Transfer of Asymmetry between Proteinogenic Amino Acids under Harsh Conditions.
The heating above 400 °C of serine, cysteine, selenocysteine and threonine leads to a complete decomposition of the amino acids and to the formation in low yields of alanine for the three formers and of 2-aminobutyric acid for the latter. At higher temperature, this amino acid is observed only when sublimable α-alkyl-α-amino acids are present, and with an enantiomeric excess dependent on several parameters. Enantiopure or enantioenriched Ser, Cys, Sel or Thr is not able to transmit its enantiomeric excess to the amino acid formed during its decomposition. The presence during the sublimation-decomposition of enantioenriched valine or isoleucine leads to the enantioenrichment of all sublimable amino acids independently of the presence of many decomposition products coming from the unstable derivative. All these studies give information on a potentially prebiotic key-reaction of abiotic transformations between α-amino acids and their evolution to homochirality.


Muscle fibres and cultured muscle cells express the B7.1/2-related inducible co-stimulatory molecule, ICOSL: implications for the pathogenesis of inflammatory myopathies.
Inducible co-stimulator ligand (ICOSL), a member of the B7 family of co-stimulatory molecules related to B7.1/2, regulates CD4 as well as CD8 T-cell responses via interaction with its receptor ICOS on activated T cells. Here we examined the expression and the functional relevance of ICOSL in human muscle cells in vivo and in vitro. We investigated 25 muscle biopsy specimens from patients with polymyositis, dermatomyositis, inclusion body myositis, Duchenne muscular dystrophy and non-myopathic controls for ICOSL expression by immunohistochemistry. Normal muscle fibres constitutively express low levels of ICOSL. However, ICOSL expression is markedly increased in muscle fibres in inflammatory myopathies. Cell surface staining was most prominent in the contact areas between muscle fibres and inflammatory cells, which in turn show expression of ICOS as a marker of T-cell activation. Muscle endothelial cells show constitutive expression of ICOSL under normal and pathological conditions. We also detected mRNA and cell surface protein expression of ICOSL on myoblasts cultured from control subjects and patients as well as in TE671 muscle rhabdomyosarcoma cells. ICOSL expression was upregulated by tumour necrosis factor-alpha (TNF-alpha), whereas interferon-gamma (IFN-gamma) had no such effect. Co-culture experiments of major histocompatibility complex (MHC) class II-positive myoblasts with CD4 T cells together with superantigen demonstrated that the expression of muscle-related ICOSL has functional consequences: the production of Th1 (IFN-gamma) and Th2 cytokines [interleukin (IL)-4 and IL-10] by CD4 T cells was markedly reduced in the presence of a neutralizing anti-ICOSL monoclonal antibody (mAb HIL-131), thus showing the importance of ICOSL co-stimulation for T-cell activation. Taken together, our results demonstrate that human muscle cells express ICOSL, a functional co-stimulatory molecule distinct from B7.1 and B7.2. ICOSL-ICOS interactions may play an important role in inflammatory myopathies, providing further evidence for the antigen-presenting capacity of muscle cells.


Comparison of Echocardiographic Variables in Patients With Severe Aortic Stenosis and Preserved Ejection Fraction Grouped by Flow and Gradient.
The pathophysiology of severe aortic stenosis (AS) is complex with vascular, valvular, and myocardial components. To better define this process, we compared echocardiographic and clinical variables in patients with severe AS and preserved EF according to flow and gradient. We retrospectively studied the clinical and echocardiographic data of 287 patients (mean age 76 ± 11 years, 57% men) from 2012 to 2017 with severe AS (indexed aortic valve area <0.6 cm2/m2) and preserved ejection fraction (>50%). Patients were divided into 4 groups based on flow (stroke volume index < or ≥35 ml/m2) and mean aortic pressure gradient (< or ≥40 mm Hg): normal flow, high gradient (NFHG), normal flow, low gradient (NFLG), low flow, high gradient (LFHG) and low flow, low gradient (LFLG). Among patients with severe AS, 23% had NFHG, 44% had NFLG, 10% had LFHG, and 23% had LFLG. Only diabetes was marginally significantly different among the clinical variables. Aortic valve area index was largest in NFLG and smallest in LFHG (p < 0.001 for pairwise comparisons). Valvuloarterial impedance was highest in LFHG (p < 0.01 for pairwise comparisons). Systemic arterial compliance was lower and systemic vascular resistance was higher in low flow compared with normal flow groups. In conclusion, LFHG had the smallest valve area index along with markers of increased vascular resistance combined with high gradients, which suggests a unique pathophysiology in this group of severe AS patients with preserved EF.


MicroRNAs: Clinical Trials and Potential Applications .
MicroRNAs are novel biomolecules with a crucial function in normal cellular physiology and in pathophysiologic conditions, including cancer. Since the first report on the link between microRNAs and cancer was published in 2002, research has revealed the potential clinical implications of microRNAs. Oncology nurses play an important role in educating patients and their families about possible applications of microRNAs in oncology. .


Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice.
Approximately 2-15% of couples experience infertility, and around half of these cases are attributed to male infertility. We previously identified TBC1D21 as a sterility-related RabGAP gene derived from infertile men. However, the in vivo function of TBC1D21 in male fertility remains unclear. Here, we show that loss of Tbc1d21 in mice resulted in male infertility, characterized by defects in sperm tail structure and diminished sperm motility. The mitochondria of the sperm-tail had an abnormal irregular arrangement, abnormal diameter, and structural defects. Moreover, the axoneme structure of sperm tails was severely disturbed. Several TBC1D21 interactors were selected via proteomic analysis and functional grouping. Two of the candidate interactors, a subunit protein of translocase in the outer membrane of mitochondria (TOMM20) and an inner arm component of the sperm tail axoneme (Dynein Heavy chain 7, DNAH7), confirmed in vivo physical co-localization with TBC1D21. In addition, TOMM20 and DNAH7 detached and dispersed outside the axoneme in Tbc1d21-deficient sperm, instead of aligning with the axoneme. From a clinical perspective, the transcript levels of TBC1D21 in sperm from teratozoospermia cases were significantly reduced when compared with those in normozoospermia. We concluded that TBC1D21 is critical for mitochondrial and axoneme development of mammalian sperm.


Transfer of ion binding site from ether-a-go-go to Shaker: Mg2+ binds to resting state to modulate channel opening.
In ether-à-go-go (eag) K(+) channels, extracellular divalent cations bind to the resting voltage sensor and thereby slow activation. Two eag-specific acidic residues in S2 and S3b coordinate the bound ion. Residues located at analogous positions are approximately 4 A apart in the x-ray structure of a Kv1.2/Kv2.1 chimera crystallized in the absence of a membrane potential. It is unknown whether these residues remain in proximity in Kv1 channels at negative voltages when the voltage sensor domain is in its resting conformation. To address this issue, we mutated Shaker residues I287 and F324, which correspond to the binding site residues in eag, to aspartate and recorded ionic and gating currents in the presence and absence of extracellular Mg(2+). In I287D+F324D, Mg(2+) significantly increased the delay before ionic current activation and slowed channel opening with no readily detectable effect on closing. Because the delay before Shaker opening reflects the initial phase of voltage-dependent activation, the results indicate that Mg(2+) binds to the voltage sensor in the resting conformation. Supporting this conclusion, Mg(2+) shifted the voltage dependence and slowed the kinetics of gating charge movement. Both the I287D and F324D mutations were required to modulate channel function. In contrast, E283, a highly conserved residue in S2, was not required for Mg(2+) binding. Ion binding affected activation by shielding the negatively charged side chains of I287D and F324D. These results show that the engineered divalent cation binding site in Shaker strongly resembles the naturally occurring site in eag. Our data provide a novel, short-range structural constraint for the resting conformation of the Shaker voltage sensor and are valuable for evaluating existing models for the resting state and voltage-dependent conformational changes that occur during activation. Comparing our data to the chimera x-ray structure, we conclude that residues in S2 and S3b remain in proximity throughout voltage-dependent activation.


A review of current evidence regarding the ICD-11 proposals for diagnosing PTSD and complex PTSD.
The World Health Organization's proposals for posttraumatic stress disorder (PTSD) in the 11th edition of the International Classification of Diseases, scheduled for release in 2018, involve a very brief set of symptoms and a distinction between two sibling disorders, PTSD and Complex PTSD. This review of studies conducted to test the validity and implications of the diagnostic proposals generally supports the proposed 3-factor structure of PTSD symptoms, the 6-factor structure of Complex PTSD symptoms, and the distinction between PTSD and Complex PTSD. Estimates derived from DSM-based items suggest the likely prevalence of ICD-11 PTSD in adults is lower than ICD-10 PTSD and lower than DSM-IV or DSM-5 PTSD, but this may change with the development of items that directly measure the ICD-11 re-experiencing requirement. Preliminary evidence suggests the prevalence of ICD-11 PTSD in community samples of children and adolescents is similar to DSM-IV and DSM-5. ICD-11 PTSD detects some individuals with significant impairment who would not receive a diagnosis under DSM-IV or DSM-5. ICD-11 CPTSD identifies a distinct group who have more often experienced multiple and sustained traumas and have greater functional impairment than those with PTSD.


Ocular manifestations of the acquired immunodeficiency syndrome.
Ophthalmologic findings in individuals with the acquired immunodeficiency syndrome (AIDS) are fairly common. A noninfectious microvasculopathy of the retina is the most frequent manifestation. Cytomegalovirus (CMV) retinitis is the opportunistic infection most likely to cause visual loss and must be differentiated from toxoplasmosis or herpetic retinitis. Ganciclovir, foscarnet, and cidofovir are the agents available to slow the progression of CMV retinitis, but they have significant toxicities.


Guidelines for Perioperative Care for Liver Transplantation: Enhanced Recovery After Surgery (ERAS) Recommendations.
Enhanced Recovery After Surgery (ERAS) is a multimodal, evidence-based, program of care developed to minimize the response to surgical stress, associated with reduced perioperative morbidity and hospital stay. This study presents the specific ERAS Society recommendations for liver transplantation (LT) based on the best available evidence and on expert consensus. PubMed and ClinicalTrials.gov were searched in April 2019 for published and ongoing randomized clinical trials on LT in the last 15 y. Studies were selected by 5 independent reviewers and were eligible if focusing on each validated ERAS item in the area of adult LT. An e-Delphi method was used with an extended interdisciplinary panel of experts to validate the final recommendations. Forty-three articles were included in the systematic review. A consensus was reached among experts after the second round. Patients should be screened for malnutrition and treated whenever possible. Prophylactic nasogastric intubation and prophylactic abdominal drainage may be omitted, and early extubation should be considered. Early oral intake, mobilization, and multimodal-balanced analgesia are recommended. The current ERAS recommendations were elaborated based on the best available evidence and endorsed by the e-Delphi method. Nevertheless, prospective studies need to confirm the clinical use of the suggested protocol.


Spatial structure and biodiversity of macrofauna around marine munition dumpsites - A case study from the Baltic Sea.
Coastal German waters contain about 1.6 million tons of dumped munition, mostly left after World Wars. This study investigated the benthic macrofauna around the 'Kolberger Heide' munition dumpsite (Baltic Sea). A total of 93 macrofauna grab samples were obtained in the proximity of the munition dumpsite and in reference areas. Environmental variables analysed included the latitude/longitude, depth, terrain ruggedness, sediment grainsize distribution, TNT concentration in the bottom water and distance to the centre of munition dumpsite. The overall abundance, biomass and diversity varied among these groups, though demonstrated no clear differences regarding the proximity to munition and modelled near-bottom dissolved TNT. Among individual taxa, however, a total of 16 species demonstrated significant correlation with TNT concentration. Moreover, TNT may serve as a predictor for the distribution of three species: molluscs Retusa truncatula, Varicorbula gibba and polychaete Spio goniocephala. Possible reasons for the species distribution including their biological traits are discussed.


Interaction of gallium, indium, and vanadyl curcumin complexes with hen egg-white lysozyme (HEWL): Mechanistic aspects and evaluation of antiamyloidogenic activity.
Many proteins and peptides can aggregate into amyloid fibrils with high-ordered and cross-β rich structure characteristics. Amyloid deposition is a common feature of neurodegenerative diseases called amyloidosis. Various natural polyphenolic compounds such as curcumin exhibited antiamyloidogenic activities, but less researches were focused on the metal complexes of these compounds. In this study, the inhibitory effects of gallium curcumin (Ga(cur)3), indium curcumin (In(cur)3), and vanadyl curcumin (VO(cur)2) on the amyloid fibrillation of hen egg white lysozyme (HEWL) have been investigated. Moreover, the details of binding interactions of these metal complexes with HEWL have been explored. The results of fluorescence quenching analyses revealed that In(cur)3 and VO(cur)2 have much higher binding affinities than Ga(cur)3 toward HEWL. The interactions of these metal complexes were accompanied by partial conformational changes in the tertiary structure of HEWL. The kinetic curves of the fibrillation process demonstrated that In(cur)3 and VO(cur)2 have higher inhibitory effects than Ga(cur)3 on the amyloid fibrillation of HEWL. The strength of binding to HEWL is completely in accordance with inhibitory activities of these metal complexes of curcumin.


Effect of Leap Motion-based 3D Immersive Virtual Reality Usage on Upper Extremity Function in Ischemic Stroke Patients.
Immersive virtual reality (VR) is a technology that provides a more realistic environmental design and object tracking than ordinary VR. The aim of this study was to investigate the effectiveness of immersive VR on upper extremity function in patients with ischemic stroke. Sixty-five patients with ischemic stroke were included in this randomized, controlled, double-blind study. Patients were randomly divided into VR (n = 33) and control (n = 32) groups. The VR group received 60 minutes of the upper extremity immersive VR rehabilitation program and the control group received 45 minutes of conventional therapy and 15 minutes of a sham VR program. Rehabilitation consisted of 18 sessions of therapy, three days per week, for six weeks. The outcome measures were the Action Research Arm Test (ARAT), Functional Independence Measure (FIM), Fugl-Meyer Upper Extremity Scale (FMUE) and Performance Assessment of Self-Care Skills (PASS). In both the VR and control groups all parameters except the PASS improved over time. However independent t-test results showed that all of the FMUE, ARAT, FIM and PASS scores were significantly higher in the VR group compared with the control (p < 0.05). The minimal clinically important difference (MCID) scores of the FMUE and ARAT were higher than the cut-off MCID scores described in the literature in the VR group, whereas the FIM scores were below the cut-off MCID scores. All scores in the control group were below the cut-off scores. Immersive VR rehabilitation appeared to be effective in improving upper extremity function and self-care skills, but it did not improve functional independence.


Egg yolk polyunsaturated fatty acids and vitamin E content alters the tocopherol status of hatched chicks.
Polyunsaturated fatty acid composition and tocopherol status of newly hatched chicks from hens fed diets containing 3.5% menhaden (MO), flax (LO), palm (PO), or sunflower oils (SO) with (+T) or without tocopherols were examined. Addition of tocopherols increased (P < 0.05) the tocopherol content of eggs and hatched chick tissues. The total tocopherol content was lower (P < 0.05) in MO + T eggs than in LO + T, PO + T, or SO + T eggs. The tocopherol content of chick tissues was as follows liver > plasma > brain. Among the tocopherol-supplemented group, The MO + T chicks incorporated the lowest (P < 0.05) level of total tocopherols in the liver and plasma when compared to chicks hatched from LO + T, PO + T, or SO + T eggs. Brain tissue incorporated the lowest level of tocopherols among all the tissues examined. The fourfold increase in egg tocopherols did not alter the brain tocopherol in MO + T, LO + T, or SO + T chicks. In the MO and LO eggs, there was a significant increase (P < 0.05) in n-3 PUFA when compared with SO or PO eggs. The C22:6 n-3 content in liver and plasma was higher (P < 0.05) in chicks hatched from MO and LO eggs than in chicks hatched from PO or SO eggs. The brain tissue of MO chicks incorporated the highest (P < 0.05) levels of C22:6 n-3 followed by the brain tissue of LO chicks.


Influence of roundness errors of bearing components on rotational accuracy of cylindrical roller bearings.
Understanding the influence of bearing component roundness errors and roller number on the rotational accuracy of rolling bearings is crucial in the design of high precision bearings. The rotational accuracy of an assembled bearing is dependent upon roller number and roundness errors of the bearing components. We propose a model for calculating the rotational accuracy of a cylindrical roller bearing; we experimentally verified the effectiveness of the model in predicting the radial run-out of the inner ring proposed in the previous paper in this series. We sought to define the key contributing factors to the rotational accuracy by studying both the influence of the coupling effect of the roller number and the influence of the roundness errors in the inner raceway, outer raceway, and rollers on the motion error. The model and results will help engineers choose reasonable manufacturing tolerances for bearing components to achieve the required rotational accuracy.


The insulin-stimulated cyclic AMP phosphodiesterase binds to a single class of protein sites on the liver plasma membrane.
The peripheral cycle AMP phosphodiesterase from rat liver plasma membranes binds with high affinity (2.4 nM) to a single class of receptor sites on the liver plasma membrane. These receptor sites appear to be proteins, as they are trypsin- and heat-labile. The sensitivity of these sites to denaturation by trypsin and heat is a first-order process. The presence of Ca2+ (5 mM) increases the affinity of these sites for the enzyme, but does not alter their total number. The receptor sites and the cyclic AMP phosphodiesterase occur in similar numbers, at around 2 pmol/mg of plasma-membrane protein. It is proposed that the peripheral, liver plasma-membrane cyclic AMP phosphodiesterase is attached to a specific site on the insulin receptor and that the binding of insulin to the receptor site triggers a conformational change in the enzyme such that the enzyme can be phosphorylated and activated by an endogenous cyclic AMP-dependent protein kinase.


GeneXpert MTB/RIF assay as initial test for diagnosis of tuberculous meningitis.
Tuberculous meningitis (TBM) remains the most dangerous form of tuberculosis with high mortality and potential complications. The prompt diagnosis and treatment of this condition remains a key for better prognosis. A 39-year-old woman presented with severe headache, fever, nausea and vomiting, with a history of headache for a month. On examination, confusion, neck rigidity, ptosis and upward plantar reflexes were present. After 7 days of empiric treatment without resolution of her symptoms, she had another spinal tap performed. The diagnosis of TBM was performed by the GeneXpert MTB/RIF assay from her cerebrospinal fluid (CSF). Antitubercular chemotherapy was started. The patient subsequently improved. Where available, the GeneXpert assay should be used immediately in CSF samples of patients suspected of TBM as an adjunct to clinical algorithms to increase the chance of a prompt diagnosis and treatment.


[EUROASPIRE III: a comparison between Turkey and Europe].
The EUROASPIRE III survey was conducted in 2006-2007 in 22 countries in Europe (76 centers) to describe risk factors, lifestyle and therapeutic management of patients with coronary heart disease (CHD), compliance with current guidelines, and to document changes over time. This study aimed to assess the results of the EUROASPIRE III survey in terms of differences between Turkey and other European countries. The results of the EUROASPIRE III survey were compared with those of 17 centers from Turkey. Consecutive patients with a diagnosis of CHD (669 medical records, 23.8% women) were identified retrospectively, of which 338 patients (50.5%) were followed-up, interviewed, and examined at least six months after the index event (acute coronary syndrome or interventional procedure). Compared to the EUROASPIRE III data, recordings from Turkey's centers at discharge on classical risk factors did not exhibit remarkable differences; however, data on weight, height, waist circumference, lipid profile, glucose, and HbA1c measurements were more incomplete. In comparison to Europe population, the most important differences were observed in the higher rates of the following: young patients with myocardial infarction (>50 years, 20% vs. 12.7%), persistence in smoking (23.1% vs. 17.2%), immobility, low HDL-cholesterol (50.2% vs. 36.7%), insufficient follow-up by physicians after the index event (12% vs. 2.2%-except Turkey), and insufficient patient education. The data from the Turkey arm of the survey show that efforts for cardiovascular disease prevention fall short of the targets, similar to Europe.


Evaluation of the effect of ozonated plant oils on the quality of osseointegration of dental implants under the influence of Cyclosporin A an in vivo study.
Immunosuppressive agents have been recognized as factors that induce changes and modifications in bone metabolism. The purpose of this study was to evaluate the effect of ozonated plant extracts (herein termed ozonated oil) under the influence of Cyclosporin A (CsA) on osseointegration. A total of 20 dental implants were placed in 20 rabbit tibiae assigned to Group A or B. CsA was injected at an immunosuppressive dose in Groups A and B as a single-dose treatment. At the day of surgery, Group A received a single topical ozonated oil treatment (0.55 mL) around dental implants; Group B, the control group, received no ozonated oil. Animals were sacrificed after 8 weeks. Radiographs were obtained at implant surgery and on the day of sacrifice. Bone quality was compared between the 2 groups. Radiographically, osseointegration was microscopically evaluated using scanning electron and light microscopies. In ozonated Group A specimens, light microscopic examination demonstrated evidence of more organized mature bone compared with Group B. Within the limits of this study, the results suggest that short-term administration of CsA, when administered with topical ozonated oil, may influence bone density and the quality of dental implant osseointegration. Therefore, topically applied ozonated oil may influence bone density and the quality of osseointegration around dental implants.


Fungating accessory breast carcinoma in Nigerian women.
Three cases of fungating accessory breast carcinoma out of a total of 22 malignant breast formations seen and treated in Ile-Ife, Nigeria between January 1977 and November 1981 are described. The clinical presentations, features and histologic findings are presented. The methods of management and the need for close observation as well as follow up for at least two years is emphasized. A frequency of 14% as seen in this series appears so high that one cannot describe the occurrence of malignant changes in the accessory breast as rare.


Scarce metals in conventional passenger vehicles and end-of-life vehicle shredder output.
Concurrent with the demand for cleaner, lighter, and more efficient vehicles, many scarce metals (SMs) are used in passenger vehicles because of their unique physical and chemical properties. To explore the recycling potential of these metals, it is important to understand their distribution in the vehicles as well as their fate at the vehicles' end-of-life. However, this information remains very scattered and sparse. In this paper, we present a study investigating the distribution of 31 SMs in selected electrical and electronic (EE) components of conventional passenger vehicles and in the end-of-life vehicle shredder fractions from a shredder plant in Switzerland. The results of the chemical analyses show that the mass fractions of Co, Sn, Sr, Ta, Y, and Zr were dominant with >20,000 g/t in the selected EE components and Ag, Ga, Mo, Sb, Sn, Sr, and Zr with >50 g/t in the analyzed shredder fractions. The largest masses of 17 SMs were found in the shredder light fraction, which is incinerated in municipal waste treatment plants mainly in Switzerland; thus, these SMs are currently not recovered. The SM mass fractions in both the EE components and the shredder fractions were projected to their total masses in 100 hypothetical midrange passenger vehicles. The resulting mass balance showed a mismatch of >50% for 23 metals, which indicates other important SM sources such as alloys.


Effects of serum on cytotoxicity of nano- and micro-sized ZnO particles.
Although an increasing number of in vitro studies are being published regarding the cytotoxicity of nanomaterials, the components of the media for toxicity assays have often varied according to the needs of the scientists. Our aim for this study was to evaluate the influence of serum-in this case, fetal bovine serum-in a cell culture medium on the toxicity of nano-sized (50-70 nm) and micro-sized (<1 μm) ZnO on human lung epithelial cells (A549). The nano- and micro-sized ZnO both exhibited their highest toxicity when exposed to serum-free media, in contrast to exposure in media containing 5 or 10 % serum. This mainly comes not only from the fact that ZnO particles in the serum-free media have a higher dosage-per-cell ratio, which results from large aggregates of particles, rapid sedimentation, absence of protein protection, and lower cell growth rate, but also that extracellular Zn2+ release contributes to cytotoxicity. Although more extracellular Zn2+ release was observed in serum-containing media, it did not contribute to nano-ZnO cytotoxicity. Furthermore, non-dissolved particles underwent size-dependent particle agglomeration, resulting in size-dependent toxicity in both serum-containing and serum-free media. A low correlation between cytotoxicity and inflammation endpoints in the serum-free medium suggested that some signaling pathways were changed or induced. Since cell growth, transcription behavior for protein production, and physicochemical properties of ZnO particles all were altered in serum-free media, we recommend the use of a serum-containing medium when evaluating the cytotoxicity of NPs.


Role of sulfur chirality in the chemical processes of biology.
Chiral structures profoundly influence chemical and biological processes. While chiral carbon biomolecules have received much attention, chirality is also possible in certain sulfur compounds; just as with carbon, there can be differences in the physiological behavior of chiral sulfur compounds. For instance, one drug enantiomer, Nexium (esomeprazole, a chiral sulfoxide), is used for its superior clinical properties as a proton pump inhibitor over the racemic mixture, Prilosec (Losec, omeprazole). This critical review introduces sulfur stereochemistry and nomenclature, and provides a comprehensive approach to chiral sulfur compounds and their enzymatic reactions in general and secondary metabolism. The major structural types of biological interest are sulfonium salts, sulfoxides, and sulfoximines. (103 references).


[Influence of sports mechanic demands in competitive tennis on the thoracolumbar spinal profile].
The aim of this study was to evaluate the influence of the sports mechanic demands of competitive tennis on the thoracolumbar spinal profile. For that reason the spinal curvature (C7 - S2) of 123 male active gymnasts aged 23,8 +/- 4,5 years with a sporting exposure of 14,4 +/- 3,8 years and of 1347 age and gender matched non- and recreational sportsmen was recorded by means of the non-invasive ultrasonic-controlled contact rod. In the sagittal projection no differences between both groups were found. However, in control and sports group the dominant side of the arms induced statistically significant differences for all parameters describing spinal curvature in the frontal and transversal plane, data evaluated showed a relevant increase in the tennis group. Furthermore, the criterion both-handed hitting technique in fore and backhand caused an additional extension of lateral inclination, pelvic and pelvic-shoulder tilt as well as pelvic-shoulder rotation to the hitting side of the arms. After examining the sports-specific mechanic strain the measuring values are to interpret as a functional adaptation to the tennis-specific demands. But there is only a reduced correlation with the results of epidemiologic studies taking the incidence and prevalence of spinal injuries in competitive tennis into special account. So the tennis-specific modifications of spinal profile are not to characterise a priori as pathogen.


Hageman factor: alterations in physical properties during activation.
Highly purified preparations of Hageman factor, a potent clotpromoting agent in normal mammalian plasma, had a sedimentation coefficient of approximately 5S before activation. After activation, the Hageman factor behaved as a much less soluble or larger molecule during ultracentrifugation and gel filtration. No significant change in sedimentation behavior was noted when the Hageman factor in plasma deficient in plasma thromboplastin antecedent was activated. The altered sedimentation behavior of purified activated Hageman factor probably reflects its decreased solubility in aqueous media.


Organization of ribosomal RNA gene repeats of the mouse.
The organization of the ribosomal RNA (rRNA) genes of the mouse was determined by Southern blot hybridization using cloned rDNA fragments as probes, which could encompass the entire spacer region between two rRNA gene regions. The rRNA genes are organized into tandem repeats of nearly uniform length of about 44 kb. The heterogeneity detected in the nontranscribed spacer appears to be caused by its sequence rather than its length difference. At least three kinds of repetitive sequences are present in the non-transcribed spacer region; two of them are located 13 kb upstream from the 5'-end of 18S RNA gene and the other located 1 to 4 kb downstream from the 3'-end of 28S RNA gene.


Effect of increasing body condition on oxidative stress and mitochondrial biogenesis in subcutaneous adipose tissue depot of nonlactating dairy cows.
With the onset of lactation, dairy cows with a body condition score >3.5 are sensitive to oxidative stress and metabolic disorders. Adipose tissue (AT) can adapt to varying metabolic demands and energy requirements by the plasticity of its size during lactation. In AT, angiogenesis is necessary to guarantee sufficient oxygen and nutrient supply for adipocytes. Cellular energy metabolism is reflected mainly by mitochondria, which can be quantified by the mitochondrial DNA copy number per cell. In the present study, we aimed to investigate the effect of overconditioning on angiogenesis and mitochondrial biogenesis in AT of nonlactating cows, irrespective of the physiological influences of lactation and pregnancy. Eight nonpregnant, nonlactating cows received a ration of increasing energy density for 15 wk, during which body weight and body condition increased substantially. Subcutaneous AT was biopsied every 8 wk, and blood was sampled monthly. The blood concentrations of indicators of oxidative stress increased continuously throughout the experimental period, possibly damaging mitochondrial DNA. Concomitantly, HIF-1α, a major marker for hypoxia, increased until wk 8, indicating insufficient angiogenesis in the rapidly expanding AT. Based on the observation that the number of apoptotic cells decreased with increasing hypoxia, the increasing mitochondrial DNA copy numbers might compensate for the hypoxia, reinforcing the production of oxidative stressors. Key transcription factors of mitochondrial biogenesis were largely unaffected. Thus, increased oxidative stress does not impair mitochondrial DNA.


Management of mechanical ventilation in patients with hospital-acquired pneumonia: A retrospective, observational study.
Hospital-acquired pneumonia (HAP) in intensive care patients is a frequent reason for mechanical ventilation (MV). The management of MV and ventilator weaning vary, depending on the type of lung inflammation. This retrospective, observational study screened the data from all patients admitted to the intensive care unit (ICU) of the Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc between 2011 and 2016. The aims were to determine the parameters of pressure-controlled ventilation, the frequencies of tracheostomy, bronchoscopy, reconnection to MV, the length of ICU and hospital stay and the mortality in subgroups with early-/late-onset HAP compared to a subgroup with community-acquired pneumonia (CAP) and patients with MV without pneumonia. The primary outcome of this study was MV length. Over the study period, a total of 2672 patients were hospitalised. Excluded were 137 organ donors, 66 patient without MV and 20 patients placed on volume-controlled ventilation. The cohort comprised 2.447 patients requiring MV. A total of 1.927 patients (78.7%) were indicated for MV without signs of pneumonia. CAP was diagnosed in 131 patients (5.4%). The criteria for HAP were met by 389 patients (16.0%). Early-onset and late-onset HAP was diagnosed in 63 (2.6%) and 326 (13.3%) patients, respectively. In the subgroups without pneumonia, with CAP, early- and late-onset HAP, the median MV times were 3, 6, 6 and 12 days, respectively, and the median peak inspiratory pressure (Pinsp) of MV was 20, 25, 25 and 27 cm H2O, respectively. The median positive end-expiratory pressure (PEEP) was 5, 8, 8 and 11 cm H2O, respectively. The median inspired oxygen concentrations (FiO2) were 0.45, 0.7, 0.7 and 0.8, respectively. The median length of hospital stays was 8, 15, 15 and 17 days. The mortality rates were 11.4%, 3.8%, 9.5% and 31.3%, respectively. During MV, the late-onset HAP subgroup was shown to have the highest Pinsp, PEEP and FiO2, the longest MV time, ICU and hospital stay, the highest frequency of tracheostomy, reconnection to MV, pulmonary hygiene bronchoscopy and the highest mortality compared to the early-onset HAP and CAP subgroups. The lowest values were found in the mechanically ventilated patients without pneumonia. The differences were due to the severity of lung damage that is graduated from CAP over early-onset HAP after late-onset HAP.


Trace amines inhibit insect odorant receptor function through antagonism of the co-receptor subunit.
Many insect behaviors are driven by olfaction, making insect olfactory receptors (ORs) appealing targets for insect control. Insect ORs are odorant-gated ion channels, with each receptor thought to be composed of a representative from a large, variable family of odorant binding subunits and a highly conserved co-receptor subunit (Orco), assembled in an unknown stoichiometry. Synthetic Orco directed agonists and antagonists have recently been identified. Several Orco antagonists have been shown to act via an allosteric mechanism to inhibit OR activation by odorants. The high degree of conservation of Orco across insect species results in Orco antagonists having broad activity at ORs from a variety of insect species and suggests that the binding site for Orco ligands may serve as a modulatory site for compounds endogenous to insects or may be a target of exogenous compounds, such as those produced by plants. To test this idea, we screened a series of biogenic and trace amines, identifying several as Orco antagonists. Of particular interest were tryptamine, a plant-produced amine, and tyramine, an amine endogenous to the insect nervous system. Tryptamine was found to be a potent antagonist of Orco, able to block Orco activation by an Orco agonist and to allosterically inhibit activation of ORs by odorants. Tyramine had effects similar to those of tryptamine, but was less potent. Importantly, both tryptamine and tyramine displayed broad activity, inhibiting odorant activation of ORs of species from three different insect orders (Diptera, Lepidoptera and Coleoptera), as well as odorant activation of six diverse ORs from a single species (the human malaria vector mosquito, Anopheles gambiae). Our results suggest that endogenous and exogenous natural compounds serve as Orco ligands modulating insect olfaction and that Orco can be an important target for the development of novel insect repellants.


Does the use of new cephalosporins follow the authorised, financed and approved indications? A study of their use in routine clinical practice in a tertiary hospital.
To evaluate the appropriateness of ceftazidime-avibactam (C-A), ceftolozane-tazobactam (C-T) and ceftaroline prescriptions according to European Medicines Agency (EMA)/Spanish Agency of Medicines and Medical Devices (AEMPS) approved indications, financed indications in the Spanish health system and hospital Infection Commission (IC) recommendations in a tertiary hospital. Observational, descriptive and retrospective study of inpatients aged ≥18 years, who were prescribed the above-mentioned antimicrobials during the period January-December 2020. Variables obtained were demographic (sex and age), pharmacological (antibiotic, use - empiric or targeted, indication) and microbiological (sensitivity testing and antibiotic tested) data. A total of 79 patients were included. C-A (n=40): 67.5% of patients were male, with a mean age of 61 (range 22-87) years. Empiric treatment was applied in 30% of the cases (n=12). De-escalation in 33.33% of individuals. Sensitivity testing was done in 92.86% of patients, including C-A in 57.69% of them. C-T (n=19): 89.47% of patients were male, with a mean age of 65 (range 18-82) years. An empiric approach was followed in 5.26% of subjects; de-escalation was performed in all cases due to culture with multidrug-resistant (MDR) Pseudomonas aeruginosa. Sensitivity testing was carried out in 100% of patients, including C-T in 26.32% of them. Ceftaroline (n=20): 70% of patients were male, with a mean age of 55.5 (range 23-79) years. Empiric treatment was applied to 30% of cases. In 50% of these subjects de-escalation was done. Sensitivity testing was done in 92.85% of them, but in none with ceftaroline. Regarding the percentage of appropriateness: approved EMA/AEMPS indications: C-A: 100%; C-T: 84.21%; ceftaroline: 75%; financed indications in the Spanish health system: C-A: 85%; C-T: 100%; ceftaroline: 15%; IC: C-A: 60%; C-T: 57.9%; ceftaroline: 15%. Our results highlight the importance of stewardship programmes in the decision-making process and in the follow-up of patients with infections caused by MDR microorganisms.


LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation.
Dysregulation of mitochondrial Ca(2+)-dependent bioenergetics has been implicated in various pathophysiological settings, including neurodegeneration and myocardial infarction. Although mitochondrial Ca(2+) transport has been characterized, and several molecules, including LETM1, have been identified, the functional role of LETM1-mediated Ca(2+) transport remains unresolved. This study examines LETM1-mediated mitochondrial Ca(2+) transport and bioenergetics in multiple cell types, including fibroblasts derived from patients with Wolf-Hirschhorn syndrome (WHS). The results show that both mitochondrial Ca(2+) influx and efflux rates are impaired in LETM1 knockdown, and similar phenotypes were observed in ΔEF hand, (D676A D688K)LETM1 mutant-overexpressed cells, and in cells derived from patients with WHS. Although LETM1 levels were lower in WHS-derived fibroblasts, the mitochondrial Ca(2+) uniporter components MCU, MCUR1, and MICU1 remain unaltered. In addition, the MCU mitoplast patch-clamp current (IMCU) was largely unaffected in LETM1-knockdown cells. Silencing of LETM1 also impaired basal mitochondrial oxygen consumption, possibly via complex IV inactivation and ATP production. Remarkably, LETM1 knockdown also resulted in increased reactive oxygen species production. Further, LETM1 silencing promoted AMPK activation, autophagy, and cell cycle arrest. Reconstitution of LETM1 or antioxidant overexpression rescued mitochondrial Ca(2+) transport and bioenergetics. These findings reveal the role of LETM1-dependent mitochondrial Ca(2+) flux in shaping cellular bioenergetics.


An insider's perspective on entrepreneurial program development at a small and a large institution.
Entrepreneurship educators have an opportunity to learn from the entrepreneurship programs at both small colleges and large universities that have already sprouted up and experienced growth, challenges, failures, and ultimate successes. Programs that have contributed to the current entrepreneurship milieu can help leaders who are launching new programs or retooling existing ones, providing information to assist in defining their outcome objectives and refining their offerings. The development of new entrepreneurship programs, one at a private liberal arts institution and one at a large state-related research university, is evaluated. The common threads of "what worked" are identified, highlighting themes that other institutions of any size undertaking new initiatives can leverage. Themes discussed include the identification of institutional champions, communication with members of the "student supply chain," and offering both non-credit, experience-based opportunities and dynamic for-credit courses. In addition, implementing a strategy that includes faculty partnerships, designated advisory boards, and refined bootstrapping skills helps to ensure that robust human and capital resources are available for program delivery, growth, and sustainability.


Looking beyond Virus Detection in RNA Sequencing Data: Lessons Learned from a Community-Based Effort to Detect Cellular Plant Pathogens and Pests.
High-throughput sequencing (HTS), more specifically RNA sequencing of plant tissues, has become an indispensable tool for plant virologists to detect and identify plant viruses. During the data analysis step, plant virologists typically compare the obtained sequences to reference virus databases. In this way, they are neglecting sequences without homologies to viruses, which usually represent the majority of sequencing reads. We hypothesized that traces of other pathogens might be detected in this unused sequence data. In the present study, our goal was to investigate whether total RNA-seq data, as generated for plant virus detection, is also suitable for the detection of other plant pathogens and pests. As proof of concept, we first analyzed RNA-seq datasets of plant materials with confirmed infections by cellular pathogens in order to check whether these non-viral pathogens could be easily detected in the data. Next, we set up a community effort to re-analyze existing Illumina RNA-seq datasets used for virus detection to check for the potential presence of non-viral pathogens or pests. In total, 101 datasets from 15 participants derived from 51 different plant species were re-analyzed, of which 37 were selected for subsequent in-depth analyses. In 29 of the 37 selected samples (78%), we found convincing traces of non-viral plant pathogens or pests. The organisms most frequently detected in this way were fungi (15/37 datasets), followed by insects (13/37) and mites (9/37). The presence of some of the detected pathogens was confirmed by independent (q)PCRs analyses. After communicating the results, 6 out of the 15 participants indicated that they were unaware of the possible presence of these pathogens in their sample(s). All participants indicated that they would broaden the scope of their bioinformatic analyses in future studies and thus check for the presence of non-viral pathogens. In conclusion, we show that it is possible to detect non-viral pathogens or pests from total RNA-seq datasets, in this case primarily fungi, insects, and mites. With this study, we hope to raise awareness among plant virologists that their data might be useful for fellow plant pathologists in other disciplines (mycology, entomology, bacteriology) as well.


A walnut-enriched diet for 2 years changes the serum oxylipin profile in healthy older persons.
Oxylipins are products derived from polyunsaturated fatty acids (PUFAs) that play a role in cardiovascular disease and aging. Fish oil-derived n-3 PUFAs promote the formation of anti-inflammatory and vasodilatory oxylipins; however, there are little data on oxylipins derived from α-linolenic acid (C18:3n-3), the primary plant-derived n-3 PUFA. Walnuts are a source of C18:3n-3. To investigate the effect on serum oxylipins of a diet enriched with walnuts at 15% energy (30-60 g/d; 2.6-5.2 g C18:3n-3/d) for 2 y compared to a control diet (abstention from walnuts) in healthy older men and women (63-79 years). The red blood cell proportion of ALA was determined by gas-chromatography as a measure of compliance. Ultra-performance liquid chromatography - tandem mass spectrometry was used to measure serum concentrations of 53 oxylipins in participants randomly assigned to the walnut diet (n = 64) or the control diet (n = 51). Two-year concentration changes (final minus baseline) were log-transformed (base log-10) and standardized (mean-centered and divided by the standard deviation of each variable). Volcano plots were then generated (fold change ≥1.5; false discovery rate ≤0.1). For each oxylipin delta surviving multiple testing, we further assessed between-intervention group differences by ANCOVA adjusting for age, sex, BMI, and the baseline concentration of the oxylipin. The 2-year change in red blood cell C18:3n-3 in the walnut group was significantly higher than that in the control group (P<0.001). Compared to the control diet, the walnut diet resulted in statistically significantly greater increases in three C18:3n-3-derived oxylipins (9-HOTrE, 13-HOTrE, and 12,13-EpODE) and in the C20:5n-3 derived 14,15-diHETE, and greater reductions of the C20:4n-6-derived 5-HETE, 19-HETE, and 5,6-diHETrE. Long-term walnut consumption changes the serum oxylipin profile in healthy older persons. Our results add novel mechanistic evidence on the cardioprotective effects of walnuts. Clinicaltrials.gov Identifier: NCT01634841.


Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex.
Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis and is altered in human cancer. Signaling is turned on and off by regulating stability of the effector β-catenin (β-cat). The multiprotein destruction complex binds and phosphorylates β-cat and transfers it to the SCF-TrCP E3-ubiquitin ligase for ubiquitination and destruction. Wnt signals act though Dishevelled to turn down the destruction complex, stabilizing β-cat. Recent work clarified underlying mechanisms, but important questions remain. We explore β-cat transfer from the destruction complex to the E3 ligase, and test models suggesting Dishevelled and APC2 compete for association with Axin. We find that Slimb/TrCP is a dynamic component of the destruction complex biomolecular condensate, while other E3 proteins are not. Recruitment requires Axin and not APC, and Axin's RGS domain plays an important role. We find that elevating Dishevelled levels in Drosophila embryos has paradoxical effects, promoting the ability of limiting levels of Axin to turn off Wnt signaling. When we elevate Dishevelled levels, it forms its own cytoplasmic puncta, but these do not recruit Axin. Superresolution imaging in mammalian cells raises the possibility that this may result by promoting Dishevelled:Dishevelled interactions at the expense of Dishevelled: Axin interactions when Dishevelled levels are high.


Measurement of nitric oxide by 4,5-diaminofluorescein without interferences.
The fluorescent reagent 4,5-diaminofluorescein (DAF-2) has been widely used for specific and quantitative measurements of nitric oxide (NO) in biological tissues. Recently it was reported that dehydroascorbic acid (DHA) and ascorbic acid (AA) interfere with the measurement of NO using DAF-2. A new method of assaying NO using DAF-2 eliminates these interferences; when frozen on dry ice, the NO in the original solution still diffuses and can react with an adjacent frozen block of DAF-2, but the confounding compounds such as DHA do not. Thus, placing the microliter-volume frozen blocks of solutions containing NO and the solutions of DAF-2 adjacent to each other for 30 min results in the concentration dependent formation of fluorescent product (DAF-2T) from the reaction of NO with DAF-2. The product has been characterized and the method validated using both fluorescence spectroscopy and capillary electrophoresis with laser induced fluorescence detection. With this approach, the presence of DHA and AA does not interfere with NO measurements, and product formation is inhibited in the presence of NO scavengers added to either of the solutions before freezing. The contactless DAF-2 method successfully assays NO in nitric oxide synthase-positive vertebrate and invertebrate tissues. This method allows nondestructive NO detection in biological samples that can subsequently be used for morphological and/or biochemical studies.


Outcomes following resection of intramedullary spinal cord cavernous malformations: a 25-year experience.
The management of intramedullary spinal cord cavernous malformations (CMs) is controversial. At Barrow Neurological Institute, the authors selectively offer surgical treatment for symptomatic spinal cord CMs. The purpose of this paper is to review the clinical outcomes in patients after resection of these lesions based on a single-center experience over a 25-year period. The records of 80 patients who underwent resection of pathologically confirmed spinal cord CMs from January 1985 to May 2010 were analyzed retrospectively. Preoperative clinical status and imaging findings were evaluated as well as immediate and long-term postoperative outcomes. Compared with their preoperative Frankel grade, 11% of patients were worse, 83% were the same, and 6% improved immediately after surgery. At a mean follow-up interval of 5 years, 10% of patients were worse, 68% were the same, and 23% were improved compared with their preoperative status. Five percent of patients underwent reoperation for resection of a symptomatic residual or recurrent lesion. Immediate complications were encountered in 6% of patients, including CSF leakage and deep venous thrombosis. Long-term complications were encountered in 14% of patients and included kyphotic deformity, stenosis, and spinal cord tethering. A significant correlation was found between long-term outcome and anteroposterior length of the lesion (p = 0.01). The resection of intramedullary spinal cord CMs can be achieved with good long-term outcomes and an acceptable risk of immediate or delayed complications.


Life-long shedding of Puumala hantavirus in wild bank voles (Myodes glareolus).
The knowledge of viral shedding patterns and viraemia in the reservoir host species is a key factor in assessing the human risk of zoonotic viruses. The shedding of hantaviruses (family Bunyaviridae) by their host rodents has widely been studied experimentally, but rarely in natural settings. Here we present the dynamics of Puumala hantavirus (PUUV) shedding and viraemia in naturally infected wild bank voles (Myodes glareolus). In a monthly capture-mark-recapture study, we analysed 18 bank voles for the presence and relative quantity of PUUV RNA in the excreta and blood from 2 months before up to 8 months after seroconversion. The proportion of animals shedding PUUV RNA in saliva, urine and faeces peaked during the first month after seroconversion, but continued throughout the study period with only a slight decline. The quantity of shed PUUV in reverse transcription quantitative PCR (RT-qPCR) positive excreta was constant over time. In blood, PUUV RNA was present for up to 7 months but both the probability of viraemia and the virus load declined with time. Our findings contradict the current view of a decline in virus shedding after the acute phase and a short viraemic period in hantavirus infection - an assumption widely adopted in current epidemiological models. We suggest the life-long shedding as a means of hantaviruses to survive over host population bottlenecks, and to disperse in fragmented habitats where local host and/or virus populations face temporary extinctions. Our results indicate that the kinetics of pathogens in wild hosts may differ considerably from those observed in laboratory settings.


Callous-unemotional traits and subtypes of conduct disorder.
There has been growing consensus that children with conduct disorder (CD) constitute a very heterogeneous group containing children who vary substantially on the development, course, and causes of the disorder. While many have recognized the importance of this heterogeneity for developing better causal theories and for developing more effective treatments, there has been little consensus as to the best way to subtype children with CD. In this paper, we review a number of approaches to subtyping, each with some evidence for its validity for certain purposes. We focus on two recent approaches that have great potential for integrating past subtyping approaches and for advancing causal theory. The first approach is the division of children with CD into those with a childhood onset to their severe antisocial behavior and those with an adolescent onset to their behavior. The second approach is to designate children within the childhood-onset group who show callous and unemotional traits, which is analogous to adult conceptualizations of psychopathy. Both approaches help designate children who many show different causal processes underlying their severe aggressive and antisocial behavior, and who may warrant different approaches to treatment.


SymGRASS: a database of sugarcane orthologous genes involved in arbuscular mycorrhiza and root nodule symbiosis.
The rationale for gathering information from plants procuring nitrogen through symbiotic interactions controlled by a common genetic program for a sustainable biofuel production is the high energy demanding application of synthetic nitrogen fertilizers. We curated sequence information publicly available for the biofuel plant sugarcane, performed an analysis of the common SYM pathway known to control symbiosis in other plants, and provide results, sequences and literature links as an online database. Sugarcane sequences and informations were downloaded from the nucEST database, cleaned and trimmed with seqclean, assembled with TGICL plus translating mapping method, and annotated. The annotation is based on BLAST searches against a local formatted plant Uniprot90 generated with CD-HIT for functional assignment, rpsBLAST to CDD database for conserved domain analysis, and BLAST search to sorghum's for Gene Ontology (GO) assignment. Gene expression was normalized according the Unigene standard, presented as ESTs/100 kb. Protein sequences known in the SYM pathway were used as queries to search the SymGRASS sequence database. Additionally, antimicrobial peptides described in the PhytAMP database served as queries to retrieve and generate expression profiles of these defense genes in the libraries compared to the libraries obtained under symbiotic interactions. We describe the SymGRASS, a database of sugarcane orthologous genes involved in arbuscular mycorrhiza (AM) and root nodule (RN) symbiosis. The database aggregates knowledge about sequences, tissues, organ, developmental stages and experimental conditions, and provides annotation and level of gene expression for sugarcane transcripts and SYM orthologous genes in sugarcane through a web interface. Several candidate genes were found for all nodes in the pathway, and interestingly a set of symbiosis specific genes was found. The knowledge integrated in SymGRASS may guide studies on molecular, cellular and physiological mechanisms by which sugarcane controls the establishment and efficiency of endophytic associations. We believe that the candidate sequences for the SYM pathway together with the pool of exclusively expressed tentative consensus (TC) sequences are crucial for the design of molecular studies to unravel the mechanisms controlling the establishment of symbioses in sugarcane, ultimately serving as a basis for the improvement of grass crops.


[Autoimmune hepatitis--new aspects of histopathology, ultrastructure and immunohistology].
Auto-immune hepatitis is accompanied by histological and immunohistological peculiarities which have been more thoroughly elucidated in recent time. Predominantly located in portal fields are lymphocytic infiltrations reaching continuously into peripheral lobules. Dendritic reticular cells were recordable from portal fields by electron microscopy. The hepatocytes recorded from peripheral lobules were hydropically swollen and formed microacini. Autoantibodies against components of the hepatocytic membrane seemed to be of relevance to pathogenesis and were recorded from animal experiments. Immunohistologically, the hepatocytic membrane exhibited HLA antigens and IgG. CD 8-positive lymphocytes were detected and were found to be in close contact with liver cells.


Detection of epistatic effects with logic regression and a classical linear regression model.
To locate multiple interacting quantitative trait loci (QTL) influencing a trait of interest within experimental populations, usually methods as the Cockerham's model are applied. Within this framework, interactions are understood as the part of the joined effect of several genes which cannot be explained as the sum of their additive effects. However, if a change in the phenotype (as disease) is caused by Boolean combinations of genotypes of several QTLs, this Cockerham's approach is often not capable to identify them properly. To detect such interactions more efficiently, we propose a logic regression framework. Even though with the logic regression approach a larger number of models has to be considered (requiring more stringent multiple testing correction) the efficient representation of higher order logic interactions in logic regression models leads to a significant increase of power to detect such interactions as compared to a Cockerham's approach. The increase in power is demonstrated analytically for a simple two-way interaction model and illustrated in more complex settings with simulation study and real data analysis.


Palliative Endovascular Techniques for Management of Peripheral Vascular Blowout Syndrome in End-Stage Malignancies.
Vascular blowout syndrome (VBOS) secondary to neoplastic erosion is a dreadful complication of advanced stage malignancies that can compromise quality of life and overall prognosis in a fragile patient population. Endovascular therapy can offer minimally invasive, life-saving maneuvers both acutely and prophylactically. Four patients with end-stage malignancies eroding into various peripheral vascular beds with impending, threatened, and acute VBOS underwent successful endovascular management. Technical success was achieved in all patients with no perioperative morbidity or mortality. In all patients, endovascular intervention controlled life-threatening hemorrhage and facilitated adjunctive therapeutic modalities such as surgical tumor debulking and/or chemoradiation. In conclusion, our small case series demonstrates that endovascular therapy can offer safe and effective palliation of peripheral VBOS secondary to neoplastic erosion.


Reproductive mortality in the United States.
Maternal mortality in the United States has declined by 50% during the last decade. This decline took place at the same time as changes in the availability and use of contraceptive measures, including temporary contraceptives and sterilization. To examine the impact of these changes on mortality we estimated the reproductive mortality rate, which includes pregnancy-related deaths as well as deaths from the side effects of contraceptive methods. The estimated reproductive mortality rate fell by 73% from 1955 to 1975. The decrease was greater for women younger than 35 years. The slower decline for women aged 35 years and older was due to oral-contraception-related deaths. By 1975, pregnancy prevention was responsible for nearly as many deaths as pregnancy itself. The reproductive mortality rate is more appropriate than the maternal mortality rate for evaluating the health risks of reproduction and contraception. We urge that national surveillance of maternal mortality should be expanded to include deaths associated with contraceptive methods.


How do health workers perceive and practice monitoring and evaluation of malaria control interventions in South-east Nigeria?
The Anambra state Malaria Control Booster Project (ANMCBP) depends on an effective monitoring and evaluation (M&E) system to continuously improve the implementation of the malaria control interventions. However, it is not clear how the health workers that are expected to be the fulcrum of the malaria M&E perceive and practise M&E. The study was carried out to determine the knowledge, perception, and practice of Malaria M&E among selected health staff, and to identify related socio-demographic factors, including cadre of staff. A semi-structured questionnaire and an observation checklist were used to collect information from selected health workers in public primary health centres in all 21 local government areas of the State. Multistage sampling technique was used in selection of respondents. The questionnaire explored knowledge, perception and practice of malaria M&E from 213 health workers. The observation checklist was used to record the actual practice of malaria M&E as observed by trained supervisors. Over 80% of health workers interviewed were able to correctly identify the malaria M&E forms; 25.4% knew the basis for categorizing Artemisinin-based combination therapy (ACT) into ACT1 - ACT4; 97.6% of the respondents felt there was need to keep proper records to have information available and 7.5% of them kept records because they were asked to do so. Over 90% of respondents reported correct practice of M&E, but on verification of actual practice, 55.6% of the respondents had at least one wrongly filled form, and half of these had none of their forms properly filled; about 68.4% of respondents had met specified timeline for data transmission. Differences observed in knowledge, perception and practice of M&E across age categories and cadres were only significant in ability to identify malaria M&E forms; diagnosis of malaria based on blood film microscopy result; perception of how age should be recorded; and reported practice of keeping data till they are requested. Among lower cadre of staff, gaps still exist in knowledge, perception and practice of malaria M&E. Gaps still exist in health workers' understanding of malaria data management, perception of efficient data transmission and observed practice of malaria M&E.


Isoform-Specific Substrate Inhibition Mechanism of Human Tryptophan Hydroxylase.
Tryptophan hydroxylase (TPH) catalyzes the initial and rate-limiting step in the biosynthesis of serotonin, which is associated with a variety of disorders such as depression and irritable bowel syndrome. TPH exists in two isoforms: TPH1 and TPH2. TPH1 catalyzes the initial step in the synthesis of serotonin in the peripheral tissues, while TPH2 catalyzes this step in the brain. In this study, the steady-state kinetic mechanism for the catalytic domain of human TPH1 has been determined. Varying substrate tryptophan (Trp) and tetrahydrobiopterin (BH4) results in a hybrid Ping Pong-ordered mechanism in which the reaction can either occur through a Ping Pong or a sequential mechanism depending on the concentration of tryptophan. The catalytic domain of TPH1 shares a sequence identity of 81% with TPH2. Despite the high sequence identity, differences in the kinetic parameters of the isoforms have been identified; i.e., only TPH1 displays substrate tryptophan inhibition. This study demonstrates that the difference can be traced to an active site loop which displays different properties in the TPH isoforms. Steady-state kinetic results of the isoforms, and variants with point mutations in a loop lining the active site, show that the kinetic parameters of only TPH1 are significantly changed upon mutations. Mutations in the active site loop of TPH1 result in an increase in the substrate inhibition constant, Ki, and therefore turnover rate. Molecular dynamics simulations reveal that this substrate inhibition mechanism occurs through a closure of the cosubstrate, BH4, binding pocket, which is induced by Trp binding.


Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes.
Adipose tissue has a central role in the regulation of energy balance and homoeostasis. There are two main types of adipose tissue: WAT (white adipose tissue) and BAT (brown adipose tissue). WAT from certain depots, in response to appropriate stimuli, can undergo a process known as browning where it takes on characteristics of BAT, notably the induction of UCP1 (uncoupling protein 1) expression and the presence of multilocular lipid droplets and multiple mitochondria. How browning is regulated is an intense topic of investigation as it has the potential to tilt the energy balance from storage to expenditure, a strategy that holds promise to combat the growing epidemic of obesity and metabolic syndrome. This review focuses on the transcriptional regulators as well as various proteins and secreted mediators that have been shown to play a role in browning. Emphasis is on describing how many of these factors exert their effects by regulating the three main transcriptional regulators of classical BAT development, namely PRDM16 (PR domain containing 16), PPARγ (peroxisome proliferator-activated receptor γ) and PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which have been shown to be the key nodes in the regulation of inducible brown fat.


Factors associated with spread of pseudorabies virus among breeding swine in quarantined herds.
Knowledge of the factors that place susceptible gilts at highest risk of pseudorabies virus (PRV) infection in a quarantined herd is crucial to reduce spread of PRV within the herd. Cohorts of PRV seronegative gilts were monitored in 17 herds that were endemically infected with PRV to determine the location of breeding females at the time of infection with PRV and identify herd characteristics and management and housing factors that may influence spread of PRV in the breeding section of swine herds endemically infected with PRV. Blood samples were collected every 1 to 2 months for an average of 13.6 months. In addition, blood was collected from a representative sample of finishing pigs (greater than or equal to 20 weeks old) 3 times per year to determine their serologic PRV status. Incidence rates and relative risks of PRV infection were estimated for 4 areas of the breeding section: gestation barn, gilt pool, farrowing room, and breeding area. Overall, 28, 11, 8, and 2 females became infected with PRV in each of these areas, respectively. The greater number of females infected in the gestation barns, compared with the number of females infected in other locations, is probably a consequence of being at risk for a longer period rather than of a higher incidence rate. Herd size, common housing for gilts in the gilt pool and sows, and serologic pattern of PRV infection in finishing pigs were associated with the detection of spread of PRV in the breeding section of the 17 herds.(ABSTRACT TRUNCATED AT 250 WORDS)


Hydrocarbons in digestive tract and liver of a basking shark.
The hydrocarbons of zooplankton pass through the digestive tract of the basking shark without fractionation or structural modification. They are resorbed in the spiral valve and deposited in the liver. In contrast to unsaturated fatty acids, the olefinic hydrocarbons are not decreased in concentration. The hydrocarbon assemblage in the digestive tract and in the liver is indicative of the food sources and feeding grounds of the shark. Squalene, abundant in shark liver, occurs only in traces in zooplankton; phytane, if present at all, constitutes less than 0.005 percent of the hydrocarbons of zooplankton and of shark liver.


Effects of Food-Derived Collagen Peptides on the Expression of Keratin and Keratin-Associated Protein Genes in the Mouse Skin.
Oral ingestion of collagen peptides (CP) has long been suggested to exert beneficial effects on the skin, but the molecular events induced by CP on the skin remain unclear. Here, we investigated the effects of oral CP administration on gene expression in hairless mouse skin and of prolyl-hydroxyproline (Pro-Hyp), a collagen-derived dipeptide, on gene expression in a coculture of mouse skin keratinocytes and fibroblasts. Using microarray analysis, we found that oral administration of CP to hairless mice for 6 weeks induced increased expression of Krtap and Krt genes in the skin. Annotation analysis using DAVID revealed that a group of the up-regulated genes, Gprc5d, Sprr2a1, Krt27 and Krtap16-7, is associated with the development of the epidermis and the hair cycle. In addition, the presence of Pro-Hyp (200 μM) induced an increase in the expression of Krtap16-7, Krtap15, Krtap14 and Krtap8-2 in keratinocytes in coculture, partially resembling the in vivo result. The Pro-Hyp-induced up-regulation of these genes was not observed when keratinocytes were cultured without fibroblasts, suggesting that the presence of fibroblasts is essential for the effects of Pro-Hyp. Our study presents new insights into the effects of CP on the skin, which might link to the hair cycle.


Comparison of endovascular and conventional vascular prostheses in an experimental infection model.
The causes and management of prosthetic graft infections have been extensively studied for conventional bypass grafts; however, the infectivity and therapy for endovascular graft infections are completely unknown. The aim of this study was to compare the biologic properties of infected aortic grafts when inserted by endoluminal or standard transabdominal techniques. Eighteen dogs underwent placement of polytetrafluoroethylene grafts in their infrarenal aortas either by an endovascular technique (8) or a standard interposition technique (10). Endovascular grafts were constructed from polytetrafluoroethylene (3 cm) and two balloon-expandable stents coaxially mounted onto a balloon catheter delivery system. The grafts were inserted through a left carotid arteriotomy under fluoroscopic control. Initially, seven grafts were infected with decreasing inocula of Staphylococcus aureus, starting at 10(7) organisms per ml for 30 minutes and then rinsed briefly (10 seconds) in normal saline solution, until a 50% infective dose for the standard grafts was determined to be 10(2) organisms per ml. After this initial experiment, a second group of 11 dogs were compared at a concentration of 10(2) S. aureus per ml. Five dogs underwent endovascular repair, and six dogs had standard graft interpositions after an identical period of bacterial exposure. All grafts were removed at 2 weeks under sterile conditions and were submitted for quantitative culture analysis. Three of the six dogs (50%) with standard grafts appeared to clear their infections, whereas only one of the five dogs (20%) with an endovascular graft was free of organisms at 14 days. This results was further manifested by statistically significant lower postmortem colony counts in the standard grafts (p < 0.01). The endoluminal position of the graft and its proximity to the arterial wall do not appear to provide protection against infection. These data suggest that if endovascular grafts become infected, they may be in a disadvantaged position for host defense mechanisms to be effective.


N-Glycosylation of a mouse IgG expressed in transgenic tobacco plants.
Since plants are emerging as an important system for the expression of recombinant glycoproteins, especially those intended for therapeutic purposes, it is important to scrutinize to what extent glycans harbored by mammalian glycoproteins produced in transgenic plants differ from their natural counterpart. We report here the first detailed analysis of the glycosylation of a functional mammalian glycoprotein expressed in a transgenic plant. The structures of the N-linked glycans attached to the heavy chains of the monoclonal antibody Guy's 13 produced in transgenic tobacco plants (plantibody Guy's 13) were identified and compared to those found in the corresponding IgG1 of murine origin. Both N-glycosylation sites located on the heavy chain of the plantibody Guy's 13 are N-glycosylated as in mouse. However, the number of Guy's 13 glycoforms is higher in the plant than in the mammalian expression system. Despite the high structural diversity of the plantibody N-glycans, glycosylation appears to be sufficient for the production of a soluble and biologically active IgG in the plant system. In addition to high-mannose-type N-glycans, 60% of the oligosaccharides N-linked to the plantibody have beta(1, 2)-xylose and alpha(1, 3)-fucose residues linked to the core Man3GlcNAc2. These plant-specific oligosaccharide structures are not a limitation to the use of plantibody Guy's 13 for topical immunotherapy. However, their immunogenicity may raise concerns for systemic applications of plantibodies in human.


Ideal Cardiovascular Health and Incident Cardiovascular Disease: Heterogeneity Across Event Subtypes and Mediating Effect of Blood Biomarkers: The PRIME Study.
The aim of this study was to investigate whether the association between baseline cardiovascular health (CVH) and incident cardiovascular disease differs according to coronary heart disease (CHD) and stroke subtypes, and to assess the mediating effect of inflammatory and hemostatic blood biomarkers. The association of ideal CVH with outcomes was derived in 9312 middle-aged men from Northern Ireland and France (whole cohort) in multivariable Cox proportional hazards regression analysis. The mediating effect of baseline inflammatory and hemostatic blood biomarkers was evaluated in a case-control study nested within the cohort after 10 years of follow-up. After a median follow-up of 10 years, 614 first CHD events and 117 first stroke events were adjudicated. Compared with those with poor CVH, those with an ideal CVH profile at baseline had a 72% lower risk of CHD (hazard ratio=0.28; 95% confidence interval, 0.17; 0.46) and a 76% lower risk of stroke (hazard ratio =0.24; 95% confidence interval, 0.06; 0.98). The magnitude of the risk reductions was similar for incident angina and myocardial infarction, but was lower for ischemic stroke. In the controls, the mean concentrations of high-sensitivity C-reactive protein, IL-6, and fibrinogen decreased with higher CVH status. Furthermore, the association of behavioral CVH with incident CHD was partly mediated by high-sensitivity C-reactive protein (16.69%), IL-6 (8.52%), and fibrinogen (7.30%) CONCLUSIONS: Our study shows no clear heterogeneity in the association of baseline CVH with the main subtypes of cardiovascular disease. This supports a universal promotion of ideal CVH for all cardiovascular disease subtypes. Furthermore, our mediation analysis suggests that the lower risk of CHD associated with ideal CVH is partly mediated by lower inflammatory and hemostatic blood biomarkers.


Lectin-like oxidized low-density lipoprotein receptor-1 delivers heat shock protein 60-fused antigen into the MHC class I presentation pathway.
Heat shock protein (Hsp) 60 elicits a potent proinflammatory response in the innate immune system and has been proposed as a danger signal of stressed or damaged cells to the immune system. Previous studies reported CD14, TLR2, and TLR4 as mediators of signaling but probably not of binding. Although the receptor for Hsp60 was proposed to be saturable and specific on macrophages, it is not well defined. In the current study, we found that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), as a receptor for Hsp60, could bind and internalize Hsp60 via the C terminus of Hsp60. Yeast two-hybrid assay revealed that the second beta-sheet containing the long-loop region of LOX-1 played an important role in this interaction. Furthermore, LOX-1 might be engaged as a common receptor for different Hsp60 species. Bone marrow-derived dendritic cells could cross-present Hsp60-fused OVA Ag on MHC class I molecules via LOX-1. Inhibition of the recognition of Hsp60 by LOX-1 decreases Hsp60-mediated cross-presentation of OVA and specific CTL response and protective tumor immunity in vivo. Taken together, these results demonstrate that LOX-1 functions as a receptor for Hsp60 and is involved in the delivery of Hsp60-fused Ag into the MHC class I presentation pathway.


Phosphoproteomic and Functional Analyses Reveal Sperm-specific Protein Changes Downstream of Kappa Opioid Receptor in Human Spermatozoa.
G-protein coupled receptors (GPCRs) belong to the seven transmembrane receptor superfamily that transduce signals via G proteins in response to external stimuli to initiate different intracellular signaling pathways which culminate in specific cellular responses. The expression of diverse GPCRs at the plasma membrane of human spermatozoa suggests their involvement in the regulation of sperm fertility. However, the signaling events downstream of many GPCRs in spermatozoa remain uncharacterized. Here, we selected the kappa-opioid receptor (KOR) as a study model and applied phosphoproteomic approach based on TMT labeling and LC-MS/MS analyses. Quantitative coverage of more than 5000 proteins with over 3500 phosphorylation sites revealed changes in the phosphorylation levels of sperm-specific proteins involved in the regulation of the sperm fertility in response to a specific agonist of KOR, U50488H. Further functional studies indicate that KOR could be involved in the regulation of sperm fertile capacity by modulation of calcium channels. Our findings suggest that human spermatozoa possess unique features in the molecular mechanisms downstream of GPCRs which could be key regulators of sperm fertility and improved knowledge of these specific processes may contribute to the development of useful biochemical tools for diagnosis and treatment of male infertility.


Interleukin-6 promoter variants, prostate cancer risk, and survival.
Inflammation has been implicated in prostate cancer (PCa) pathogenesis. Promoter DNA variants responsible for differential expression of key cytokines may therefore influence susceptibility to PCa. Two interleukin-6 (IL-6) promoter variants, -174G>C and -6331T>C, were genotyped for association with PCa risk and survival using the Risk Factors for Prostate Cancer Study (RFPCS, 825 cases and 732 controls) and the Melbourne Collaborative Cohort Study (MCCS, 818 cases and 1,745 controls). Impact of genotypes on IL-6 transcriptional activity was measured using Low Density Arrays. A significant increase in IL-6 transcriptional activity in malignant compared to benign prostate tissue supports a role for IL-6 in PCa. The -174G>C variant showed no association with PCa risk, overall survival, or IL-6 transcriptional activity. The -6331 C-allele was significantly associated with an increased risk in the RFPCS (OR = 1.29, 95% CI = 1.08-1.54), but not in the MCCS. In the MCCS however, cases presenting with a CC genotype conferred a higher risk of mortality (HR = 2.27, 95% CI = 1.34-3.85), which was maintained although reduced overall in the pooled analysis with RFPCS (HR = 1.68, 95% CI = 1.10-2.54). Furthermore, we associate the minor C-allele with a significant decrease in IL-6 transcriptional activity. While our study refutes a role for IL-6 -174G>C, it is the first to implicate -6331T>C with PCa risk and poor survival. Our observation that -6331T>C has a significant impact on IL-6 transcriptional activity, calls for further investigations into the role of this variant as a novel PCa biomarker.


Redox Proteomic Analysis Reveals Oxidative Modifications of Proteins by Increased Levels of Intracellular Reactive Oxygen Species during Hypoxia Adaptation of Aspergillus fumigatus.
Aspergillus fumigatus faces abrupt changes in oxygen concentrations at the site of infection. An increasing number of studies has demonstrated that elevated production of intracellular reactive oxygen species (ROS) under low oxygen conditions plays a regulatory role in modulating cellular responses for adaptation to hypoxia. To learn more about this process in A. fumigatus, intracellular ROS production during hypoxia has been determined. The results confirm increased amounts of intracellular ROS in A. fumigatus exposed to decreased oxygen levels. Moreover, nuclear accumulation of the major oxidative stress regulator AfYap1 is observed after low oxygen cultivation. For further analysis, iodoTMT labeling of redox-sensitive cysteine residues is applied to identify proteins that are reversibly oxidized. This analysis reveals that proteins with important roles in maintaining redox balance and protein folding, such as the thioredoxin Asp f 29 and the disulfide-isomerase PdiA, undergo substantial thiol modification under hypoxia. The data also show that the mitochondrial respiratory complex IV assembly protein Coa6 is significantly oxidized by hypoxic ROS. Deletion of the corresponding gene results in a complete absence of hypoxic growth, indicating the importance of complex IV during adaptation of A. fumigatus to oxygen-limiting conditions.


Predictors of Athlete's Performance in Ultra-Endurance Mountain Races.
In previous studies, ultra-endurance performance has been associated with training and psychological variables. However, performance under extreme conditions is understudied, mainly due to difficulties in making field measures. The aim of this study was to analyze the role of training, hydration, nutrition, oral health status, and stress-related psychological factors in athletes' performance in ultra-endurance mountain events. We analyzed the variables of race time and training, hydration state, nutrition, oral health status, and stress-related psychological factors in 448 ultra-endurance mountain race finishers divided into three groups according to race length (less than 45 km, 45-90 km, and greater than 90 km), using a questionnaire. Higher performance in ultra-endurance mountain races was associated with better oral health status and higher accumulative altitude covered per week as well as higher positive accumulative change of altitude per week during training. In longer distance races, experience, a larger volume of training, and better hydration/nutrition prior to the competition were associated with better performance. Ultra-endurance mountain athletes competing in longer races (>90 km) have more experience and follow harder training schedules compared with athletes competing in shorter distances. In longer races, a larger fluid intake before the competition was the single best predictor of performance. For races between 45 and 90 km, training intensity and volume were key predictors of performance, and for races below 45 km, oral health status was a key predictor of performance. Psychological factors previously reported as ultra-endurance mountain race performance predictors were inconsistent or failed to predict the performance of athletes in the present research.


Fragmented Sleep, Fragmented Mind: The Role of Sleep in Dissociative Symptoms.
In psychopathology, dissociation typically refers to a disturbance in the normal integration of thoughts, feelings, and experiences into consciousness and memory. In this article, we review the literature on how sleep disturbances relate to dissociative symptoms and memory failure. We contend that this body of research offers a fresh perspective on dissociation. Specifically, we argue that dissociative symptoms are associated with a labile sleep-wake cycle, in which dreamlike mentation invades the waking state, produces memory failures, and fuels dissociative experiences. The research domain of sleep and dissociation can accommodate the dominant idea in the clinical literature that trauma is the distal cause of dissociation, and it holds substantial promise to inspire new treatments for dissociative symptoms (e.g., interventions that focus on normalization of the sleep-wake cycle). We conclude with worthwhile paths for further investigations and suggest that the sleep-dissociation approach may help reconcile competing interpretations of dissociative symptoms.


Somatomedin A levels in patients with Cushing's disease.
The serum levels of immunoreactive somatomedin A (SMA) in 23 patients with Cushing's disease, aged 6-61 years, were within the range of healthy subjects for their ages. No correlation was found between SMA and the excretion of cortisol. After im administration of hGH (8 IU = 4 mg) daily for 3 days there was a significant rise in SMA, both determined by radioimmunoassay and radioreceptor assay. Thus no impairment was found in the GH-dependent SMA levels or the ability of hGH to generate somatomedin, which indicates that the growth retarding effect of cortisol is most likely due to a direct effect on the tissue. After treatment with stereotactic radiation to the hypophysis there was a significant decrease in cortisol excretion without any change in SMA levels, indicating the possibility to achieve a selective impairment of the ACTH-cortisol axis.


Mimicry of erythropoietin by a nonpeptide molecule.
Erythropoietin (EPO) controls the proliferation and differentiation of erythroid progenitor cells into red blood cells. EPO induces these effects by dimerization of the EPO receptors (EPOR) present on these cells. To discover nonpeptide molecules capable of mimicking the effects of EPO, we identified a small molecule capable of binding to one chain of EPOR and used it to synthesize molecules capable of inducing dimerization of the EPOR. We first identified compound 1 (N-3-[2-(4-biphenyl)-6-chloro-5-methyl]indolyl-acetyl-L-lysine methyl ester) by screening the in-house chemical collection for inhibitors of EPO binding to human EPOR and then prepared compound 5, which contains eight copies of compound 1 held together by a central core. Although both compounds inhibited EPO binding of EPOR, only compound 5 induced dimerization of soluble EPOR. Binding of EPO to its receptor in cells results in activation of many intracellular signaling molecules, including transcription factors like signal transducer and activator of transcription (STAT) proteins, leading to growth and differentiation of these cells. Consistent with its ability to induce dimerization of EPOR in solution, compound 5 exhibited much of the same biological activities as EPO, such as (i) the activation of a STAT-dependent luciferase reporter gene in BAF3 cells expressing human EPOR, (ii) supporting the proliferation of several tumor cell lines expressing the human or mouse EPOR, and (iii) the in vitro differentiation of human progenitor cells into colonies of erythrocytic lineage. These data demonstrate that a nonpeptide molecule is capable of inducing EPOR dimerization and mimicking the biological activities of EPO.


Endoscopic endonasal versus transcranial approach to tuberculum sellae and planum sphenoidale meningiomas in a similar cohort of patients.
OBJECTIVE Planum sphenoidale (PS) and tuberculum sellae (TS) meningiomas cause visual symptoms due to compression of the optic chiasm. The treatment of choice is surgical removal with the goal of improving vision and achieving complete tumor removal. Two options exist to remove these tumors: the transcranial approach (TCA) and the endonasal endoscopic approach (EEA). Significant controversy exists regarding which approach provides the best results and whether there is a subset of patients for whom an EEA may be more suitable. Comparisons using a similar cohort of patients, namely, those suitable for gross-total resection with EEA, are lacking from the literature. METHODS The authors reviewed all cases of PS and TS meningiomas that were surgically removed at Weill Cornell Medical College between 2000 and 2015 (TCA) and 2008 and 2015 (EEA). All cases were shown to a panel of 3 neurosurgeons to find only those tumors that could be removed equally well either through an EEA or TCA to standardize both groups. Volumetric measurements of preoperative and postoperative tumor size, FLAIR images, and apparent diffusion coefficient maps were assessed by 2 independent reviewers and compared to assess extent of resection and trauma to the surrounding brain. Visual outcome and complications were also compared. RESULTS Thirty-two patients were identified who underwent either EEA (n = 17) or TCA (n = 15). The preoperative tumor size was comparable (mean 5.58 ± 3.42 vs 5.04 ± 3.38 cm3 [± SD], p = 0.661). The average extent of resection achieved was not significantly different between the 2 groups (98.80% ± 3.32% vs 95.13% ± 11.69%, p = 0.206). Postoperatively, the TCA group demonstrated a significant increase in the FLAIR/edema signal compared with EEA patients (4.15 ± 7.10 vs -0.69 ± 2.73 cm3, p = 0.014). In addition, the postoperative diffusion-weighted imaging signal of cytotoxic ischemic damage was significantly higher in the TCA group than in the EEA group (1.88 ± 1.96 vs 0.40 ± 0.55 cm3, p =0.008). Overall, significantly more EEA patients experienced improved or stable visual outcomes compared with TCA patients (93% vs 56%, p = 0.049). Visual deterioration was greater after TCA than EEA (44% vs 0%, p = 0.012). While more patients experienced postoperative seizures after TCA than after EEA (27% vs 0%, p = 0.038), there was a trend toward more CSF leakage and anosmia after EEA than after TCA (11.8% vs 0%, p = 0.486 and 11.8% vs 0%, p = 0.118, respectively). CONCLUSIONS In this small single-institution study of similarly sized and located PS and TS meningiomas, EEA provided equivalent rates of resection with better visual results, less trauma to the brain, and fewer seizures. These preliminary results merit further investigation in a larger multiinstitutional study and may support EEA resection by experienced surgeons in a subset of carefully selected PS and TS meningiomas.


Photoactivated cyclization of aryl-containing enediynes coated gold nanoparticles: enhancement of the DNA cleavage ability of enediynes.
Two novel enediynes containing an aromatic ring and substituted by two thiol functions as end-groups were designed and studied as functionalizing agent of gold nanoparticles. Phototriggered cyclization of the capping agent under UV-visible irradiation was investigated. Interestingly, the length of the thiol-substituted chain was shown to influence significantly the cyclization rate. Depending on the length of the spacer, either polymerization or simple cyclization of the coating agent was evidenced. The present study underscores the possibility of finely controlling the fate of the coating agent (polymerization/cyclization). Nanocomposites were characterized by UV-visible absorption spectroscopy, dynamic light scattering (DLS) technique and transmission electron microscopy (TEM) measurements. Finally, the ability of the colloidal solutions to induce photoinitiated damages to PcDNA3 supercoiled DNA was evaluated. Interestingly, an increase as high as 50% of the DNA cleavage could be registered when adding enediynes-capped gold nanoparticles to solutions of enediynes. In particular, the enhancement of DNA scission was observed in both thermal and photochemical activation modes.


Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort.
Comorbidities, are common in COPD, have been associated with poor outcomes and are thought to relate to systemic inflammation. To investigate comorbidities in relation to systemic inflammation and outcomes we recorded comorbidities in a well characterized cohort (ECLIPSE study) for 2164 clinically stable COPD subjects, 337 smokers and 245 non-smokers with normal lung function. COPD patients had a higher prevalence of osteoporosis, anxiety/panic attacks, heart trouble, heart attack, and heart failure, than smokers or nonsmokers. Heart failure (Hazard Ratio [HR] 1.9, 95% Confidence Interval [CI] 1.3-2.9), ischemic heart disease (HR 1.5, 95% CI 1.1-2.0), heart disease (HR 1.5, 95% CI 1.2-2.0), and diabetes (HR 1.7, 95% CI 1.2-2.4) had increased odds of mortality when coexistent with COPD. Multiple comorbidities had accumulative effect on mortality. COPD and cardiovascular disease was associated with poorer quality of life, higher MRC dyspnea scores, reduced 6MWD, higher BODE index scores. Osteoporosis, hypertension and diabetes were associated with higher MRC dyspnea scores and reduced 6MWD. Higher blood concentrations of fibrinogen, IL-6 and IL-8 levels occurred in those with heart disease. Comorbidity is associated with poor clinical outcomes in COPD. The comorbidities of heart disease, hypertension and diabetes are associated with increased systemic inflammation.


Reproducing kernel Hilbert spaces regression: a general framework for genetic evaluation.
Reproducing kernel Hilbert spaces (RKHS) methods are widely used for statistical learning in many areas of endeavor. Recently, these methods have been suggested as a way of incorporating dense markers into genetic models. This note argues that RKHS regression provides a general framework for genetic evaluation that can be used either for pedigree- or marker-based regressions and under any genetic model, infinitesimal or not, and additive or not. Most of the standard models for genetic evaluation, such as infinitesimal animal or sire models, and marker-assisted selection models appear as special cases of RKHS methods.


Aetiological heterogeneity of head and neck squamous cell carcinomas: the role of human papillomavirus infections, smoking and alcohol.
Tobacco and alcohol consumption are the main risk factors for head and neck squamous cell carcinoma (HNSCC). In addition, human papillomavirus (HPV) infection plays a causal role in oropharyngeal cancer (OPC), a subset of HNSCC. We assessed the independent effects of tobacco, alcohol and HPV infection on OPC risk in the head and neck cancer (HeNCe) Life study, a hospital-based case-control study of HNSCC with frequency-matched controls by age and sex from four Montreal hospitals. Interviewers collected information on socio-demographic and behavioural factors. We tested exfoliated oral cells for HPV DNA by polymerase chain reaction (PCR). We included only OPC cases (n = 188) and controls (n = 427) without missing values for HPV, smoking or alcohol. We examined associations by estimating odds ratios (ORs) and corresponding 95% confidence intervals (CI) using unconditional logistic regression. Smoking (OR = 1.90, 95% CI: 1.04-3.45) and alcohol (OR = 2.74, 95% CI: 1.45-5.15) were associated with an increased risk of OPC independent of HPV status. Positivity for HPV 16 among heavy smokers and heavy alcohol users was associated with a 30.4-fold (95% CI: 8.94-103.26) and 18.6-fold (95% CI: 5.75-60.13) elevation in risk of OPC relative to participants who were HPV negative, respectively. Moreover, the combined effect of heavy smoking and alcohol comsumption with HPV 16 infection substantially increased OPC risk (OR = 48.76, 95% CI: 15.83-150.17) and (OR = 50.60, 95% CI: 15.96-160.40), respectively. Our results support the independent roles of smoking, alcohol and HPV infection in OPC risk and a possible combined effect. Efforts should be made to tackle these major risk factors simultaneously.