-sample magnetometer showed the paramagnetic nature of the so-formed carbon nanotubes formed.


Relative Hypodense Vertebral Artery Sign on Computerized Tomography in Atherosclerotic Near Occlusion.
A 52-year-old white male presented with an acute onset of slurred speech along with hypoesthesia in the entire left arm. The acute computed tomography (CT) showed relative hypodensity in the intracranial segment of left vertebral artery (VA) that was not present in historical images, pointing to the possible lack of flow. The site of occlusion was confirmed by magnetic resonance imaging (MRI) that showed susceptibility effect in the affected artery. By means of historical native CT comparison the site of VA thrombosis was correctly predicted. Local atherosclerotic thrombosis of the VA could be relatively hypodense on native CT and still have positive susceptibility weighted imaging (SWI) sign.


Greed: What Is It Good for?
What is greed good for? Greed is ubiquitous, suggesting that it must have some benefits, but it is also often condemned. In a representative sample of the Dutch population (N = 2,367, 51.3% female, Mage = 54.06, SD = 17.90), we examined two questions. First, inspired by Eriksson et al., we studied whether greedy people generate more personal and household income (economic outcomes), have more sexual partners, longer relationships, and more offspring (evolutionary outcomes), and are more satisfied in life (psychological outcomes). We found that greedy individuals had higher economic outcomes, mixed evolutionary outcomes, and lower psychological outcomes. Second, we compared greed and self-interest. We found that they differed in terms of economic outcomes, and partly in terms of evolutionary outcomes, but that they were similar in terms of psychological outcomes. This research provides insights into what greed is and does. Directions for further research are discussed.


Characterization of a Novel Polysaccharide-Iron(III) Complex and Its Anti-Anemia and Nonspecific Immune Regulating Activities.
Dioscorea opposita Thunb is the famous food and traditional medicine in China and it was rich in polysaccharides. Polysaccharides of Dioscorea Opposita Thunb possess immunoregulatory activity, free radical scavenging activity and anti-diabetic activity. A novel polysaccharide- iron(III) complex (CYPIC) was synthesized by using crude polysaccharide extracted from Dioscorea opposita Thunb. The component, structure, morphology and molecular weights of CYPIC were analysed, and the anti-anemia, acute toxicity and nonspecific immune regulating activities of CYPIC were assayed. The results showed that CYPIC could increase red blood cell count (RBC), hemoglobin (Hb), hematocrit (HCT), thymus and spleen index of mice with iron deficiency anemia (IDA). Although the structure and deeper mechanisms of CYPIC should be further studied, CYPIC has the potential to be used as an iron supplement for the treatment of iron deficiency anemia. The large scale industrial production was suggested due to the simple preparation processing of CYPIC.


Topography of the northern hemisphere of Mars from the Mars Orbiter Laser Altimeter.
The first 18 tracks of laser altimeter data across the northern hemisphere of Mars from the Mars Global Surveyor spacecraft show that the planet at latitudes north of 50 degrees is exceptionally flat; slopes and surface roughness increase toward the equator. The polar layered terrain appears to be a thick ice-rich formation with a non-equilibrium planform indicative of ablation near the periphery. Slope relations suggest that the northern Tharsis province was uplifted in the past. A profile across Ares Vallis channel suggests that the discharge through the channel was much greater than previously estimated. The martian atmosphere shows significant 1-micrometer atmospheric opacities, particularly in low-lying areas such as Valles Marineris.


Obesity, a serious etiologic factor for male subfertility in modern society.
Obesity, defined as excessive accumulation of fat in adipose tissue, is a metabolic disorder resulting from behavioral, environmental and heritable causes. Obesity increases the risks of hypertension, diabetes, cardiovascular disease, sleep apnea, respiratory problems, osteoarthritis and cancer. Meanwhile, the negative impact of obesity on male reproduction is gradually recognized. According to the clinical investigations and animal experiments, obesity is correlated with reductions in sperm concentration and motility, increase in sperm DNA damage and changes in reproductive hormones. Several mechanisms can elucidate the effects of obesity on sperm functions and male subfertility, i.e., the excessive conversion of androgens into estrogens in redundant adipose tissue causes sexual hormone imbalance, subsequently resulting in hypogonadism. Secondly, adipokines produced by adipose tissue induce severe inflammation and oxidative stress in male reproductive tract, directly impairing testicular and epididymal tissues. Moreover, increased scrotal adiposity leads to increase gonadal heat, continuously hurting spermatogenesis. Therefore, obesity alters the systematic and regional environment crucial for spermatogenesis in testis and sperm maturation in epididymis, and finally results in poor sperm quality including decreased sperm motility, abnormal sperm morphology and acrosome reaction, changed membrane lipids and increased DNA damage. Furthermore, recent studies indicate that epigenetic changes may be a consequence of increased adiposity. A major effort to identify epigenetic determinants of obesity revealed that sperm DNA methylation and non-coding RNA modification are associated with BMI changes and proposed to inherit metabolic comorbidities across generations. This review will explain how obesity-related changes in males to influence sperm function and male fertility as well.


Application of combined median-averaging filters to scintigraphic image processing.
Statistical and deterministic properties of median filters are briefly discussed and their inherent advantages as a prospective tool in scintigraphic data processing are pointed out. The ability of median filters of suppressing impulse noise while the edge-like features of an image are preserved, is demonstrated on phantom data. The residual high-frequency noise remaining after median filtering can be subsequently reduced by standard smoothing procedures. A simple algorithm, made up of the superposition of a median and an averaging filter, is presented and shown to be a promising candidate in the quest for fast and easy-to-implement processing routine.


Multiplex Cellular Communities in Multi-Gigapixel Colorectal Cancer Histology Images for Tissue Phenotyping.
In computational pathology, automated tissue phenotyping in cancer histology images is a fundamental tool for profiling tumor microenvironments. Current tissue phenotyping methods use features derived from image patches which may not carry biological significance. In this work, we propose a novel multiplex cellular community-based algorithm for tissue phenotyping integrating cell-level features within a graph-based hierarchical framework. We demonstrate that such integration offers better performance compared to prior deep learning and texture-based methods as well as to cellular community based methods using uniplex networks. To this end, we construct celllevel graphs using texture, alpha diversity and multi-resolution deep features. Using these graphs, we compute cellular connectivity features which are then employed for the construction of a patch-level multiplex network. Over this network, we compute multiplex cellular communities using a novel objective function. The proposed objective function computes a low-dimensional subspace from each cellular network and subsequently seeks a common low-dimensional subspace using the Grassmann manifold. We evaluate our proposed algorithm on three publicly available datasets for tissue phenotyping, demonstrating a significant improvement over existing state-of-the-art methods.


[Distribution of intravenously injected enzymes of heterologous, homologous and autologous origin. Distribution and transport of cell enzymes within the extracellular space. III (author's transl)].
The disappearance rates of intravenously injected enzymes of heterologous, homologous and autologous origin were determined in rats. Within four hours after administration, the activities show an exponential decline, that is either mono- or biphasic. The constant of the exponential function is a measure of the capillary permeability. In the case of biphasic disappearance this holds true only for the first slope, whereas the second one represents the elimination of active enzyme molecules from the extracellular space. If the decline in enzyme activity is monophasic the elimination of those enzymes from the interstitial space is limited by the permeability of the capillary membrane. Enzymes of homologous and autologous origin (extracts of liver or muscle) show a close correlation between their molecular weights and their rates of distribution within the extracellular compartment. For heterologous enzymes (crystallized) such a correlation could not be found. Possible causes for these differences in distribution are discussed. Heterologous and/or crystallized enzymes seem not to be suited for studies on the distribution of cell enzymes within the extracellular space. After enzymes are released from injured cells they undergo the processes of distribution, transport and elimination which are superimposed. The effects of the distribution and transport of enzymes on the results of clinical studies on enzyme elimination are discussed. It seems questionable at this point to assume that from the elimination rate of enzymes and their actual plasma activity one can account for the amount of enzymes originally released from injured cells.


Prevalence of Anaplasma marginale in different tick species from Ngorongoro Crater, Tanzania.
In 2001, Ngorongoro Crater was infested with high density of ticks on grassland, livestock and wildlife which was also associated with high mortality. Adult ticks were collected, identified, processed for nucleic acids extraction and a molecular analysis was performed to determine the range of tick species harboring Anaplasma marginale. The real-time PCR was used in the amplification of rickettsia DNA in tick pools (n=527) from 11 identified tick species. Six tick species were detected with A. marginale DNA including Amblyomma gemma, Rhipicephalus appendiculatus, R. compositus, R.decoloratus, R. praetextatus and R. pulchellus. The detection rate in each tick species was 3%, 0.7%, 2%, 13%, 1.8%, and 6.2%, respectively. Five of the positive tick species excluding R.decoloratus have previously not been described to transmit A. marginale. High diversity of tick species detected with A. marginale in Ngorongoro Crater is likely to increase a risk to susceptible animals of contracting the infection.


[Effect of alcoholic intoxication on various indicators of the functional state of the acoustic analyzer].
The clinico-audiometric studies have shown that under the influence of acute alcoholic intoxication the normal examinees manifest dysfunction of the acoustic analyzer, whose intensity depends on the time elapsed since the moment of alcohol intake. In patients with alcoholism, chronic alcoholic intoxication results in the formation of steady dysfunction in the form of treble hypoacusis which correlates both with the stage and other clinico-dynamic parameters of the disease. In patients in the initial stage of acute alcoholic hallucinosis, acoustic analyzer function is characterized by marked disorders of audition in its central parts, which as acute alcoholic hallucinosis develops, tend towards aggravation.


Heavy alcohol consumption among marginalised African refugee young people in Melbourne, Australia: motivations for drinking, experiences of alcohol-related problems and strategies for managing drinking.
Little is known about substance use among resettled refugee populations. This study aimed to describe motivations for drinking, experiences of alcohol-related problems and strategies for managing drinking among marginalised African refugee young people in Melbourne, Australia. Face-to-face interviews were conducted with 16 self-identified African refugees recruited from street-based settings in 2012-2013. Interview transcripts were analysed inductively to identify key themes. Participants gathered in public spaces to consume alcohol on a daily or near-daily basis. Three key motivations for heavy alcohol consumption were identified: drinking to cope with trauma, drinking to cope with boredom and frustration and drinking as a social experience. Participants reported experiencing a range of health and social consequences of their alcohol consumption, including breakdown of family relationships, homelessness, interpersonal violence, contact with the justice system and poor health. Strategies for managing drinking included attending counselling or residential detoxification programmes, self-imposed physical isolation and intentionally committing crime in order to be incarcerated. These findings highlight the urgent need for targeted harm reduction education for African young people who consume alcohol. Given the importance of social relationships within this community, use of peer-based strategies are likely to be particularly effective. Development and implementation of programmes that address the underlying health and psychosocial causes and consequences of heavy alcohol use are also needed.


Subjective and objective binge eating in relation to eating disorder symptomatology, depressive symptoms, and self-esteem among treatment-seeking adolescents with bulimia nervosa.
This study investigated the importance of the distinction between objective (OBE) and subjective binge eating (SBE) among 80 treatment-seeking adolescents with bulimia nervosa. We explored relationships among OBEs, SBEs, eating disorder (ED) symptomatology, depression, and self-esteem using two approaches. Group comparisons showed that OBE and SBE groups did not differ on ED symptoms or self-esteem; however, the SBE group had significantly greater depression. Examining continuous variables, OBEs (not SBEs) accounted for significant unique variance in global ED pathology, vomiting, and self-esteem. SBEs (not OBEs) accounted for significant unique variance in restraint and depression. Both OBEs and SBEs accounted for significant unique variance in eating concern; neither accounted for unique variance in weight/shape concern, laxative use, diuretic use, or driven exercise. Loss of control, rather than amount of food, may be most important in defining binge eating. Additionally, OBEs may indicate broader ED pathology, while SBEs may indicate restrictive/depressive symptomatology.


Reassembly of the peptidyltransferase centre of larger subparticles of rabbit reticulocyte ribosomes from a core-particle and split-protein fraction.
We report the reconstruction, from a core-particle and split-protein fraction, of the larger subribosomal particle of rabbit reticulocytes. The reassembled particle was active in polyphenylalanine synthesis and in the puromycin reaction. The core-particles and split-protein fractions were obtained by treatment of the larger subparticle with salt solutions containing NH4+ and Mg2+ in the molar ratio 40:1 over the range 2.25-2.75 M-NH4Cl/56-69mM-MgCl2 at 0 degrees C. This treatment led to the loss of about eight proteins (approx. 17% of the protein moiety), which were found wholly or largely in the split-protein fraction as shown by two-dimensional gel electrophoresis. The core particle retained 5S rRNA and had much decreased (no more than 10% of control) ability to function in the puromycin reaction or in poly (U)-directed polyphenylalanine synthesis. Activity was recovered when the recombined core-particle and split-protein fractions were dialysed overnight at 4 degrees C against 0.3M-NH4Cl/15mM-MgCl2/1mM-dithiothreitol/15% (v/v) glycerol/20mM-Tris/HCl, pH 7.6, and then heated for 1 h at 37 degreesEES C. The recovery was 40-80% of the original activity. Raising the concentration of MgCL2 to 300 mM in 2.5 M-NH4CL led to the removal of seven rather than eight proteins, and the core particle remained active in the puromycin reaction. We infer that the protein retained by raising the concentration of Mg2+ is an essential component of the peptidyltransferase centre of the ribosome.


The molecularly imprinted polymer essentials: curation of anticancer, ophthalmic, and projected gene therapy drug delivery systems.
The development of polymeric materials as drug delivery systems has advanced from systems that rely on classical passive targeting to carriers that can sustain the precisely controlled release of payloads upon physicochemical triggers in desired microenvironment. Molecularly imprinted polymers (MIP), materials designed to capture specific molecules based on their molecular shape and charge distribution, are attractive candidates for fulfilling these purposes. In particular, drug-imprinted polymers coupled with active targeting mechanisms have been explored as potential drug delivery systems. In this review, we have curated important recent efforts in the development of drug-imprinted polymers in a variety of clinical applications, especially oncology and ophthalmology. MIP possesses properties that may complement the traditional delivery systems of these two disciplines, such as passive enhanced permeability and retention effect (EPR) in cancer tumors, and passive drug diffusion in delivering ophthalmic therapeutics. Furthermore, the prospects of MIP integration with the emerging gene therapies will be discussed.


Crystal structure of phospholipase A2 in complex with 1-naphthaleneacetic acid.
Phospholipase A2 (PLA2 ) is one of the rate limiting enzymes involved in the production of arachidonic acid, a potent inflammatory mediator. PLA2 is widely distributed all over the animal kingdom. It is also seen in inflammatory exudation and venoms of different organisms. The studies demonstrated that PLA2 inhibitors have broad spectrum activities that they can either be used against inflammation or envenomation. In this study, the inhibitory activity of 1-napthaleneacetic acid (NAA) against porcine pancreatic PLA2 has been explained through isothermal titration calorimetry and enzyme kinetics studies. The atomic level of interactions of NAA with PLA2 was also studied using X-ray crystallography. Apart from these findings, the theoretical binding affinities and mode of interactions of two naphthalene-based NSAIDs such as naproxen (NAP) and nabumetone (NAB) were studied through molecular modeling. The studies proved that the selected ligands are binding at the doorway of the active site cleft and hindering the substrate entry to the active site. The study brings out a potential scaffold for the designing of broad spectrum PLA2 inhibitors which can be used for inflammation or envenomation. © 2018 IUBMB Life, 70(10):995-1001, 2018.


Activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase does not respond to ubiquinone uptake in cultured cells.
The cellular content of ubiquinone was increased approx. 10-fold by incubation of neuroblastoma cells in medium containing exogenous ubiquinone. Under these conditions the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, assayed after preincubation of cell homogenates with or without fluoride, was not suppressed. Similar results were obtained with human skin fibroblast cultures to which free ubiquinone or low-density lipoprotein-ubiquinone complex had been added. Consistent with the lack of suppression of HMG-CoA reductase, the rate of incorporation of [1-14C] acetate into ubiquinone was not diminished in cells exposed to exogenous ubiquinone. Measurements of [3H]mevalonolactone incorporation into cellular ubiquinones indicated that exogenous ubiquinone did not affect ubiquinone synthesis at a point in the pathway distal to the formation of mevalonate. The results suggest that cultured mammalian cells lack an end-product 'feedback' mechanism for regulation of HMG-CoA reductase in response to ubiquinone uptake.


Development in situ for gratings recorded in photoresist.
A technique for developing recording gratings in situ in Photoresist Shipley S-1822 is described. The developing process is accomplished by use of a spray without removing the sample from the optical setup. The results for the diffraction efficiency show that there is not a large difference between gratings achieved with the traditional wet development process and those obtained with the in situ developing technique. The potential of this in situ developing technique is shown with a moiré interferometric experimental setup used for displacement showing.


AXIN-AMPK signaling: Implications for healthy aging.
The energy sensor AMP kinase (AMPK) and the master scaffolding protein, AXIN, are two major regulators of biological processes in metazoans. AXIN-dependent regulation of AMPK activation plays a crucial role in maintaining metabolic homeostasis during glucose-deprived and energy-stressed conditions. The two proteins are also required for muscle function. While studies have refined our knowledge of various cellular events that promote the formation of AXIN-AMPK complexes and the involvement of effector proteins, more work is needed to understand precisely how the pathway is regulated in response to various forms of stress. In this review, we discuss recent data on AXIN and AMPK interaction and its role in physiological changes leading to improved muscle health and an extension of lifespan. We argue that AXIN-AMPK signaling plays an essential role in maintaining muscle function and manipulating the pathway in a tissue-specific manner could delay muscle aging. Therefore, research on understanding the factors that regulate AXIN-AMPK signaling holds the potential for developing novel therapeutics to slow down or revert the age-associated decline in muscle function, thereby extending the healthspan of animals.


Neurohumoral features of myocardial stunning due to sudden emotional stress.
Reversible left ventricular dysfunction precipitated by emotional stress has been reported, but the mechanism remains unknown. We evaluated 19 patients who presented with left ventricular dysfunction after sudden emotional stress. All patients underwent coronary angiography and serial echocardiography; five underwent endomyocardial biopsy. Plasma catecholamine levels in 13 patients with stress-related myocardial dysfunction were compared with those in 7 patients with Killip class III myocardial infarction. The median age of patients with stress-induced cardiomyopathy was 63 years, and 95 percent were women. Clinical presentations included chest pain, pulmonary edema, and cardiogenic shock. Diffuse T-wave inversion and a prolonged QT interval occurred in most patients. Seventeen patients had mildly elevated serum troponin I levels, but only 1 of 19 had angiographic evidence of clinically significant coronary disease. Severe left ventricular dysfunction was present on admission (median ejection fraction, 0.20; interquartile range, 0.15 to 0.30) and rapidly resolved in all patients (ejection fraction at two to four weeks, 0.60; interquartile range, 0.55 to 0.65; P<0.001). Endomyocardial biopsy showed mononuclear infiltrates and contraction-band necrosis. Plasma catecholamine levels at presentation were markedly higher among patients with stress-induced cardiomyopathy than among those with Killip class III myocardial infarction (median epinephrine level, 1264 pg per milliliter [interquartile range, 916 to 1374] vs. 376 pg per milliliter [interquartile range, 275 to 476]; norepinephrine level, 2284 pg per milliliter [interquartile range, 1709 to 2910] vs. 1100 pg per milliliter [interquartile range, 914 to 1320]; and dopamine level, 111 pg per milliliter [interquartile range, 106 to 146] vs. 61 pg per milliliter [interquartile range, 46 to 77]; P<0.005 for all comparisons). Emotional stress can precipitate severe, reversible left ventricular dysfunction in patients without coronary disease. Exaggerated sympathetic stimulation is probably central to the cause of this syndrome.


Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts.
To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer's Disease (AD) Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181). We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL). FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181. The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.


HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts.
Proinflammatory cytokines and eicosanoids are central players in intestinal inflammation. IL-1, a key cytokine associated with intestinal mucosal inflammation, induces COX-2 expression in human colonic myofibroblasts (CMF) and increased prostaglandin E(2) secretion is associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). We have previously demonstrated that IL-1alpha-induced cyclooxygenase-2 (COX-2) expression is the result of NF-kappaB- and ERK-mediated transcription, as well as COX-2 message stabilization, which depends on p38, MAPKAPK-2 (MK-2) and human antigen R (HuR) RNA binding protein activation. Lipoxygenase (LOX)-derived hydroxyeicosatetraenoic acids (HETEs) are elevated in IBD and colonic adenomas and "cross talk" has been observed between the COX and LOX pathways. Since COX-2 expression is primarily in CMFs in colonic adenomas, we examined the impact of LOX metabolites, particularly HETEs, on IL-1alpha-induced COX-2 expression in human CMFs. Although 5(S)-, 12(R)-, and 15(S)-HETEs alone had little to no effect on COX-2 expression, they enhanced IL-1-mediated COX-2 expression 3.6 +/- 0.5-fold. Studies utilizing heterogeneous nuclear RNA amplification and 5,6-dichloro-beta-d-ribofuranosylbenzimidazole treatment were undertaken to measure COX-2 transcription and message stabilization, respectively. We found that HETEs enhanced IL-1-induced COX-2 mRNA levels in CMF as the result of increased p38, MK-2, and HuR activity, increasing message stability greater than that observed with IL-1 alone. Thus HETEs can act synergistically with IL-1alpha to induce COX-2 expression in human CMFs. HETEs may play a role in both colonic inflammation and in increasing the risk of CRC in IBD independently and via induction of COX-2-mediated prostaglandin secretion.


Accurate thickness measurement of graphene.
Graphene has emerged as a material with a vast variety of applications. The electronic, optical and mechanical properties of graphene are strongly influenced by the number of layers present in a sample. As a result, the dimensional characterization of graphene films is crucial, especially with the continued development of new synthesis methods and applications. A number of techniques exist to determine the thickness of graphene films including optical contrast, Raman scattering and scanning probe microscopy techniques. Atomic force microscopy (AFM), in particular, is used extensively since it provides three-dimensional images that enable the measurement of the lateral dimensions of graphene films as well as the thickness, and by extension the number of layers present. However, in the literature AFM has proven to be inaccurate with a wide range of measured values for single layer graphene thickness reported (between 0.4 and 1.7 nm). This discrepancy has been attributed to tip-surface interactions, image feedback settings and surface chemistry. In this work, we use standard and carbon nanotube modified AFM probes and a relatively new AFM imaging mode known as PeakForce tapping mode to establish a protocol that will allow users to accurately determine the thickness of graphene films. In particular, the error in measuring the first layer is reduced from 0.1-1.3 nm to 0.1-0.3 nm. Furthermore, in the process we establish that the graphene-substrate adsorbate layer and imaging force, in particular the pressure the tip exerts on the surface, are crucial components in the accurate measurement of graphene using AFM. These findings can be applied to other 2D materials.


Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women.
Epidemiologic evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase plays an important role in energy homeostasis and inhibits the actions of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the cyclic AMP-responsive element binding protein-dependent regulation of aromatase is a determinant of breast tumor formation through local production of estrogens. The present work aimed to examine the effect of adipokines on aromatase expression and identify additional mechanisms by which prostaglandin E(2) causes increased aromatase expression in human breast adipose stromal cells. Treatment of human adipose stromal cells with forskolin and phorbol 12-myristate 13-acetate (PMA), to mimic prostaglandin E(2), resulted in nuclear translocation of CRTC2. Aromatase promoter II (PII) activity assays showed that CRTC2 in addition to forskolin/PMA treatment significantly increased PII-induced activity. CRTC2 binding to PII was examined by chromatin immunoprecipitation, and forskolin/PMA treatment was associated with increased binding to PII. Treatment of human adipose stromal cells with leptin significantly up-regulated aromatase expression associated with nuclear translocation of CRTC2 and increased binding of CRTC2 to PII. Adiponectin treatment significantly decreased forskolin/PMA-stimulated aromatase expression, consistent with the decreased nuclear translocation of CRTC2 and the decreased binding of CRTC2 to PII. The expression and activity of the AMP-activated protein kinase LKB1 was examined and found to be significantly decreased following either forskolin/PMA or leptin treatment. In contrast, adiponectin significantly increased LKB1 expression and activity. In conclusion, the regulation of aromatase by CRTC2, in response to the altered hormonal milieu associated with menopause and obesity, provides a critical link between obesity and breast cancer.


Isolation of DNA from saliva of betel quid chewers using treated cards.
Betel quid (BQ) chewing, a common tradition in tropical areas, often poses a problem during collection and DNA analysis of buccal samples from many indigenous communities for population genetic studies and in forensic analysis of chewed BQ residues. This study evaluated the use of FTA card, a chemically treated filter paper, in collecting buccal samples from long-term BQ users and subsequent PCR-based analysis using nine STR markers. A low overall success rate of amplification was observed in the samples extracted using a standard organic extraction procedure (7%) as compared with those prepared using the FTA card (89%). The presence of inhibitors in liquid DNA samples was verified when control DNA failed to amplify in the presence of an equal volume of liquid BQ samples. The use of the FTA card is more practical during field sampling than handling tubes containing buccal swabs.


[Use of Meropenem in preterm newborns. Survey of the literature and case series].
The aim of this paper was to evaluate usefulness and safety of Meropenem in severe infections in neonatal intensive care unit (NICU) patients. New broad spectrum carbapenem class of -lactam antibiotics has been investigated for the treatment of a wide range of infections, including nosocomial infections with cephalosporin-resistant pathogens, an emergent problem in NICU, and meningitis. Meropenem represents the first cabapenem-class that has received Food and Drug Administration (FDA) approval for use in children 3 months of age and older. The pharmacokinetics of Meropenem has been well studied in preterm neonates. We report the use of Meropenem in 26 neonates with median gestational age (GA) of 27 weeks (25-32) and median birth weight of 940 g (510-1900), with severe infections due to Gram-negative or Gram-positive organisms, from 2001 to 2004. The median postnatal age was 21 days (4-75). Meropenem was administrated intravenously in 30 min at dosage of 20 mg/kg every 12 h (every 8 h in Pseudomonas Aeruginosa infections). In all cases Meropenem has been used as second choice. No adverse effects (eosinophilia, trombocytosis or thrombocytopenia, increase in liver enzyme, increase in creatinine, diarrhea, vomiting and seizures) were observed. Clinical and bacterial response was ontaine in all cases but one. This report suggests that Meropenem may be a useful and safe antimicrobial agent in neonatal infections caused by resistant organisms and in meningitis. Further studies are needed to confirm these results.


Diazo Compounds as Highly Tunable Reactants in 1,3-Dipolar Cycloaddition Reactions with Cycloalkynes().
Diazo compounds, which can be accessed directly from azides by deimidogenation, are shown to be extremely versatile dipoles in 1,3-dipolar cycloaddition reactions with a cyclooctyne. The reactivity of a diazo compound can be much greater or much less than its azide analog, and is enhanced markedly in polar-protic solvents. These reactivities are predictable from frontier molecular orbital energies. The most reactive diazo compound exhibited the highest known second-order rate constant to date for a dipolar cycloaddition with a cycloalkyne. These data provide a new modality for effecting chemoselective reactions in a biological context.


Nonlinear phase noise in coherent optical OFDM transmission systems.
We derive an analytical formula to estimate the variance of nonlinear phase noise caused by the interaction of amplified spontaneous emission (ASE) noise with fiber nonlinearity such as self-phase modulation (SPM), cross-phase modulation (XPM), and four-wave mixing (FWM) in coherent orthogonal frequency division multiplexing (OFDM) systems. The analytical results agree very well with numerical simulations, enabling the study of the nonlinear penalties in long-haul coherent OFDM systems without extensive numerical simulation. Our results show that the nonlinear phase noise induced by FWM is significantly larger than that induced by SPM and XPM, which is in contrast to traditional WDM systems where ASE-FWM interaction is negligible in quasi-linear systems. We also found that fiber chromatic dispersion can reduce the nonlinear phase noise. The variance of the total phase noise increases linearly with the bit rate, and does not depend significantly on the number of subcarriers for systems with moderate fiber chromatic dispersion.


Bangladesh's digital health journey: reflections on a decade of quiet revolution.
Bangladesh has made remarkable progress in digital health in recent years. Through one of the world's largest deployments to date of the open-source District Health Information Software 2 (DHIS2), the country now has a national public sector health data warehouse. Information from previously fragmented data systems is now unified in a common data repository, enabling data exchange for health information systems and decision-making. Work is ongoing to create lifetime electronic health records for all citizens that can be transferred between health facilities. Extensive customization of open-source software has laid the foundations for a national digital networking system. Initiatives have focused on producing digital solutions to aid priorities such as strengthening the health system as a whole as well as supporting specific technical interventions, for example improving the civil registration and vital statistics system. Digital solutions have also supported the Bangladesh health workforce strategy through a set of registries that electronically captures and maintains human resource information for the entire public health sector, including monitoring staff attendance through the use of low-cost biometric fingerprint time-attendance machines. Citizens are encouraged to engage in shaping health services via a web-based complaints and suggestions system, and a new system to raise health awareness via public digital displays has started in Dhaka. Strong support at the highest political level has been critical to the success of efforts to introduce these innovations. The endeavour has also generated a cadre of enthusiastic eHealth proponents, who are focused on further strengthening and expanding the existing systems and on harnessing the vast amount of information amassed at the central data repository through big data analysis, artificial intelligence and machine learning.


Reconstruction of vocal tract geometries from biomechanical simulations.
Medical imaging techniques are usually utilized to acquire the vocal tract geometry in 3D, which may then be used, eg, for acoustic/fluid simulation. As an alternative, such a geometry may also be acquired from a biomechanical simulation, which allows to alter the anatomy and/or articulation to study a variety of configurations. In a biomechanical model, each physical structure is described by its geometry and its properties (such as mass, stiffness, and muscles). In such a model, the vocal tract itself does not have an explicit representation, since it is a cavity rather than a physical structure. Instead, its geometry is defined implicitly by all the structures surrounding the cavity, and such an implicit representation may not be suitable for visualization or for acoustic/fluid simulation. In this work, we propose a method to reconstruct the vocal tract geometry at each time step during the biomechanical simulation. Complexity of the problem, which arises from model alignment artifacts, is addressed by the proposed method. In addition to the main cavity, other small cavities, including the piriform fossa, the sublingual cavity, and the interdental space, can be reconstructed. These cavities may appear or disappear by the position of the larynx, the mandible, and the tongue. To illustrate our method, various static and temporal geometries of the vocal tract are reconstructed and visualized. As a proof of concept, the reconstructed geometries of three cardinal vowels are further used in an acoustic simulation, and the corresponding transfer functions are derived.


Extraction of skin lesions from non-dermoscopic images for surgical excision of melanoma.
Computerized prescreening of suspicious moles and lesions for malignancy is of great importance for assessing the need and the priority of the removal surgery. Detection can be done by images captured by standard cameras, which are more preferable due to low cost and availability. One important step in computerized evaluation is accurate detection of lesion's region, i.e., segmentation of an image into two regions as lesion and normal skin. In this paper, a new method based on deep neural networks is proposed for accurate extraction of a lesion region. The input image is preprocessed, and then, its patches are fed to a convolutional neural network. Local texture and global structure of the patches are processed in order to assign pixels to lesion or normal classes. A method for effective selection of training patches is proposed for more accurate detection of a lesion's border. Our results indicate that the proposed method could reach the accuracy of 98.7% and the sensitivity of 95.2% in segmentation of lesion regions over the dataset of clinical images. The experimental results of qualitative and quantitative evaluations demonstrate that our method can outperform other state-of-the-art algorithms exist in the literature.


Visual Abstract of "How Should We Approach Body Size Diversity in Clinical Trials?"
This visual abstract is based on an article from the July 2023 issue of the journal.


Encapsulation of Caenorhabditis elegans in Water-in-Water Microdroplets to Study the Worm Viability: Alternative Avenue to Manipulate Microdroplet Environment.
Due to the great biocompatibility of the aqueous two phase system (ATPS), biological cells have been widely encapsulated in ATPS microdroplets (diameter < 50 μm). However, the immobilization of relatively large multicellular organisms such as Caenorhabditis elegans in ATPS droplets remains challenging as the spontaneous generation of droplets greater than 200 μm is difficult without external perturbations. In this study, we utilize a microneedle-assisted coflow microfludic channel to passively form ATPS microdroplets larger than 200 μm and successfully entrap C. elegans in the microdroplets. We monitor the worm viability and its temporal stroke frequency up to 6 h. We study the effects of dextran (DEX)-to-polyethylene glycol (PEG) flow ratios and worm concentration on the droplet diameter, worm encapsulation efficiency, and the number of droplets containing individual worms. Larger ATPS microdroplets (>200 μm) form in the ranges of capillary number (Ca) between 0.020 to 0.20 and Weber number (We) between 10-5 and 10-3. An ATPS with the encapsulation ability and biocompatibility can offer an alternative immobilization tool for multicellular organisms to existing platforms such as water/oil droplets.


A Multivariate Method for Estimating and comparing whole brain functional connectomes from fMRI and PET data.
Positron emission tomography (PET) and magnetic resonance imaging (MRI) are two commonly used imaging techniques to visualize brain function. The use of inter-network covariation (a functional connectome) is a widely used approach to infer links among different brain networks. While whole brain resting fMRI connectomes are widely used, PET data has mostly been analyzed using a few regions of interest. There has been much less work estimating PET spatial networks and almost no work on their connectivity (covariation) in the context of a whole brain data-driven connectome, nor have there been direct comparisons between whole brain PET and fMRI connectomes. Here we present an approach to leverage spatially constrained ICA to compute an estimate of the PET connectome. Results reveal highly modularized connectome patterns that are complementary to that identified from resting fMRI. Similarly, we were able to identify comparable resting networks from a PiB PET scan that can be directly compared to networks in rest fMRI data and results reveal similar, but not identical, network spatial patterns, with the PET networks being slightly smoother and, in some cases, showing variations in subnodes. The resulting networks, decomposed into spatial maps and subject expressions (loading parameters) linked to resting fMRI provide a new way to evaluate the complementary information in PET and fMRI and open up new possibilities for biomarker development.Clinical Relevance-This study analyzes the whole-brain PET and fMRI connectomes, capturing the complementary information from both imaging modalities, thereby introducing a new scope for biomarker development.


Reshaping of triangular silver nanoplates by a non-halide etchant and its application in melamine sensing.
Although triangular silver (Ag) nanoplates are intrinsically unstable, this characteristic has been taken advantage of in the development of a novel sensing platform. However, most of these applications have relied on halide ions as etchants. In the current work, we used sodium 4-vinylbenzenesulfonate (Na-VBS) as a new powerful etchant of triangular silver (Ag) nanoplates. When aged with Na-VBS at room temperature, Na-VBS etched Ag nanoplates nearly as powerfully as halides did, and these nanoplates rapidly transformed into oblate nanospheroids. This shape evolution permitted tuning of the corresponding localized surface plasmon resonance (LSPR) features of the Ag nanostructures. Interestingly, passivation of the Ag nanoplate surface with melamine was shown to protect the nanoplates from Na-VBS-induced etching. The rate of change of the color and spectral features of the Ag nanoplate solution exposed to Na-VBS was found to be strongly correlated with the concentration of melamine in the solution. This association allowed us to apply this system to the development of a novel platform for sensing melamine.


Cooperative dynamics of proteins unraveled by network models.
Recent years have seen a significant increase in the number of computational studies that adopted network models for investigating biomolecular systems dynamics and interactions. In particular, elastic network models have proven useful in elucidating the dynamics and allosteric signaling mechanisms of proteins and their complexes. Here we present an overview of two most widely used elastic network models, the Gaussian Network Model (GNM) and Anisotropic Network Model (ANM). We illustrate their use in (i) explaining the anisotropic response of proteins observed in external pulling experiments, (ii) identifying residues that possess high allosteric potentials, and demonstrating in this context the propensity of catalytic sites and metal-binding sites for enabling efficient signal transduction, and (iii) assisting in structure refinement, molecular replacement and comparative modeling of ligand-bound forms via efficient sampling of energetically favored conformers.


A statistical approach for array CGH data analysis.
Microarray-CGH experiments are used to detect and map chromosomal imbalances, by hybridizing targets of genomic DNA from a test and a reference sample to sequences immobilized on a slide. These probes are genomic DNA sequences (BACs) that are mapped on the genome. The signal has a spatial coherence that can be handled by specific statistical tools. Segmentation methods seem to be a natural framework for this purpose. A CGH profile can be viewed as a succession of segments that represent homogeneous regions in the genome whose BACs share the same relative copy number on average. We model a CGH profile by a random Gaussian process whose distribution parameters are affected by abrupt changes at unknown coordinates. Two major problems arise: to determine which parameters are affected by the abrupt changes (the mean and the variance, or the mean only), and the selection of the number of segments in the profile. We demonstrate that existing methods for estimating the number of segments are not well adapted in the case of array CGH data, and we propose an adaptive criterion that detects previously mapped chromosomal aberrations. The performances of this method are discussed based on simulations and publicly available data sets. Then we discuss the choice of modeling for array CGH data and show that the model with a homogeneous variance is adapted to this context. Array CGH data analysis is an emerging field that needs appropriate statistical tools. Process segmentation and model selection provide a theoretical framework that allows precise biological interpretations. Adaptive methods for model selection give promising results concerning the estimation of the number of altered regions on the genome.


Nanomaterials and Nanotechnology-Associated Innovations against Viral Infections with a Focus on Coronaviruses.
Viral infections have recently emerged not only as a health threat to people but rapidly became the cause of universal fatality on a large scale. Nanomaterials comprising functionalized nanoparticles (NPs) and quantum dots and nanotechnology-associated innovative detection methods, vaccine design, and nanodrug production have shown immense promise for interfacing with pathogenic viruses and restricting their entrance into cells. These viruses have been scrutinized using rapid diagnostic detection and therapeutic interventional options against the caused infections including vaccine development for prevention and control. Coronaviruses, namely SARS-CoV, MERS-CoV, and SARS-CoV-2, have endangered human life, and the COVID-19 (caused by SARS-CoV-2) outbreak has become a perilous challenge to public health globally with huge accompanying morbidity rates. Thus, it is imperative to expedite the drug and vaccine development efforts that would help mitigate this pandemic. In this regard, smart and innovative nano-based technologies and approaches encompassing applications of green nanomedicine, bio-inspired methods, multifunctional bioengineered nanomaterials, and biomimetic drug delivery systems/carriers can help resolve the critical issues regarding detection, prevention, and treatment of viral infections. This perspective review expounds recent nanoscience advancements for the detection and treatment of viral infections with focus on coronaviruses and encompasses nano-based formulations and delivery platforms, nanovaccines, and promising methods for clinical diagnosis, especially regarding SARS-CoV-2.


Unique {H(SiR(3))(2)}, (H(2)SiR(3)), H(HSiR(3)), and (H(2))SiR(3) ligand sets supported by the {Fe(Cp)(L)} platform (L=CO, PR(3)).
This work deals with the type and incidence of nonclassical Si--H and H--H interactions in a family of silylhydride complexes [Fe(Cp)(OC)(SiMe(n)Cl(3-n))H(X)] (X=SiMe(n)Cl(3-n), H, Me, n=0-3) and [Fe(Cp)(Me(3)P)(SiMe(n)Cl(3-n))(2)H] (n=0-3). DFT calculations complemented by atom-in-molecule analysis and calculations of NMR hydrogen-silicon coupling constants revealed a surprising diversity of nonclassical Si--H and H--H interligand interactions. The compounds [Fe(Cp)(L)(SiMe(n)Cl(3-n))(2)H] (L=CO, PMe(3); n=0-3) exhibit an unusual distortion from the ideal piano-stool geometry in that the silyl ligands are strongly shifted toward the hydride and there is a strong trend towards flattening of the {FeSi(2)H} fragment. Such a distortion leads to short Si--H contacts (range 2.030-2.075 A) and large Mayer bond orders. A novel feature of these extended Si--H interactions is that they are rather insensitive towards the substitution at the silicon atom and the orientation of the silyl ligand relatively the Fe--H bond. NMR spectroscopy and bonding features of the related complexes [Fe(Cp)(OC)(SiMe(n)Cl(3-n))H(Me)] (n=0-3) allow for their rationalization as usual eta(2)-Si--H silane sigma-complexes. The series of "dihydride" complexes [Fe(Cp)(OC)(SiMe(n)Cl(3-n))H(2)] (n=0-3) is different from the previous two families in that the type of interligand interactions strongly depends on the substitution on silicon. They can be classified either as usual dihydrogen complexes, for example, [Fe(Cp)(OC)(SiMe(2)Cl)(eta(2)-H(2))], or as compounds with nonclassical H--Si interactions, for example, [Fe(Cp)(OC)(H)(2)(SiMe(3))] (16). These nonclassical interligand interactions are characterized by increased negative J(H,Si) (e.g. -27.5 Hz) and increased J(H,H) (e.g. 67.7 Hz).


Novel delivery methods bypassing the blood-brain and blood-tumor barriers.
Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood-cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeutic interventions. Although ongoing research has yielded some potential options for future GBM therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications.


A global sampler of single particle tracking solutions for single molecule microscopy.
The dependence on model-fitting to evaluate particle trajectories makes it difficult for single particle tracking (SPT) to resolve the heterogeneous molecular motions typical of cells. We present here a global spatiotemporal sampler for SPT solutions using a Metropolis-Hastings algorithm. The sampler does not find just the most likely solution but also assesses its likelihood and presents alternative solutions. This enables the estimation of the tracking error. Furthermore the algorithm samples the parameters that govern the tracking process and therefore does not require any tweaking by the user. We demonstrate the algorithm on synthetic and single molecule data sets. Metrics for the comparison of SPT are generalised to be applied to a SPT sampler. We illustrate using the example of the diffusion coefficient how the distribution of the tracking solutions can be propagated into a distribution of derived quantities. We also discuss the major challenges that are posed by the realisation of a SPT sampler.


Two radioassays for serum vitamin B12 and folate determination compared in a reference interval study.
For 154 subjects, we verified that vitamin B12 and folate status was normal, using as criteria the average polymorphonuclear lobe count, mean corpuscular volume, and hemoglobin concentration. We then used blood from these subjects to compare values obtained with two radioassay kits, each designed for simultaneous vitamin B12 and folate determination. Although regression analysis showed reasonable correlation between the folate (r = 0.87) and vitamin B12 (r = 0.94) kits, we observed significant differences in the overall mean values for vitamin B12 (p less than 0.01) and folate (p less than 0.001) as measured with the kits in this population. Radioassay standard-curve data for the folate assays were similar, but these data indicated greater sensitivity at low concentrations for one vitamin B12 kit than the other. Using reference intervals recommended in the kit inserts, we found that the vitamin B12 status for 9% of these subjects would have been misclassified by one kit, 2% by the other.


Sexual risk, substance use, mental health, and trauma experiences of gang-involved homeless youth.
This study examined the associations of sexual risk behaviors, substance use, mental health, and trauma with varying levels of gang involvement in a sample of Los Angeles-based homeless youths. Data were collected from 505 homeless youths who self-reported various health information and whether they have ever identified as or been closely affiliated with a gang member. Multivariable logistic regression assessed associations of lifetime gang involvement with risk taking behaviors and negative health outcomes. Results revealed seventeen percent of youths have ever identified as a gang member and 46% as gang affiliated. Both gang members and affiliates were at greater risk of many negative behaviors than non-gang involved youths. Gang members and affiliates were more likely to report recent methamphetamine use, cocaine use, chronic marijuana use, having sex while intoxicated, and symptoms of depression, symptoms of posttraumatic stress disorder. They were also more likely to have experienced childhood sexual abuse and witnessing family violence. Gang members were more likely to ever attempt suicide, experience recent partner violence, and report physical abuse during childhood. Results suggest that lifetime gang involvement is related to a trajectory of negative outcomes and amplified risk for youths experiencing homelessness. Additionally, being closely connected to a gang member appears to have just as much as an impact on risk as personally identifying as a gang member. Given the lack of knowledge regarding the intersection between youth homelessness and gang involvement, future research is needed to inform policies and programs that can address the specific needs of this population.


Novel function for beta 1 integrins in keratinocyte cell-cell interactions.
We have examined the expression, localization, and function of beta 1 integrins on cultured human epidermal keratinocytes using polyclonal and monoclonal antibodies against the beta 1, alpha 2, alpha 3, and alpha 5 integrin subunits. The beta 1 polypeptide, common to all class 1 integrins, was localized primarily in areas of cell-cell contacts of cultured keratinocytes, as were alpha 2 and alpha 3 polypeptides, suggesting a possible role in cell-cell adhesion for these integrin polypeptides. In contrast, the fibronectin receptor alpha 5 subunit showed no such accumulations in regions of cell-cell contact but was more diffusely distributed in the keratinocyte plasma membrane, consistent with the absence of fibronectin at cell-cell contact sites. Colonies of cultured keratinocytes could be dissociated by treatment with monoclonal antibody specific to the beta 1 polypeptide. Such dissociation of cell-cell contacts also occurred under conditions where the monoclonal antibody had no effect on cell-substrate adhesion. Therefore, beta 1 integrin-dependent cell-cell adhesion can be inhibited without affecting other cell-adhesive interactions. Antibody treatment of keratinocytes maintained in either low (0.15 mM) or high (1.2 mM) CaCl2 also resulted in the loss of organization of intracellular F-actin filaments and beta 1 integrins, even when the anti-beta 1 monoclonal antibody had no dissociating effect on keratinocyte colonies at the higher calcium concentration. Our results indicate that beta 1 integrins play roles in the maintenance of cell-cell contacts between keratinocytes and in the organization of intracellular microfilaments. They suggest that in epithelial cells integrins can function in cell-cell interactions as well as in cell-substrate adhesion.