Efficacy and tolerability of quinidine as salvage therapy for monomorphic ventricular tachycardia in patients with structural heart disease.

Abstract:
INTRODUCTION
Quinidine is an effective therapy for a subset of polymorphic ventricular tachycardia and ventricular fibrillation (VF) syndromes; however, the efficacy of quinidine in scar-related monomorphic ventricular tachycardia (MMVT) is unclear.

METHODS AND RESULTS
Between 2009 and 2020 a single VT referral center, a total of 23 patients with MMVT and structural heart disease (age 66.7 ± 10.9, 20 males, 15 with ischemic cardiomyopathy, mean LVEF 22.2 ± 12.3%, 9 with left ventricular assist device [LVAD]) were treated with quinidine (14 quinidine gluconate; 996 ± 321 mg, 8 quinidine sulfate; 1062 ± 588 mg). Quinidine was used in combination with other antiarrhythmics (AAD) in 19 (13 also on amiodarone). All patients previously failed >1 AAD (amiodarone 100%, mexiletine 73%, sotalol 32%, other 32%) and eight had prior ablations (median of 1.5). Quinidine was initiated in the setting of VT storm despite AADs (6), inability to tolerate other AADs (4), or recurrent VT(12). Ventricular arrhythmias recurred despite quinidine in 13 (59%) patients at a median of 26 (4-240) days after quinidine initiation. In patients with recurrent MMVT, VT cycle length increased from 359 to 434 ms (p = .02). Six (27.3%) patients remained on quinidine at 1 year with recurrence of ventricular arrhythmias in all. The following adverse effects were seen: gastrointestinal side effects (6), QT prolongation (2), rash (1), thrombocytopenia (1), neurologic side effects (1). One patient discontinued due to cost.

CONCLUSION
Quinidine therapy has limited tolerability and long-term efficacy when used in the management of amiodarone-refractory scar-related MMVT.

quinidine
ventricular tachycardia
ventricular tachycardia/fibrillation


Analytical methods used for the authentication of food of animal origin.

Abstract: Since adulteration can have serious consequences on human health, it affects market growth by destroying consumer confidence. Therefore, authentication of food is important for food processors, retailers and consumers, but also for regulatory authorities. However, a complex nature of food and an increase in types of adulterants make their detection difficult, so that food authentication often poses a challenge. This review focuses on analytical approaches to authentication of food of animal origin, with an emphasis put on determination of specific ingredients, geographical origin and adulteration by virtue of substitution. This review highlights a current overview of the application of target approaches in cases when the compound of interest is known and non-target approaches for screening issues. Papers cited herein mainly concern milk, cheese, meat and honey. Moreover, advantages, disadvantages as well as challenges regarding the use of both approaches in official food control but also in food industry are investigated.

Abbas|Ouissam|O| Zadravec|Manuela|M| Baeten|Vincent|V| Mikuš|Tomislav|T| Lešić|Tina|T| Vulić|Ana|A| Prpić|Jelena|J| Jemeršić|Lorena|L| Pleadin|Jelka|J|

Chromatography, spectroscopy, DNA-based techniques


When time affects space: Dispersal ability and extreme weather events determine metacommunity organization in marine sediments.

Abstract: Community ecology has traditionally assumed that the distribution of species is mainly influenced by environmental processes. There is, however, growing evidence that environmental (habitat characteristics and biotic interactions) and spatial processes (factors that affect a local assemblage regardless of environmental conditions - typically related to dispersal and movement of species) interactively shape biological assemblages. A metacommunity, which is a set of local assemblages connected by dispersal of individuals, is spatial in nature and can be used as a straightforward approach for investigating the interactive and independent effects of both environmental and spatial processes. Here, we examined (i) how environmental and spatial processes affect the metacommunity organization of marine macroinvertebrates inhabiting the intertidal sediments of a biodiverse coastal ecosystem; (ii) whether the influence of these processes is constant through time or is affected by extreme weather events (storms); and (iii) whether the relative importance of these processes depends on the dispersal abilities of organisms. We found that macrobenthic assemblages are influenced by each of environmental and spatial variables; however, spatial processes exerted a stronger role. We also found that this influence changes through time and is modified by storms. Moreover, we observed that the influence of environmental and spatial processes varies according to the dispersal capabilities of organisms. More effective dispersers (i.e., species with planktonic larvae) are more affected by spatial processes whereas environmental variables had a stronger effect on weaker dispersers (i.e. species with low motility in larval and adult stages). These findings highlight that accounting for spatial processes and differences in species life histories is essential to improve our understanding of species distribution and coexistence patterns in intertidal soft-sediments. Furthermore, it shows that storms modify the structure of coastal assemblages. Given that the influence of spatial and environmental processes is not consistent through time, it is of utmost importance that future studies replicate sampling over different periods so the influence of temporal and stochastic factors on macrobenthic metacommunities can be better understood.

Corte|Guilherme N|GN|
Gonçalves-Souza|Thiago|T|
Checon|Helio H|HH|
Siegle|Eduardo|E|
Coleman|Ross A|RA|
Amaral|A Cecília Z|ACZ|

Biological assemblages
Storms
Soft-sediments
Larval dispersion
Macrobenthos
Variation partitioning


Evaluation of Changes in Intraocular Pressure with a Noncontact Tonometer in Healthy Volunteers.

Abstract:
Purpose
We investigated whether or not intrasession or intersession fluctuations in intraocular pressure occur in healthy people using a noncontact tonometer.

Materials and Methods
A noncontact tonometer was used to measure intraocular pressure in the bilateral eyes of healthy subjects for 5 consecutive days. Paired t-tests and one- and two-way repeated-measures analyses of variance were performed for the acquired data. A p-value <0.05 was considered to indicate statistical significance.

Results
Eighty eyes of 40 healthy subjects were enrolled in the study. On day 1, intraocular pressure was significantly higher in the right eye than in the left eye (P = 0.014). The one-way repeated-measures analysis of variance revealed that intraocular pressure in the left eye was significantly lower on day 1 than on days 2 to 5 (P = 0.000-0.018); however, there were no significant differences among intraocular pressures measured on days 1 to 5 in the right eye. The two-way repeated-measures analysis of variance revealed no significant difference in intraocular pressure between the right and left eyes (P = 0.913).

Conclusion
Although measurements using the noncontact tonometer were relatively stable, intraocular pressure was high on day 1.

intraocular pressure
noncontact tonometer
intrasession variability
normal subject
repeated measurement


An in vitro approach for lipolysis measurement using high-resolution mass spectrometry and partial least squares based analysis.

Abstract: The elevation of free fatty acids (FFAs) has been regarded as a universal metabolic signature of excessive adipocyte lipolysis. Nowadays, in vitro lipolysis assay is generally essential for drug screening prior to the animal study. Here, we present a novel in vitro approach for lipolysis measurement combining UHPLC-Orbitrap and partial least squares (PLS) based analysis. Firstly, the calibration matrix was constructed by serial proportions of mixed samples (blended with control and model samples). Then, lipidome profiling was performed by UHPLC-Orbitrap, and 403 variables were extracted and aligned as dataset. Owing to the high resolution of Orbitrap analyzer and open source lipid identification software, 28 FFAs were further screened and identified. Based on the relative intensity of the screened FFAs, PLS regression model was constructed for lipolysis measurement. After leave-one-out cross-validation, ten principal components have been designated to build the final PLS model with excellent performances (RMSECV, 0.0268; RMSEC, 0.0173; R2, 0.9977). In addition, the high predictive accuracy (R2 = 0.9907 and RMSEP = 0.0345) of the trained PLS model was also demonstrated using test samples. Finally, taking curcumin as a model compound, its antilipolytic effect on palmitic acid-induced lipolysis was successfully predicted as 31.78% by the proposed approach. Besides, supplementary evidences of curcumin induced modification in FFAs compositions as well as lipidome were given by PLS extended methods. Different from general biological assays, high resolution MS-based method provide more sophisticated information included in biological events. Thus, the novel biological evaluation model proposed here showed promising perspectives for drug evaluation or disease diagnosis.

Chang|Wen-Qi|WQ| Zhou|Jian-Liang|JL| Li|Yi|Y| Shi|Zi-Qi|ZQ| Wang|Li|L| Yang|Jie|J| Li|Ping|P| Liu|Li-Fang|LF| Xin|Gui-Zhong|GZ|

Lipolysis measurement
Mass spectrometry
Partial least squares
Free fatty acids
Orbitrap


Molecular design of an environmentally sensitive fluorescent nucleoside, 3-deaza-2'-deoxyadenosine derivative: distinguishing thymine by probing the DNA minor groove.

Abstract: An environmentally sensitive fluorescent nucleoside containing a 3-deazaadenine skeleton has been developed, and its photophysical properties were investigated. Newly developed C3-naphthylethynylated 3-deaza-2'-deoxyadenosine ((3nz) A, 1) exhibited dual fluorescence emission from an intramolecular charge-transfer state and a locally excited state, depending upon molecular coplanarity. DNA probes containing 1 clearly discriminated a perfectly matched thymine base on the complementary strand by a distinct change in emission wavelength.

Suzuki|Azusa|A| Yanaba|Takumi|T| Saito|Isao|I| Saito|Yoshio|Y|

fluorescent nucleosides
DNA
bioorganic chemistry
deazaadenine
naphthalene


Switchable Coupling of Vibrations to Two-Electron Carbon-Nanotube Quantum Dot States.

Abstract: We report transport measurements on a quantum dot in a partly suspended carbon nanotube. Electrostatic tuning allows us to modify and even switch "on" and "off" the coupling to the quantized stretching vibration across several charge states. The magnetic-field dependence indicates that only the two-electron spin-triplet excited state couples to the mechanical motion, indicating mechanical coupling to both the valley degree of freedom and the exchange interaction, in contrast to standard models.

Weber|P|P|
Calvo|H L|HL|
Bohle|J|J|
Goß|K|K|
Meyer|C|C|
Wegewijs|M R|MR|
Stampfer|C|C|

electron-phonon coupling in low-dimensional structures


Anthropometric findings from birth to adulthood and their relation with karyotpye distribution in Turkish girls with Turner syndrome.

Abstract: To evaluate the anthropometric features of girls with Turner syndrome (TS) at birth and presentation and the effect of karyotype on these parameters. Data were collected from 842 patients with TS from 35 different centers, who were followed-up between 1984 and 2014 and whose diagnosis age ranged from birth to 18 years. Of the 842 patients, 122 girls who received growth hormone, estrogen or oxandrolone were excluded, and 720 girls were included in the study. In this cohort, the frequency of small for gestational age (SGA) birth was 33%. The frequency of SGA birth was 4.2% (2/48) in preterm and 36% (174/483) in term neonates (P < 0.001). The mean birth length was 1.3 cm shorter and mean birth weight was 0.36 kg lower than that of the normal population. The mean age at diagnosis was 10.1 ± 4.4 years. Mean height, weight and body mass index standard deviation scores at presentation were -3.1 ± 1.7, -1.4 ± 1.5, and 0.4 ± 1.7, respectively. Patients with isochromosome Xq were significantly heavier than those with other karyotype groups (P = 0.007). Age at presentation was negatively correlated and mid-parental height was positively correlated with height at presentation. Mid-parental height and age at presentation were the only parameters that were associated with height of children with TS. The frequency of SGA birth was found higher in preterm than term neonates but the mechanism could not be clarified. We found no effect of karyotype on height of girls with TS, whereas weight was greater in 46,X,i(Xq) and 45,X/46,X,i(Xq) karyotype groups.

Sari|Erkan|E|
Bereket|Abdullah|A|
Yeşilkaya|Ediz|E|
Baş|Firdevs|F|
Bundak|Rüveyde|R|
Aydın|Banu Küçükemre|BK|
Darcan|Şükran|Ş|
Dündar|Bumin|B|
Büyükinan|Muammer|M|
Kara|Cengiz|C|
Adal|Erdal|E|
Akıncı|Ayşehan|A|
Atabek|Mehmet Emre|ME|
Demirel|Fatma|F|
Çelik|Nurullah|N|
Özkan|Behzat|B|
Özhan|Bayram|B|
Orbak|Zerrin|Z|
Ersoy|Betül|B|
Doğan|Murat|M|
Ataş|Ali|A|
Turan|Serap|S|
Gökşen|Damla|D|
Tarım|Ömer|Ö|
Yüksel|Bilgin|B|
Ercan|Oya|O|
Hatun|Şükrü|Ş|
Şimşek|Enver|E|
Ökten|Ayşenur|A|
Abacı|Ayhan|A|
Döneray|Hakan|H|
Özbek|Mehmet Nuri|MN|
Keskin|Mehmet|M|
Önal|Hasan|H|
Akyürek|Nesibe|N|
Bulan|Kezban|K|
Tepe|Derya|D|
Emeksiz|Hamdi Cihan|HC|
Demir|Korcan|K|
Kızılay|Deniz|D|
Topaloğlu|Ali Kemal|AK|
Eren|Erdal|E|
Özen|Samim|S|
Demirbilek|Hüseyin|H|
Abalı|Saygın|S|
Akın|Leyla|L|
Eklioğlu|Beray Selver|BS|
Kaba|Sultan|S|
Anık|Ahmet|A|
Baş|Serpil|S|
Unuvar|Tolga|T|
Sağlam|Halil|H|
Bolu|Semih|S|
Özgen|Tolga|T|
Doğan|Durmuş|D|
Çakır|Esra Deniz|ED|
Şen|Yaşar|Y|
Andıran|Nesibe|N|
Çizmecioğlu|Filiz|F|
Evliyaoğlu|Olcay|O|
Karagüzel|Gülay|G|
Pirgon|Özgür|Ö|
Çatlı|Gönül|G|
Can|Hatice Dilek|HD|
Gürbüz|Fatih|F|
Binay|Çiğdem|Ç|
Baş|Veysel Nijat|VN|
Fidancı|Kürşat|K|
Gül|Davut|D|
Polat|Adem|A|
Acıkel|Cengizhan|C|
Cinaz|Peyami|P|
Darendeliler|Feyza|F|


Identification and biological evaluation of secondary metabolites from the endolichenic fungus Aspergillus versicolor.

Abstract: A chemical investigation of the endolichenic fungus Aspergillus versicolor (125a), which was found in the lichen Lobaria quercizans, resulted in the isolation of four novel diphenyl ethers, named diorcinols F-H (1-3, resp.) and 3-methoxyviolaceol-II (4), eight new bisabolane sesquiterpenoids, named (-)-(R)-cyclo-hydroxysydonic acid (5), (-)-(7S,8R)-8-hydroxysydowic acid (6), (-)-(7R,10S)-10-hydroxysydowic acid (7), (-)-(7R,10R)-iso-10-hydroxysydowic acid (8), (-)-12-acetoxy-1-deoxysydonic acid (9), (-)-12-acetoxysydonic acid (10), (-)-12-hydroxysydonic acid (11), and (-)-(R)-11-dehydrosydonic acid (12), two new tris(pyrogallol ethers), named sydowiols D (13) and E (14), and fifteen known compounds, 15-29. All of the structures were determined by spectroscopic analyses, and a number of them were further identified through chemical transformations and electronic circular dichroism (ECD) calculations. Preliminary bioassays of these isolates for the determination of their inhibitory activities against the fungus Candida albicans, and their cytotoxicities against the human cancer cell lines PC3, A549, A2780, MDA-MB-231, and HEPG2 were also evaluated.

Li|Xiao-Bin|XB| Zhou|Yan-Hui|YH| Zhu|Rong-Xiu|RX| Chang|Wen-Qiang|WQ| Yuan|Hui-Qing|HQ| Gao|Wei|W| Zhang|Lu-Lu|LL| Zhao|Zun-Tian|ZT| Lou|Hong-Xiang|HX|

Endolichenic fungus
Aspergillus versicolor
Bisabolane sesquiterpenoid
Sesquiterpenoids
Antifungal activity
Cytotoxic activity
Fungi


Characterization of a Knock-In Mouse Line Expressing a Fusion Protein of κ Opioid Receptor Conjugated with tdTomato: 3-Dimensional Brain Imaging via CLARITY.

Abstract: Activation of κ opioid receptor (KOR) produces analgesia, antipruritic effect, sedation and dysphoria. To characterize neuroanatomy of KOR at high resolutions and circumvent issues of specificity of KOR antibodies, we generated a knock-in mouse line expressing KOR fused at the C terminus with the fluorescent protein tdTomato (KtdT). The selective KOR agonist U50,488H caused anti-scratch effect and hypolocomotion, indicating intact KOR neuronal circuitries. Clearing of brains with CLARITY revealed three-dimensional (3-D) images of distribution of KOR, and any G-protein-coupled receptors, for the first time. 3-D brain images of KtdT and immunohistochemistry (IHC) on brain sections with antibodies against tdTomato show similar distribution to that of autoradiography of [3H]U69,593 binding to KOR in wild-type mice. KtdT was observed in regions involved in reward and aversion, pain modulation, and neuroendocrine regulation. KOR is present in several areas with unknown roles, including the claustrum (CLA), dorsal endopiriform nucleus, paraventricular nucleus of the thalamus (PVT), lateral habenula (LHb), and substantia nigra pars reticulata (SNr), which are discussed. Prominent KtdT-containing fibers were observed to project from caudate putamen (CP) and nucleus accumbens (ACB) to substantia innominata (SI) and SNr. Double IHC revealed co-localization of KtdT with tyrosine hydroxylase (TH) in brain regions, including CP, ACB, and ventral tegmental area (VTA). KOR was visualized at the cellular level, such as co-localization with TH and agonist-induced KOR translocation into intracellular space in some VTA neurons. These mice thus represent a powerful and heretofore unparalleled tool for neuroanatomy of KOR at both the 3-D and cellular levels.

Chen|Chongguang|C|0000-0003-3097-8176
Willhouse|Alex H|AH|
Huang|Peng|P|
Ko|Nora|N|
Wang|Yujun|Y|0000-0002-1206-5325
Xu|Bin|B|
Huang|Lan Hsuan Melody|LHM|
Kieffer|Brigitte|B|0000-0002-8809-8334
Barbe|Mary F|MF|
Liu-Chen|Lee-Yuan|LY|

κ opioid receptor
CLARITY
neuroanatomy
3-D imaging


Aspirin in the primary prevention of cardiovascular disease on diabetic patients: Systematic review and meta-analysis.

Abstract:
AIMS
The publication of new trials brought additional data to the controversial topic of aspirin use in diabetic patients for primary prevention. Therefore, we aimed to systematically review all randomized controlled trials evaluating the clinical impact of aspirin in this setting.

METHODS
We searched for randomized controlled trials (RCTs) evaluating the impact of aspirin in patients with diabetes in primary prevention, in MEDLINE, EMBASE, CENTRAL (November/2018). The primary outcomes were all-cause mortality and the composite outcome of major adverse cardiovascular events (MACE). A meta-analysis was performed deriving risk ratios (RR) and 95% confidence intervals (CI).

RESULTS
All-cause mortality was not significantly reduced with RR 0.96 (95% CI 0.90-1.03; 7RCT; 27,595 patients). Regarding MACE, there was an 8% risk reduction (RR 0.92, 95% CI 0.84-0.999; I2=0%; 8RCT; 29,814 patients). The risks of major bleeding (RR 1.30, 95% CI 1.10-1.53; 2RCTs, 18,019 patients), and major GI bleeding (RR 1.39, 95% CI 1.08-1.80; 2RCTs, 18,019 patients) were significantly increased. The risks of cardiovascular mortality, myocardial infarction, stroke and amputation were not significantly different from control arm.

CONCLUSIONS
Aspirin use among diabetic patients in primary prevention appears was associated with increased risk of major bleeding, a modest decrease of MACE and lack of mortality benefit.

Caldeira|Daniel|D|
Alves|Mariana|M|
David|Cláudio|C|
Costa|João|J|
Ferreira|Joaquim J|JJ|
Pinto|Fausto J|FJ|

D001241:Aspirin
D002318:Cardiovascular Diseases
D003920:Diabetes Mellitus
D006801:Humans
D010975:Platelet Aggregation Inhibitors
D011322:Primary Prevention

Primary prevention
Cardiovascular disease
Antiplatelet
Cerebrovascular disease
Coronary disease
Diabetes mellitus
Net clinical benefit
Peripheral arterial disease
Revascularization


Complete mitochondrial genome of the blue shark Prionace glauca (Elasmobranchii: Carcharhiniformes).

Abstract: In this study, we first presented the complete mitochondrial genome of the blue shark Prionace Glauca, a pelagic and oceanic species. It is 16,705 bp in length and contains 2 rRNA genes, 22 tRNA genes, 13 protein-coding genes and 1 putative control region. The overall base composition is 31.6% A, 24.4% C, 13.1% G and 30.9% T. Overlaps and short inter-genic spaces are located in the genome. The tRNA-Ser2 loses the dihydrouridine arm and cannot be folded into the typical clover-leaf secondary structure. Two start codons (GTG and ATG) with two stop codons (TAG and TAA) or with one incomplete stop codon (T) are found in the 13 protein-coding genes. The control region contains high A + T (69.9%) and low G (12.0%).

Chen|Xiao|X| Xiang|Dan|D| Ai|Weiming|W| Shi|Xiaofang|X|

D000818:Animals
D001482:Base Composition
D050259:Genes, Mitochondrial
D054629:Genome, Mitochondrial
D016366:Open Reading Frames
D012754:Sharks


Metabolite profiling of Epinephelus fuscoguttatus infected with vibriosis reveals Omega 9 as potential metabolite biomarker.

Abstract: In this study, we report the starvation effect and vibriosis infection on a tropical fish, the tiger grouper (Epinephelus fuscoguttatus). The tiger groupers were infected with Vibrio vulnificus for 21 days. Gas chromatography-mass spectrometry combined with multivariate analysis was used to assess the variation in metabolite profiles of E. fuscoguttatus. Metabolite productions in infected fishes were significantly influenced by fatty acid production. The Omega 9 (ω-9) was abundant under the challenged conditions compared to Omega 3 (ω-3) and Omega 6 (ω-6). A total of six fatty acids from the ω-9 group were detected in high concentration in the infected fishes compared to the control groupers. These metabolites are Oleic acid, Palmitoleic acid, 6,9-Octadecenoic acid, 8,11-Eicosadienoic acid, cis-Erucic acid and 5,8,11-Eicosatrienoic acid. The production of ω-9 differed significantly (p ≤ 0.001) in the challenged samples. The detected ω-9 compounds were quantified based on three different extraction techniques with Supelco 37-component FAME mix (Supelco, USA). The highest concentration of ω-9 groups compared to the other fatty acids detected is 1320.79 mg/4 g and the lowest is 939 mg/4 g in challenged-starved; meanwhile, in challenged-fed, the highest concentration detected is 1220.87 mg/4 g and the lowest is 917.25 mg/4 g. These changes demonstrate that ω-9 can be used as a biomarker of infection in fish.

Nurdalila|A'wani Aziz|AA|
Mayalvanan|Yosmetha|Y|
Baharum|Syarul Nataqain|SN|

Metabolites
Epinephelus fuscoguttatus
Vibrio vulnificus
Gas chromatography-mass spectrometry
Omega 9 (ω-9)


Discovery of 3-substituted aminocyclopentanes as potent and orally bioavailable NR2B subtype-selective NMDA antagonists.

Abstract: A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.

Layton|Mark E|ME|
Kelly|Michael J|MJ|
Rodzinak|Kevin J|KJ|
Sanderson|Philip E|PE|
Young|Steven D|SD|
Bednar|Rodney A|RA|
Dilella|Anthony G|AG|
McDonald|Terrence P|TP|
Wang|Hao|H|
Mosser|Scott D|SD|
Fay|John F|JF|
Cunningham|Michael E|ME|
Reiss|Duane R|DR|
Fandozzi|Christine|C|
Trainor|Nicole|N|
Liang|Annie|A|
Lis|Edward V|EV|
Seabrook|Guy R|GR|
Urban|Mark O|MO|
Yergey|James|J|
Koblan|Kenneth S|KS|

D018691:Excitatory Amino Acid Antagonists

NMDA
neuropathic pain
NR2B antagonist
Parkinson’s disease


Central pupillary light reflex circuits in the cat: II. Morphology, ultrastructure, and inputs of preganglionic motoneurons.

Abstract: Preganglionic motoneurons supplying the ciliary ganglion control lens accommodation and pupil diameter. In cats, these motoneurons make up the preganglionic Edinger-Westphal population, which lies rostral, dorsal, and ventral to the oculomotor nucleus. A recent cat study suggested that caudal motoneurons control the lens and rostral motoneurons control the pupil. This led us to examine the morphology, ultrastructure, and pretectal inputs of these populations. Preganglionic motoneurons retrogradely labeled by introducing tracer into the cat ciliary ganglion generally fell into two morphologic categories. Fusiform neurons were located rostrally, in the anteromedian nucleus and between the oculomotor nuclei. Multipolar neurons were found caudally, dorsal and ventral to the oculomotor nucleus. The dendrites of preganglionic motoneurons within the anteromedian nucleus crossed the midline, providing a possible basis for consensual responses. Ultrastructurally, several different classes of synaptic profiles contact preganglionic motoneurons, suggesting that their activity may be modified by a variety of inputs. Furthermore, there were differences in the synaptic populations contacting the rostral vs. caudal populations, supporting the contention that these populations display functional differences. Anterogradely labeled pretectal terminals were observed in close association with labeled preganglionic motoneurons, particularly in the rostral population. Ultrastructural analysis revealed that these terminals, packed with clear, spherical vesicles, made asymmetric synaptic contacts onto motoneurons in the rostral population, indicating that these cells serve the pupillary light reflex. Thus, the preganglionic motoneurons found in the cat display morphologic, ultrastructural, and connectional differences suggesting that this rostral preganglionic population is specialized for pupil control, whereas more caudal elements control the lens.

D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate

ciliary ganglion
lens
pupil
Edinger-Westphal
oculomotor
parasympathetic


A Processable Shape Memory Polymer System for Biomedical Applications.

Abstract: Polyurethane shape memory polymers (SMPs) with tunable thermomechanical properties and advanced processing capabilities are synthesized, characterized, and implemented in the design of a microactuator medical device prototype. The ability to manipulate glass transition temperature (Tg ) and crosslink density in low-molecular weight aliphatic thermoplastic polyurethane SMPs is demonstrated using a synthetic approach that employs UV catalyzed thiol-ene "click" reactions to achieve postpolymerization crosslinking. Polyurethanes containing varying C=C functionalization are synthesized, solution blended with polythiol crosslinking agents and photoinitiator and subjected to UV irradiation, and the effects of number of synthetic parameters on crosslink density are reported. Thermomechanical properties are highly tunable, including glass transitions tailorable between 30 and 105 °C and rubbery moduli tailorable between 0.4 and 20 MPa. This new SMP system exhibits high toughness for many formulations, especially in the case of low crosslink density materials, for which toughness exceeds 90 MJ m(-3) at select straining temperatures. To demonstrate the advanced processing capability and synthetic versatility of this new SMP system, a laser-actuated SMP microgripper device for minimally invasive delivery of endovascular devices is fabricated, shown to exhibit an average gripping force of 1.43 ± 0.37 N and successfully deployed in an in vitro experimental setup under simulated physiological conditions.

Hearon|Keith|K|
Wierzbicki|Mark A|MA|
Nash|Landon D|LD|
Landsman|Todd L|TL|
Laramy|Christine|C|
Lonnecker|Alexander T|AT|
Gibbons|Michael C|MC|
Ur|Sarah|S|
Cardinal|Kristen O|KO|
Wilson|Thomas S|TS|
Wooley|Karen L|KL|
Maitland|Duncan J|DJ|

shape memory polymers
polyurethane
biomedical devices
structure-property relationships
thiol-ene “click” chemistry


Prevalence and seroepidemiology of Haemophilus parasuis in Sichuan province, China.

Abstract: Haemophilus parasuis, the causative agent of Glässer's disease, has been reported as widespread, but little is known about its epidemiology in the Sichuan province of China. The goal of our research is to reveal the prevalence and distribution of H. parasuis in this area. Sampling and isolation were performed across Sichuan; isolates were processed using serotyping multiplex PCR (serotyping-mPCR) and agar gel diffusion (AGD) for confirmation of serovar identity. This study was carried out from January 2014 to May 2016 and 254 H. parasuis field strains were isolated from 576 clinical samples collected from pigs displaying clinical symptoms. The isolation frequency was 44.10%. Statistically very significant differences of infection incidence were found in three age groups (P < 0.01) and different seasons (P < 0.01). Serovars 5 (25.98%) and 4 (23.62%) were the most prevalent, however, non-typeable isolates accounted for nearly 7.87%. In terms of geographical distribution, serovars 5 and 4 were mostly prevalent in west and east Sichuan. The results confirmed that the combined approach was dependable and revealed the diversity and distribution of serovars in Sichuan province, which is vital for efforts aimed at developing vaccine candidates allowing for the prevention or control of H. parasuis outbreaks.

Wang|Zhenghao|Z| Zhao|Qin|Q| Wei|Hailin|H| Wen|Xintian|X| Cao|Sanjie|S| Huang|Xiaobo|X| Wu|Rui|R| Yan|Qigui|Q| Huang|Yong|Y| Wen|Yiping|Y|

Seroepidemiology
Haemophilus parasuis
Serovar


Rotenone alters behavior and reproductive functions of freshwater catfish, Mystus cavasius, through deficits of dopaminergic neurons in the brain.

Abstract: Rotenone, commonly used as a pesticide in agriculture and as a piscicide in aquaculture, is a toxic compound that causes dopaminergic neuronal cell loss in the substantia nigra pars compacta of the brain. At the neuroendocrine level, dopamine (DA) drives behavioral (locomotion, emotion, feeding, and social interactions, etc.) and reproductive functions of fish. In the current investigation, we examined effects of rotenone toxicity on neurobehavioral and reproductive functions in whole brain and in selected brain regions in an Indian freshwater catfish, locally known as gulsha (Mystus cavasius). After fish were exposed to water containing rotenone at 0, 2.5, 25, and 250 μg/L for 2 days, significant reductions of DA, 3,4-dihydroxyphenylacetic acid (DOPAC; a DA metabolite), and their ratio (DOPAC/DA) were observed in whole brain at 250 μg/L ambient concentrations of rotenone. When fish were treated with rotenone at 250 μg/L concentration for 2 days, there was a significant reduction of DA, DOPAC and DOPAC/DA in diencephalon, DA and DOPAC in pituitary, and only DA in the telencephalon, compared with control fish. In parallel, numbers of tyrosine hydroxylase-positive (TH+) neurons declined significantly in the diencephalon and pituitary after rotenone treatment. Slowed, spontaneous movement and reduced feeding behavior were observed in rotenone-treated fish. Rotenone treatment resulted in a significantly higher gonadosomatic index with many mature vitellogenic oocytes in ovaries and lowered dopaminergic activity in these fish. These results indicate that rotenone influences neurobehavioral and reproductive functions through dopaminergic neuronal cell loss in gulsha brain.

Badruzzaman|Muhammad|M|
Shahjahan|Md|M|
Roy|Prodip Kumar|PK|
Islam|Md Taimur|MT|

Reproduction Catfish Dopamine Locomotion Pituitary Hypothalamus


Association Between the Cerebral Autoregulation Index (Pressure Reactivity), Patient's Clinical Outcome, and Quality of ABP(t) and ICP(t) Signals for CA Monitoring.

Abstract: Background and Objectives: The aim of this study was to explore the association between the cerebral autoregulation (CA) index, the pressure reactivity index (PRx), the patient's clinical outcome, and the quality of arterial blood pressure (ABP(t)) and intracranial blood pressure (ICP(t)) signals by comparing two filtering methods to derive the PRx. Materials and Methods: Data from 60 traumatic brain injury (TBI) patients were collected. Moving averaging and FIR (Finite Impulse Response) filtering were performed on the ABP(t) and ICP(t) signals, and the PRx was estimated from both filtered datasets. Sensitivity, specificity, and receiver-operating characteristic (ROC) curves with the area under the curves (AUCs) were determined using patient outcomes as a reference. The outcome chosen for comparison among the two filtering methods were mortality and survival. Results: The FIR filtering approach, compared with clinical outcome, had a sensitivity of 70%, a specificity of 81%, and a level of significance p = 0.001 with an area under the curve (AUC) of 0.78. The moving average filtering method compared with the clinical outcome had a sensitivity of 58%, a specificity of 72%, and a level of significance p = 0.054, with an area under the curve (AUC) of 0.66. Conclusions: The FIR (optimal) filtering approach was found to be more sensitive for discriminating between two clinical outcomes, namely intact (survival) and impaired (death) cerebral autoregulation for TBI treatment decision making.

Bajpai|Basant K|BK|0000-0002-7035-8740
Preiksaitis|Aidanas|A|
Vosylius|Saulius|S|
Rocka|Saulius|S|

pressure reactivity index
arterial blood pressure
traumatic brain injury
receiver-operating characteristic
area under the curve
cerebral blood flow
cerebral perfusion pressure
cerebrovascular autoregulation
intracranial pressure


Association of conjugated linoleic acid consumption and liver enzymes in human studies: A systematic review and meta-analysis of randomized controlled clinical trials.

Abstract:
OBJECTIVE
The aim of this study was to systematically review the association of conjugated linoleic acid (CLA) consumption in two forms of foods enriched or supplemented with CLA on serum liver enzymes in human studies.

METHODS
We searched PubMed, Google Scholar, Cochrane Library, ScienceDirect, ProQuest, and Ovid up to January 2015. Studies that examined the effect of CLA supplementation or foods enriched with CLA on liver enzymes concentrations among healthy adults were included. The mean difference and SD of changes in serum liver enzymes between the intervention and control groups were used as effect size for the meta-analysis.

RESULTS
The analysis demonstrated that CLA supplementation led to slight and nonsignificant decreases in alkaline phosphatase (ALP) levels (mean difference [MD] -0.216; 95% confidence interval [CI], -0.60 to 0.17; P = 0.28). CLA intake can nonsignificantly increase alanine transaminase (ALT) levels (MD = 0.107 U/L; 95% CI, -0.29 to 0.244; P = 0.124) and can significantly increase aspartate aminotransferase (AST) levels (MD = 0.171 U/L; 95% CI, 0.034-0.307; P = 0.01). Subgroup analysis based on CLA source showed that CLA supplementation or foods enriched with CLA did not significantly alter ALT levels. Subgroup analysis showed that CLA supplementation led to significant increases in AST levels (MD = 0.224 U/L; 95% CI, 0.071-0.376; P = 0.004). However, foods enriched with CLA did not have any significant effects on AST levels.

CONCLUSION
CLA supplementation was associated with a significantly increased circulating AST without any significant effect on ALP and ALT levels. Prospective studies are necessary to assess the clinical outcomes of the association between CLA and liver enzyme concentrations.

D016032:Randomized Controlled Trials as Topic

Conjugated linoleic acid
Systematic review
Meta-analysis
Alkaline phosphatase
Aspartate aminotransferase
Alanine aminotransferase


The Role and Mechanism of Epithelial-to-Mesenchymal Transition in Prostate Cancer Progression.

Abstract: In prostate cancer (PCa), similar to many other cancers, distant organ metastasis symbolizes the beginning of the end disease, which eventually leads to cancer death. Many mechanisms have been identified in this process that can be rationalized into targeted therapy. Among them, epithelial-to-mesenchymal transition (EMT) is originally characterized as a critical step for cell trans-differentiation during embryo development and now recognized in promoting cancer cells invasiveness because of high mobility and migratory abilities of mesenchymal cells once converted from carcinoma cells. Nevertheless, the underlying pathways leading to EMT appear to be very diverse in different cancer types, which certainly represent a challenge for developing effective intervention. In this article, we have carefully reviewed the key factors involved in EMT of PCa with clinical correlation in hope to facilitate the development of new therapeutic strategy that is expected to reduce the disease mortality.

Lo|U-Ging|UG| Lee|Cheng-Fan|CF| Lee|Ming-Shyue|MS| Hsieh|Jer-Tsong|JT|

D015972:Gene Expression Regulation, Neoplastic

epithelial-to-mesenchymal transition
prostate cancer progression
metastasis


Technologies and Applications Toward Preservation of Cells in a Dry State for Therapies.

Abstract: Cell-based therapeutics promise to transform the treatment of a wide range of diseases, many of which, up to this point, are incurable. During the past decade, an increasing number of cell therapies have been approved by government regulatory agencies in the United States, Europe, and Japan. Thousands of clinical trials based on live cell therapies are now taking place around the world. But most of these live cell therapies face temporal and/or spatial distances between manufacture and administration, posing a risk of degradation in potency. Cryopreservation has become the predominant biobanking approach to maintain the product's safety and efficacy during transportation and storage. However, the necessity of cryogenic shipment and storage could limit patient access to these emerging therapies and increase the costs of logistics. In the (bio)pharmaceutical industries, freeze-drying and desiccation are established preservation procedures for manufacturing small molecule drugs, liposomes, and monoclonal antibodies. Over the past two decades, there has been a growing body of research exploring the freeze-drying or drying of mammalian cells, with varying degrees of success. This article provides an overview of the technologies that were adopted or developed in these pioneering studies, paving the road toward the preservation of cell-based therapeutics in a dry state for biomanufacturing.

freeze-drying
desiccation
biomanufacturing
late embryogenesis abundant protein
trehalose


The distribution of calcified nodule and plaque rupture in patients with peripheral artery disease: an intravascular ultrasound analysis.

Abstract: In addition to plaque rupture (PR), calcified nodule (CN) may also have the potential to develop into arterial thrombus in the peripheral arteries. This study evaluated the distribution of plaque ruptures and calcified nodules in the peripheral arteries and their impact on the outcome of endovascular therapy (EVT). Consecutive 159 patients who underwent EVT with intravascular ultrasound guidance were enrolled. The position of CNs and PRs were assigned to any of common iliac artery, external iliac artery, common femoral artery, and superficial femoral artery. Forty-six (29%) patients had calcified nodule and twenty-eight (18%) patients had plaque rupture somewhere in the lower limb arteries. Although calcified nodules were evenly distributed throughout the length of the arteries plaque ruptures were predominantly located in the proximal segment of the iliofemoral arteries. Stent expansion ratio was significantly smaller in the target arteries with calcified nodules than in those with plaque rupture. Multivariate logistic regression analysis identified hemodialysis as an independent clinical predictor of calcified nodule (odds ratio 8.15, 95% confidence interval 1.73-38.3; P = 0.008). CN definitely affects incomplete stent deployment in the peripheral artery contributing to adverse events, on the other hand, PR has more acceptable outcomes after stent implantation. In the clinical setting, it is important that we realize the features of peripheral artery disease and its patient characteristics which having CNs and PRs to make a strategy for revascularization.

Horimatsu|Tetsuo|T| Fujii|Kenichi|K| Fukunaga|Masashi|M| Miki|Kojiro|K| Nishimura|Machiko|M| Naito|Yoshiro|Y| Shibuya|Masahiko|M| Imanaka|Takahiro|T| Kawai|Kenji|K| Tamaru|Hiroto|H| Sumiyoshi|Akinori|A| Saita|Ten|T| Masuyama|Tohru|T| Ishihara|Masaharu|M|

Calcified nodule
Plaque rupture
Peripheral artery disease


Tuning the Doping Ratio and Phase Transition Temperature of VO2 Thin Film by Dual-Target Co-Sputtering.

Abstract: A new simple way for tuning the phase transition temperature (PTT) of VO2 thin films has been proposed to solve the problem of changing the doping ratio by using the dual-target co-sputtering method. A series of samples with W doping ratios of 0%, 0.5%, 1%, 1.5% and 2% have been fabricated by sputtering V films with the power of pure and 2% W-doped V targets from 500 W: 0 W, 500 W: 250 W, 500 W: 500 W, 250 W: 500 W to 0 W: 500 W respectively and then annealed in an oxygen atmosphere to form VO2. The XRD results of both pure and W-doped VO2 samples reveal that VO2 forms and is the main component after annealing. The PTT can be tuned by controlling the sputtering power ratio of the pure and doped targets. It can be tuned easily from 64.3 °C to 36.5 °C by using the pure and 2% W-doped targets for demonstration, with W doping ratios from 0% to 2%. It is also valid for other doping elements and is a promising approach for the large-scale production of sputtering.

Chen|Xu|X| Wu|Mingfei|M| Liu|Xingxing|X| Wang|Ding|D| Liu|Feng|F| Chen|Yuwei|Y|0000-0003-0148-3609 Yi|Fei|F| Huang|Wanxia|W| Wang|Shaowei|S|0000-0002-6624-2016

doping
phase transition
VO2
thin films
co-sputtering


Analysis and Quantification of Oxidized Low-Density Lipoprotein-Induced Lipid Droplets in Macrophages Through High-Content Screening: Application for Antiatherogenic Drugs Discovery.

Abstract: In vascular systems, macrophages can engulf circulating oxidized (ox) low-density lipoprotein (LDL), leading to the accumulation of intracellular lipid droplets, which forms foam cells. Macrophage-derived foam cells are an important therapeutic target for atherosclerosis. However, quantifying intracellular lipid droplets in macrophages is difficult. The purpose of this study was to use high-content screening (HCS) and fluorescence staining to analyze and quantify accumulation of intracellular lipid droplets in macrophages. A murine macrophage cell line RAW 264.7 was seeded in a 96-well black plate and treated with ox-LDL. After fixation, the cells were stained with the lipophilic and nuclear fluorescent dyes briefly. The number and mean fluorescence intensity of the intracellular lipid droplets in the macrophages were detected by an HCS reader. Using HCS to quantify lipid droplets in macrophages could be applied for antiatherogenic drug discovery, and its sensitivity is much higher than that of oil red O staining.

lipid droplets
macrophages
high-content screening
foam cells
oxidized low-density lipoprotein


Cannabis cultivation: Methodological issues for obtaining medical-grade product.

Abstract: As studies continue to reveal favorable findings for the use of cannabidiol in the management of childhood epilepsy syndromes and other disorders, best practices for the large-scale production of Cannabis are needed for timely product development and research purposes. The processes of two institutions with extensive experience in producing large-scale cannabidiol chemotype Cannabis crops-GW Pharmaceuticals and the University of Mississippi-are described, including breeding, indoor and outdoor growing, harvesting, and extraction methods. Such practices have yielded desirable outcomes in Cannabis breeding and production: GW Pharmaceuticals has a collection of chemotypes dominant in any one of eight cannabinoids, two of which-cannabidiol and cannabidivarin-are supporting epilepsy clinical trial research, whereas in addition to a germplasm bank of high-THC, high-CBD, and intermediate type cannabis varieties, the team at University of Mississippi has established an in vitro propagation protocol for cannabis with no detectable variations in morphologic, physiologic, biochemical, and genetic profiles as compared to the mother plants. Improvements in phytocannabinoid yields and growing efficiency are expected as research continues at these institutions. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".

Chandra|Suman|S|
Lata|Hemant|H|
ElSohly|Mahmoud A|MA|
Walker|Larry A|LA|
Potter|David|D|

Cannabidiol Chemotype Phytocannabinoid Cannabidivarin Organogenesis Pharmacognosy


Activation of Cryptic Antibiotic Biosynthetic Gene Clusters Guided by RNA-seq Data from Both Streptomyces ansochromogenes and ΔwblA.

Abstract: With the increase of drug resistance caused by the improper use and abuse of antibiotics, human beings are facing a global health crisis. Sequencing of Streptomyces genomes revealed the presence of an important reservoir of secondary metabolic gene clusters for previously unsuspected products with potentially valuable bioactivity. It has therefore become necessary to activate these cryptic pathways through various strategies. Here, we used RNA-seq data to perform a comparative transcriptome analysis of Streptomyces ansochromogenes (wild-type, WT) and its global regulatory gene disruption mutant ΔwblA, in which some differentially expressed genes are associated with the abolished nikkomycin biosynthesis and activated tylosin analogue compounds (TACs) production, and also with the oviedomycin production that is induced by the genetic manipulation of two differentially expressed genes (san7324 and san7324L) encoding RsbR. These results provide a significant clue for the discovery of new drug candidates and the activation of cryptic biosynthetic gene clusters.

Li|Yue|Y|0000-0003-1557-3568 Yu|Haiying|H| Guan|Hanye|H| Li|Jingjing|J| Zhang|Jihui|J| Xiang|Hua|H| Li|Jine|J|0000-0002-5542-4973 Tan|Huarong|H|

Streptomyces
oviedomycin
RNA-seq analysis
cryptic gene cluster
tylosin analogue compounds 1,2,3 (TACs)


Combined effects of peer presence, social cues, and rewards on cognitive control in adolescents.

Abstract: Developmental scientists have examined the independent effects of peer presence, social cues, and rewards on adolescent decision-making and cognitive control. Yet, these contextual factors often co-occur in real world social situations. The current study examined the combined effects of all three factors on cognitive control, and its underlying neural circuitry, using a task to better capture adolescents' real world social interactions. A sample of 176 participants ages 13-25, was scanned while performing an adapted go/no-go task alone or in the presence of a virtual peer. The task included brief positive social cues and sustained periods of positive arousal. Adolescents showed diminished cognitive control to positive social cues when anticipating a reward in the presence of peers relative to when alone, a pattern not observed in older participants. This behavioral pattern was paralleled by enhanced orbitofrontal activation. The results demonstrate the synergistic impact of social and reward influences on cognitive control in adolescents.

Breiner|Kaitlyn|K|
Li|Anfei|A|
Cohen|Alexandra O|AO|
Steinberg|Laurence|L|
Bonnie|Richard J|RJ|
Scott|Elizabeth S|ES|
Taylor-Thompson|Kim|K|
Rudolph|Marc D|MD|
Chein|Jason|J|
Richeson|Jennifer A|JA|
Dellarco|Danielle V|DV|
Fair|Damien A|DA|
Casey|B J|BJ|
Galván|Adriana|A|0000-0001-6907-4217

peers
reward
cognitive control
adolescents
fMRI
orbitofrontal cortex


Effect of Sphenoid Sinus Pneumatization on the Surgical Windows for Extended Endoscopic Endonasal Transsphenoidal Surgery.

Abstract:
BACKGROUND
Little is known on the impact of the pattern and extent of pneumatization of the sphenoid sinus (SS) on the dimensions of the surgical windows used in extended endoscopic endonasal transsphenoidal approaches. We therefore investigated whether the distances between the 2 optic canals and between the paired paraclival carotid arteries are influenced by the pattern and extent of pneumatization of the SS.

METHODS
One hundred high-resolution computed tomography scans from 47 adult female and 53 adult male patients were analyzed. The pattern of SS pneumatization was classified into conchal, presellar, and sellar types. Sellar-type sinuses were then classified according to a newer detailed classification system. Maximal anteroposterior (AP), transverse (TR), and craniocaudal diameters of the SS, interoptic distance at the limbus sphenoidale (IODL) and at the entrance of the optic canal (IODE) and the intercarotid distance between the paraclival carotids (ICD) were measured. A 2-tailed Mann-Whitney U test and Pearson correlation coefficient (R) were used for statistical analysis. A P value <0.05 was considered statistically significant.

RESULTS
Positive correlation was found between IODL and both AP and TR diameters of the SS; between IODE and both AP and TR diameters of the SS; and between ICD and all diameters of the SS. The highest correlation for each of the IODL, IODE, and ICD was noted with the TR diameter of the SS.

CONCLUSIONS
During the development of the SS, pneumatization progress likely exerts quantitative and direction-specific forces, which gradually increase the interoptic and intercarotid distances.

Azab|Waleed A|WA|
Abdelnabi|Ehab A|EA|
Mostafa|Kamal H|KH|
Burhamah|Talal A|TA|
Alhaj|Ahmad K H|AKH|
Khalil|Ahmed M B|AMB|
Yousef|Waleed|W|
Nasim|Khurram|K|

D057605:Natural Orifice Endoscopic Surgery

Sphenoid Pneumatization Endoscopic Endonasal Transsphenoidal Optic Carotid


Raf-like kinases and receptor-like (pseudo)kinase GHR1 are required for stomatal vapor pressure difference response.

Abstract: Stomatal pores close rapidly in response to low-air-humidity-induced leaf-to-air vapor pressure difference (VPD) increases, thereby reducing excessive water loss. The hydroactive signal-transduction mechanisms mediating high VPD-induced stomatal closure remain largely unknown. The kinetics of stomatal high-VPD responses were investigated by using time-resolved gas-exchange analyses of higher-order mutants in guard-cell signal-transduction branches. We show that the slow-type anion channel SLAC1 plays a relatively more substantial role than the rapid-type anion channel ALMT12/QUAC1 in stomatal VPD signaling. VPD-induced stomatal closure is not affected in mpk12/mpk4GC double mutants that completely disrupt stomatal CO2 signaling, indicating that VPD signaling is independent of the early CO2 signal-transduction pathway. Calcium imaging shows that osmotic stress causes cytoplasmic Ca2+ transients in guard cells. Nevertheless, osca1-2/1.3/2.2/2.3/3.1 Ca2+-permeable channel quintuple, osca1.3/1.7-channel double, cngc5/6-channel double, cngc20-channel single, cngc19/20crispr-channel double, glr3.2/3.3-channel double, cpk-kinase quintuple, cbl1/4/5/8/9 quintuple, and cbl2/3rf double mutants showed wild-type-like stomatal VPD responses. A B3-family Raf-like mitogen-activated protein (MAP)-kinase kinase kinase, M3Kδ5/RAF6, activates the OST1/SnRK2.6 kinase in plant cells. Interestingly, B3 Raf-kinase m3kδ5 and m3kδ1/δ5/δ6/δ7 (raf3/6/5/4) quadruple mutants, but not a 14-gene raf-kinase mutant including osmotic stress-linked B4-family Raf-kinases, exhibited slowed high-VPD responses, suggesting that B3-family Raf-kinases play an important role in stomatal VPD signaling. Moreover, high VPD-induced stomatal closure was impaired in receptor-like pseudokinase GUARD CELL HYDROGEN PEROXIDE-RESISTANT1 (GHR1) mutant alleles. Notably, the classical transient "wrong-way" VPD response was absent in ghr1 mutant alleles. These findings reveal genes and signaling mechanisms in the elusive high VPD-induced stomatal closing response pathway.

Hsu|Po-Kai|PK|
Takahashi|Yohei|Y|
Merilo|Ebe|E|
Costa|Alex|A|0000-0002-2628-1176
Zhang|Li|L|
Kernig|Klara|K|
Lee|Katie H|KH|
Schroeder|Julian I|JI|

GUARD CELL HYDROGEN PEROXIDE-RESISTANT1
Raf-like MAP kinase kinase kinases
abscisic acid
relative air humidity
vapor pressure deficit


Circulating Levels of Inflammation and the Effect on Exercise-Related Changes in Bone Mass, Structure and Strength in Middle-Aged and Older Men.

Abstract: Chronic, low-grade systematic inflammation has been associated with bone loss and increased fracture risk. We previously reported that exercise improved femoral neck bone mineral density (BMD), geometry and strength and lumbar spine trabecular BMD in middle-aged and older men, but had no effect on markers of inflammation. The aim of this study was to examine the association between basal inflammatory status and the adaptive skeletal responses to exercise. Secondary analysis was completed on 91 men aged 50-79 years who participated in an 18-month program of progressive resistance training plus weight-bearing impact exercise (3 day/week) with and without additional calcium-vitamin D3. Markers of inflammation (serum hs-CRP, TNF-α and IL-6) and DXA and QCT-derived BMD, bone structure and strength at the lumbar spine and proximal femur were measured at baseline and 18 months. Multiple regression was used to assess associations between skeletal changes and both baseline levels of individual inflammatory markers and a composite inflammatory index derived from the number of markers categorized into the highest tertile. Baseline serum hs-CRP, TNFα and IL-6 and the composite inflammatory index score were not associated with skeletal changes at any site after adjusting for age, change in lean mass, disease(s)/medication use and adherence to the exercise intervention. In conclusion, this study indicates that basal inflammatory status does not influence the osteogenic response to exercise training in healthy middle-aged and older men.

Dalla Via|Jack|J|
Duckham|Rachel L|RL|
Peake|Jonathan M|JM|
Kukuljan|Sonja|S|
Nowson|Caryl A|CA|
Daly|Robin M|RM|0000-0002-9897-1598

Inflammation
Men
Exercise
Bone mineral density
Bone strength


Recent advances in brassinosteroid biosynthetic pathway: insight into novel brassinosteroid shortcut pathway.

Abstract: Brassinosteroids (BRs) are plant steroid hormones involved in plant growth and environmental adaptation. It is well known that oxidation/hydroxylation steps in the BR biosynthetic pathway are catalyzed by cytochrome P450 enzymes. It has been proposed that brassinolide is biosynthesized from campesterol via campestanol (CN) in the original BR biosynthetic pathway. However, a recent enzymatic analysis of cytochrome P450 enzymes and re-evaluation of the endogenous amount of BRs in BR-deficient mutants included an investigation of the novel BR biosynthetic pathway (CN-independent pathway) not via CN. This review highlights comprehensive recent advances in the biochemical research of BR biosynthetic enzymes and the CN-independent pathway. This review also focuses the biosynthesis inhibitors and the antagonists/agonists that are utilized not only as plant growth regulators but also as tools for the chemical and biological investigation of the physiological functions of BRs.

brassinosteroid
cytochrome P450
biosynthesis
plant growth regulator


Impact of staying at home measures during COVID-19 pandemic on the lifestyle of Qatar's population: Perceived changes in diet, physical activity, and body weight.

Abstract: Countries worldwide imposed different swift protective measures such as movement restrictions and staying at home measures to mitigate the spread of COVID-19. Despite the benefits gained from such measures in containing the spread of the infection, adverse lifestyle consequences happened. In this study we aimed to assess the impact of staying at home measures imposed during COVID-19 pandemic on dietary behaviors, physical activity, and body weight in Qatar's population. A population based cross sectional survey was conducted between December 2020 and February 2021 targeting adults ≥18 years. A total of 1408 participants completed the survey in four languages. Concerning the overall diet perception, 27.8%, and 33.2% perceived that their overall diet has become less healthy, or healthier respectively, since the start of staying at home measures. Almost half of all participants reported weight gain. Participants reported increased sitting/reclining time (1.94 h/day mean increase), screen times (2.05 h/day mean increase) with p < 0.001, and decreased exercise time (0.11 h/day mean reduction) with p < 0.001. The ordinal logistic regression analysis showed that the numbers of unhealthy dietary behaviors adopted by participants, and adverse changes in exercise, setting/reclining and screen times were significantly associated with weight gain. The results of this study indicate that peoples in Qatar have experienced adverse lifestyle changes with regard to their diet, physical activity, and body weight. More emphasis should be put on encouraging people to maintain healthy lifestyle behaviors during home confinement measures that might be imposed during any public health crises or any potential future outbreaks.

Abed Alah|Muna|M|
Abdeen|Sami|S|
Kehyayan|Vahe|V|
Bougmiza|Iheb|I|

COVID-19
Lifestyle
Qatar
Diet
Physical activity
Weight


Functional and structural change in diabetic eyes. Interim results from an ongoing longitudinal prospective study.

Abstract:
PURPOSE
To presents results after 18 months of follow-up of a longitudinal study aiming at exploring the correlation between diabetic retinal vascular lesions and functional change.

METHODS
Patients were consecutively recruited from attendees to the screening program for diabetic retinopathy. Subjects are followed every sixth month for the first 3 years and thereafter annually up to 5 years. Progression of diabetic retinopathy is evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale and improvement/deterioration in visual fields by predefined significance limits for change.

RESULTS
Of 81 subjects, with no/mild/moderate diabetic retinopathy included, 76 have passed the 18-month visit. At that time, retinal progression by two steps according to the ETDRS scale had occurred in two subjects. Visual acuity was -0.14 logMAR and had decreased with two letters (0.04 logMAR) (p < 0.001) from baseline. The global visual field index mean deviation was almost unchanged with a negligible improvement of 0.03 dB (p = 0.79). In 21 subjects, repeated significant deterioration was seen in ≥10% of all points tested in the field, while almost no improved points were noted. The two subjects with retinal progression were not among those 21 with indication of perimetric progression.

CONCLUSIONS
This is, to our knowledge, the first longitudinal study evaluating change of visual fields in a representative diabetic cohort with no or mild/moderate retinopathy. In this interim report, we demonstrate deteriorated perimetric sensitivity in subjects already at 18 months of follow-up. The results will have implications for evaluating change in visual function in future clinical trials.

D000328:Adult
D001794:Blood Pressure
D003922:Diabetes Mellitus, Type 1
D003924:Diabetes Mellitus, Type 2
D003930:Diabetic Retinopathy
D018450:Disease Progression
D005260:Female
D005500:Follow-Up Studies
D006442:Glycated Hemoglobin A
D006801:Humans
D008297:Male
D011446:Prospective Studies
D012160:Retina
D014792:Visual Acuity
D058609:Visual Field Tests
D014794:Visual Fields

diabetic retinopathy
visual function
longitudinal study design
perimetry


Information and support needs of young women regarding breast cancer risk and genetic testing: adapting effective interventions for a novel population.

Abstract: Young women from hereditary breast and ovarian cancer (HBOC) families face a unique set of challenges in managing their HBOC risk, where obtaining essential information to inform decision making is key. Previous work suggests that this need for specific health information also comes at a time of heightened distress and greater individuation from family. In this report, we describe our adaptation of a previously-studied behavioral intervention for this population, utilizing a systematic approach outlined by the Centers for Disease Control and Prevention. First, we assessed the information needs and levels of distress in this population and correlates of this distress. These data then were used to inform the adaptation and piloting of a three-session telephone-based peer coaching intervention. One hundred young women (M age = 25 years) who were first or second degree relatives of BRCA1/2 mutation carriers participated. Sixty-three percent of the sample endorsed unmet HBOC information needs and they, on average, reported moderate levels of cancer-related distress (M = 21.9, SD = 14.6). Greater familial disruption was associated with greater cancer-related distress in multivariable models (p < .05). Ten women who participated in the survey completed the intervention pilot. They reported lower distress from pre- to post- (15.8 vs. 12.0), as well as significantly lower decisional conflict (p < .05) and greater endorsement of an array of healthy coping strategies (i.e., active coping, instrumental coping, positive reframing, planning, p's < .05). Our survey results suggest that young adult women from HBOC families have unmet cancer genetic information and support needs. Our pilot intervention was able to reduce levels of decisional conflict and promote the use of effective coping strategies. This approach needs to be further tested in a larger randomized trial.

O'Neill|Suzanne C|SC|
Evans|Chalanda|C|
Hamilton|Rebekah J|RJ|
Peshkin|Beth N|BN|
Isaacs|Claudine|C|
Friedman|Sue|S|
Tercyak|Kenneth P|KP|

D006301:Health Services Needs and Demand

D061325:Hereditary Breast and Ovarian Cancer Syndrome

Women Breast Intervention Peer BRCA Telephone


Development of a novel hybrid strategy for transcatheter pulmonary valve placement in patients following transannular patch repair of tetralogy of fallot.

Abstract:
BACKGROUND
Transcatheter pulmonary valve replacement (tPVR) is an accepted therapy for treatment of dysfunctional right ventricular outflow tract (RVOT) conduits. At present, the majority of Fallot patients who undergo transannular patch (TAP) repair are not candidates for tPVR due to the large irregular nature of their RVOT. Herein, we describe a novel approach to assessing the RVOT in this group, which may then be used to design, test, and carry out hybrid RVOT modification and transcatheter valve implantation in this population.

METHODS
A retrospective analysis of TAP patients who underwent 3D modeling of the RVOT which was then used to develop individualized hybrid procedures designed to modify the RVOT, thereby rendering patients suitable for transcatheter valve implantation.

RESULTS
Eight consecutive patients underwent 3D RVOT modeling followed by hybrid implantation of a transcatheter valve via a perventricular approach. A landing zone stent was placed in all and four required additional intravascular geometric remodeling of the RVOT prior to valve implant. Transcatheter valves were successfully implanted in all. There were no instances of valve malposition, embolization, or death. There was one minor procedural complication. No patient had more than trivial pulmonary regurgitation at follow-up.

CONCLUSIONS
Using a hybrid approach to remodel the RVOT in TAP patients supported by preprocedural 3D-model planning allows for successful tPVR implantation in this population. A larger cohort and longer follow-up will be needed to determine the ultimate utility of this approach.

Phillips|Alistair B M|AB|
Nevin|Phillip|P|
Shah|Avni|A|
Olshove|Vincent|V|
Garg|Ruchira|R|
Zahn|Evan M|EM|

D019918:Heart Valve Prosthesis Implantation

pulmonary valve
congenital
tetralogy Fallot


Changes in plasma levels of B-type natriuretic peptide with acute exacerbations of chronic obstructive pulmonary disease.

Abstract:
BACKGROUND
Elevated plasma B-type natriuretic peptide (BNP) levels and their association with heart failure have been reported in subjects with acute exacerbations of chronic obstructive pulmonary disease (AECOPD).

PURPOSE
To examine and compare plasma BNP levels and diastolic and systolic dysfunction in subjects with AECOPD and stable chronic obstructive pulmonary disease (COPD).

METHODS
In all, 87 unselected consecutive hospitalizations due to AECOPD in 61 subjects and a total of 190 consecutive subjects with stable COPD were recruited. Plasma BNP levels were compared cross-sectionally and longitudinally. Transthoracic echocardiographic examinations were also performed in the hospitalized subjects.

RESULTS
In the hospitalized subjects, the median plasma BNP level (interquartile range) was 55.4 (26.9-129.3) pg/mL and was higher than that of patients with stable COPD: 18.3 (10.0-45.3) for Global Initiative for Chronic Obstructive Lung Disease grade I; 25.8 (11.0-53.7) for grade II; 22.1 (9.1-52.6) for grade III; and 17.2 (9.6-22.9) pg/mL for grade I V, all P<0.001. In 15 subjects studied prospectively, the median plasma BNP level was 19.4 (9.8-32.2) pg/mL before AECOPD, 72.7 (27.7-146.3) pg/mL during AECOPD, and 14.6 (12.9-39.0) pg/mL after AECOPD (P<0.0033 and P<0.0013, respectively). Median plasma BNP levels during AECOPD were significantly higher in ten unsuccessfully discharged subjects 260.5 (59.4-555.0) than in 48 successfully discharged subjects 48.5 (24.2-104.0) pg/mL (P=0.0066). Only 5.6% of AECOPD subjects were associated with systolic dysfunction defined as a left ventricular ejection fraction (LVEF) <50%; a further 7.4% were considered to have impaired relaxation defined as an E/A wave velocity ratio <0.8 and a deceleration time of E >240 ms. BNP levels were weakly correlated with the E/peak early diastolic velocity of the mitral annulus (Ea) ratio (Spearman's rank correlation coefficient =0.353, P=0.018), but they were not correlated with the LVEF (Spearman's rank correlation coefficient =-0.221, P=0.108).

CONCLUSION
A modest elevation of plasma BNP is observed during AECOPD. It appears that AECOPD may have an impact on plasma BNP levels that is not attributable to heart failure.

Nishimura|Koichi|K|
Nishimura|Takashi|T|
Onishi|Katsuya|K|
Oga|Toru|T|
Hasegawa|Yoshinori|Y|
Jones|Paul W|PW|

D029424:Pulmonary Disease, Chronic Obstructive


Influence of procyanidin supplementation on the immune responses of broilers challenged with lipopolysaccharide.

Abstract: In the present study, the effect of dietary procyanidin (PCA, from pine needles) supplementation on the innate immunity of broilers were investigated. The experiment was designed as a 2 × 4 factorial arrangement (eight cages / treatment; six birds (one-day-old) / cage) with dietary PCA concentrations (0, 0.05, 0.075 and 0.1%) and two immune treatments (injection of lipopolysaccharide (LPS) (0.5 mg/kg body weight) or saline). LPS was dissolved in sterile 9 g/L (w/v) NaCl solution at 16, 18, 20 days of age to mimic immune stress. The remaining birds were injected with saline as a placebo. The results indicated that, prior to LPS challenge, the PCA diet had no significant effect on bird growth performance. The injection of LPS was also not associated with any significant changes in poultry performance. LPS injection increased the activity of nitrogen oxides (NOx) and the concentrations of inflammatory cytokines (interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-2, IL-4, IL-6 and IL-10) in serum; dietary PCA decreased these concentrations (P < 0.05) in the PCA 0.1% group, further illustrating the immune effect of PCA. In conclusion, PCA supplementation has a beneficial effect on LPS challenge, which may be associated with the inhibition of the secretion of cytokines and decrease in the proinflammatory marker NOx.

Wu|Qiu Jue|QJ|
Wang|Yu Qin|YQ|
Qi|Yan Xia|YX|

procyanidin
broiler
lipopolysaccharide
cytokines
nitric oxide


Keratin 8 is a novel autoantigen of rheumatoid arthritis.

Abstract:
OBJECTIVE
This research aims to verify Keratin 8 (K8) as a specific autoantigen in rheumatoid arthritis (RA).

METHODS
First, total RNA was extracted from HaCaT cell to obtain cDNA by inverse transcription. Then, PCR was performed to amplify corresponding gene by K8 primers. Next, cloning, expression, and purification technology were used to obtain the recombinant human K8 (rhK8). At last, the purified rhK8, after identified by mass spectrometer, was used to perform further disease-related Western blotting and ELISA test with real clinical samples.

RESULTS
Purified rhK8 was successfully obtained and then Western blotting confirmed antigenicity of K8 in rheumatoid arthritis. The reactivity of serum IgG against rhK8 was further detected in 34 of 50 RA patients (68%). The reactivity of RA serum IgG antibodies against K8 was significantly higher than healthy controls and systemic lupus erythematosus (SLE) patients.

CONCLUSION
This research confirmed Keratin 8 as a novel autoantigen of RA.

Wang|Xiaoxu|X| Chen|Peng|P| Cui|Jiawen|J| Yang|Chunhe|C| Du|Hongwu|H|

Keratin 8
Autoantigen
Rheumatoid arthritis


Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells.

Abstract: The triggering of gemcitabine (GEM) drug resistance in pancreatic cancer by the receptor for advanced glycation end products (RAGE) has been demonstrated. Hence, finding a safe and effective adjuvant for preventing pancreatic cancer progression is imperative. Quercetin is a flavonoid that is abundant in apples, grapes, red raspberry, and onions and has been reported to inhibit RAGE. This research aimed to investigate the mechanisms of quercetin in regulating cell death and enhancing drug effects through RAGE reduction, especially in GEM-resistant pancreatic cancer cells. Our results showed that silencing RAGE expression by RAGE-specific siRNA transfection significantly increased cell death by apoptosis, autophagy and GEM-induced cytotoxicity by suppressing the PI3K/AKT/mTOR axis in MIA Paca-2 and MIA Paca-2 GEMR cells (GEM-resistant cells). Notably, quercetin showed a dramatic effect similar to RAGE silencing that effectively attenuated RAGE expression to facilitate cell cycle arrest, autophagy, apoptosis, and GEM chemosensitivity in MIA Paca-2 GEMR cells, suggesting that an additional reaction occurred under combined quercetin and GEM treatment. In conclusion, the results demonstrated that the molecular mechanisms of quercetin in regulating apoptosis and autophagy-related pathways and increasing GEM chemosensitivity in pancreatic cancer cells involved inhibition of RAGE expression.

Lan|Chieh-Yu|CY| Chen|Sheng-Yi|SY| Kuo|Chia-Wen|CW| Lu|Chi-Cheng|CC| Yen|Gow-Chin|GC|

D004354:Drug Screening Assays, Antitumor

D000067759:Receptor for Advanced Glycation End Products

Quercetin
RAGE
Pancreatic cancer
Autophagy
Gemcitabine resistance


A rare case of hepatocellular carcinoma with bile duct invasion diagnosed by peroral cholangioscopy.

Abstract: Video 1Peroral cholangioscopy showed a 20-mm-diameter, stalked, floating, round mass in the hilar region. The surface of the tumor was covered with white fur, and the tumor tissue was partially exposed in a map-like pattern. The mass was penetrable even with a guidewire, and it bled easily. Biopsies were performed using biopsy forceps, and the tumor bled easily even with biopsy.

Ito|Risako|R| Kobayashi|Masanori|M| Ohtsuka|Kazuo|K| Tanabe|Minoru|M| Okamoto|Ryuichi|R|

HCC, hepatocellular carcinoma
POCS, peroral cholangioscopy


A Dyciandiamine-Based Methacrylate-Epoxy Dual-Cure Blend-System for Stereolithography.

Abstract: In this research, an epoxy-based dual-cure system is developed and characterized for SLA additive manufacturing. Dual-cure systems consist of UV-curable acrylates and thermal active components. The second curing step offers an additional degree of freedom to design specific material properties. In this study, a blend of varying concentrations of an epoxy/curing agent mix, respectively, DGEBA, DICY and photocurable methacrylate, was used to create a material that is printable in the SLA process into a UV-cured or green part and subsequently thermally cured to achieve superior thermal and mechanical properties. Calorimetric measurements were performed to determine the reactivity of the thermal reaction at different concentrations of epoxy. The fully cured specimens were tested in mechanical and dynamic mechanical measurements, and the results showed a significant improvement in tensile stress and glass transition temperature with rising epoxy concentrations. Fractured surfaces from tensile testing were investigated to further characterize the failure of tested samples, and thermal degradation was determined in TGA measurements, which showed no significant changes with an increasing epoxy concentration.

dual-cure
additive manufacturing (AM)
stereolithography (SLA)


Chromatin Landscape During Skeletal Muscle Differentiation.

Abstract: Cellular commitment and differentiation involve highly coordinated mechanisms by which tissue-specific genes are activated while others are repressed. These mechanisms rely on the activity of specific transcription factors, chromatin remodeling enzymes, and higher-order chromatin organization in order to modulate transcriptional regulation on multiple cellular contexts. Tissue-specific transcription factors are key mediators of cell fate specification with the ability to reprogram cell types into different lineages. A classic example of a master transcription factor is the muscle specific factor MyoD, which belongs to the family of myogenic regulatory factors (MRFs). MRFs regulate cell fate determination and terminal differentiation of the myogenic precursors in a multistep process that eventually culminate with formation of muscle fibers. This developmental progression involves the activation and proliferation of muscle stem cells, commitment, and cell cycle exit and fusion of mononucleated myoblast to generate myotubes and myofibers. Although the epigenetics of muscle regeneration has been extensively addressed and discussed over the recent years, the influence of higher-order chromatin organization in skeletal muscle regeneration is still a field of development. In this review, we will focus on the epigenetic mechanisms modulating muscle gene expression and on the incipient work that addresses three-dimensional genome architecture and its influence in cell fate determination and differentiation to achieve skeletal myogenesis. We will visit known alterations of genome organization mediated by chromosomal fusions giving rise to novel regulatory landscapes, enhancing oncogenic activation in muscle, such as alveolar rhabdomyosarcomas (ARMS).

Hernández-Hernández|Oscar|O|
Ávila-Avilés|Rodolfo Daniel|RD|
Hernández-Hernández|J Manuel|JM|

MyoD
myogenic regulatory factors
muscle regeneration
myogenesis
satellite cells


Epidemiology of vulvar neoplasia in the NIH-AARP Study.

Abstract:
OBJECTIVE
To clarify risk factors for rare vulvar neoplasms.

METHODS
Within the NIH-AARP Study, among 201,469 women interviewed in 1995-1996 and followed for a mean of 13.8years, there were 370 diagnoses of incident vulvar neoplasms, including 170 invasive and 198 vulvar intraepithelial neoplasms grade 3 (VIN3). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated via multivariate logistic regression for various demographic, reproductive and lifestyle factors, with separate consideration of relations according to invasiveness, histology and age at diagnosis.

RESULTS
Consistent with descriptive data, we found non-white women at lower risks of vulvar neoplasia than white women (HR=0.59, 95% CI 0.36-0.95). Significant risk factors for VIN3 included being divorced/separated (HR vs. currently married=1.77, 95% CI 1.24-2.51), a current cigarette smoker (3.88, 95% CI 2.64-5.72), a user of oral contraceptives (1.46, 95% CI 1.06-2.01), or a current user of menopausal hormones (1.73, 95% CI 1.24-2.41). Significant risk factors for invasive cancers were being obese (HR for BMI ≥30 vs. <25=1.62, 95% CI 1.10-2.40) or a current smoker (1.86, 95% CI 1.21-2.87). Cigarette smoking was a risk factor mainly for neoplasms shown in other investigations to be HPV-related, namely VIN3 and invasive squamous cell cancers (SCCs) occurring in the younger stratum of cases. In contrast, obesity was primarily associated with the development of invasive SCCs.

CONCLUSIONS
Our results support that vulvar neoplasia is a heterogeneous disease. VIN3 demonstrated risk factors consistent with an HPV-related etiology, while invasive cancers were additionally affected by obesity, suggesting that further attention should focus on the role of chronic inflammatory conditions.

Brinton|Louise A|LA|
Thistle|Jake E|JE|
Liao|Linda M|LM|
Trabert|Britton|B|

Epidemiology
Vulvar neoplasia
Risk
Invasive
VIN3
Squamous cell carcinomas


Safety and efficacy of concomitant chemotherapeutic wafers and iodine-125 seeds for recurrent glioblastoma.

Abstract:
BACKGROUND
Patients with recurrent malignant gliomas have a uniformly poor prognosis. However, further treatment is often warranted at the time of recurrence. Low-activity implanted brachytherapeutic devices, such as iodine-125 seeds, and implantable chemotherapeutic devices such as 1, 3-bis (2-chloroethyl)-nitrosourea (BCNU) impregnated polymer wafers (Gliadel(®)) have been shown to be safe and modestly effective, but a comparison of combination therapy versus Gliadel(®) implantation alone has not been performed.

METHODS
We retrospectively examined 24 patients following re-resection of recurrent glioblastoma, with 17 patients undergoing implantation of both Gliadel(®) and iodine-125 seeds, and 7 patients undergoing implantation of Gliadel(®) only. Outcomes examined included adverse events, survival after re-resection (SAR), and time to tumor progression after re-resection (PAR).

RESULTS
Implantation of both Gliadel(®) and low activity iodine-125 seeds is safe with only two wound infections noted, a complication rate comparable to previous reports. The combination appears to confer a median SAR benefit if the activity per tumor resection volume exceeds 0.8 mCi/mL (60 versus 31 weeks, P = 0.02), and this benefit remained significant on multivariate analysis (HR =0.26 [CI:0.07-0.93], P = 0.03). Gross total resection of tumor was also significantly associated with longer time to PAR (HR =5.4 [CI: 1.13-26.0], P = 0.03).

CONCLUSIONS
The concomitant use of Gliadel(®) and low activity iodine-125 seeds following re-resection of recurrent glioblastoma is safe. Our study demonstrated a significant benefit in SAR if the iodine-125 activity per tumor volume is greater than 0.8 mCi/mL. While our sample size is small, our results are in agreement with previous studies demonstrating the efficacy of combination treatment.

Ko|Andrew L|AL|
Fink|Kathleen R|KR|
Stelzer|Keith M|KM|
Silbergeld|Daniel L|DL|

iodine-125
recurrent glioblastoma
Gliadel®
surgical re-resection


Caffeine and glucosamine mobility shifts by adduction with 2-butanol depended on interaction energy, charge delocalization, and steric hindrance in ion mobility spectrometry.

Abstract: Ion mobility spectrometry (IMS) is an analytical technique that separates gas-phase ions drifting under an electric field according to their size to charge ratio. We used electrospray ionization-drift tube IMS coupled to quadrupole mass spectrometry to measure the mobilities of glucosamine (GH+ ) and caffeine (CH+ ) ions in pure nitrogen or when the shift reagent (SR) 2-butanol was introduced in the drift gas at 6.9 mmol m-3 . Binding energies of 2-butanol-ion adducts were calculated using Gaussian 09 at the CAMB3LYP/6-311++G(d,p) level of theory. The mobility shifts with the introduction of 2-butanol in the drift gas were -2.4% (GH+ ) and -1.7% (CH+ ) and were due to clustering of GH+ and CH+ with 2-butanol. The formation of GBH+ was favored over that of CBH+ because GBH+ formed more stable hydrogen bonds (83.3 kJ/mol) than CBH+ (81.7 kJ/mol) for the reason that the positive charge on CH+ is less sterically available than on GH+ and the charge is stabilized by resonance in CH+ . These results are a confirmation of the arguments used to explain the drift behavior of these ions when ethyl lactate SR was used (Bull Kor Chem Soc 2014, 1023-1028). This study is a step forward to predict IMS separations of overlapping peaks in IMS spectra, simplifying a procedure that is trial and error by now.

caffeine
glucosamine
2-butanol
ion mobility spectrometry
buffer gas modifier
dopant


Pain as metaphor: metaphor and medicine.

Abstract: Like many other disciplines, medicine often resorts to metaphor in order to explain complicated concepts that are imperfectly understood. But what happens when medicine's metaphors close off thinking, restricting interpretations and opinions to those of the negative kind? This paper considers the deleterious effects of destructive metaphors that cluster around pain. First, the metaphoric basis of all knowledge is introduced. Next, a particular subset of medical metaphors in the domain of neurology (doors/keys/wires) are shown to encourage mechanistic thinking. Because schematics are often used in medical textbooks to simplify the complex, this paper traces the visual metaphors implied in such schematics. Mechanistic-metaphorical thinking results in the accumulation of vast amounts of data through experimentation, but this paper asks what the real value of the information is since patients can generally only expect modest benefits--or none at all--for relief from chronic pain conditions. Elucidation of mechanism through careful experimentation creates an illusion of vast medical knowledge that, to a significant degree, is metaphor-based. This paper argues that for pain outcomes to change, our metaphors must change first.


Effects of nicotine and stress exposure across generations in C57BL/6 mice.

Abstract: Chronic administration of nicotine or exposure to stress can produce long-lasting behavioral and physiological changes in humans and animals alike. Further, the impact of nicotine and stress exposure can be inherited by offspring to produce persistent changes in physiology and behavior. To determine if nicotine and stress interact across generations to influence offspring behavior we exposed F0 male mice to nicotine and F1 male and female mice to chronic unpredictable stress during adolescence. We then measured locomotor sensitization to repeated nicotine injections in the subsequent F2 and F3 generations. Stress exposure alone (F1) did not influence locomotor sensitization in any lineage. However, in the F1 male lineage, F0 nicotine exposure abrogated locomotor sensitization in F2 male and transiently enhanced locomotor sensitization in F2 female offspring. These effects were not passed down to the F3 generations or observed in the F1 female lineage. F1 stress exposure modulated the effects of prior F0 nicotine exposure in a sex-dependent manner. Specifically, stress blunted the nicotine-induced enhancement in locomotor sensitization observed in F2 female offspring of F1 males. The effect of F0 nicotine and F1 stress exposure in females appears to have skipped a generation and enhanced nicotine sensitization only in the F3 generation, and only in females. This novel multigenerational exposure paradigm examining the inheritance of two different environmental exposures demonstrates that nicotine responses can be modified by nicotine and stress exposure from previous generations, and these effects are strongly influenced by sex.

Yohn|Nicole L|NL|
Caruso|Michael J|MJ|0000-0002-5809-4930
Blendy|Julie A|JA|

D011297:Prenatal Exposure Delayed Effects

nicotine
mice
chronic unpredictable stress
adolescent
locomotor sensitization
Transgenerational inheritance


Neuroprotective therapies in glaucoma: II. Genetic nanotechnology tools.

Abstract: Neurotrophic factor genome engineering could have many potential applications not only in the deeper understanding of neurodegenerative disorders but also in improved therapeutics. The fields of nanomedicine, regenerative medicine, and gene/cell-based therapy have been revolutionized by the development of safer and efficient non-viral technologies for gene delivery and genome editing with modern techniques for insertion of the neurotrophic factors into clinically relevant cells for a more sustained pharmaceutical effect. It has been suggested that the long-term expression of neurotrophic factors is the ultimate approach to prevent and/or treat neurodegenerative disorders such as glaucoma in patients who do not respond to available treatments or are at the progressive stage of the disease. Recent preclinical research suggests that novel neuroprotective gene and cell therapeutics could be promising approaches for both non-invasive neuroprotection and regenerative functions in the eye. Several progenitor and retinal cell types have been investigated as potential candidates for glaucoma neurotrophin therapy either as targets for gene therapy, options for cell replacement therapy, or as vehicles for gene delivery. Therefore, in parallel with deeper understanding of the specific protective effects of different neurotrophic factors and the potential therapeutic cell candidates for glaucoma neuroprotection, the development of non-invasive and highly specific gene delivery methods with safe and effective technologies to modify cell candidates for life-long neuroprotection in the eye is essential before investing in this field.

glaucoma
nanotechnology
ZFN- TALEN-CRISPR/Cas
gene and cell therapy
minicircle DNA vectors
neurodegenerative disease
neurotrophic factor therapy
transposon systems


Chemoenzymatic Synthesis of Pleiogenone A: An Antiproliferative Trihydroxyalkylcyclohexenone Isolated from Pleiogynium timorense.

Abstract: The first total synthesis of polyhydroxylated cyclohexenone 1, isolated from Pleiogynium timorense and named pleiogenone A, is reported that also serves as a proof of structure and absolute configuration. Enzymatic dihydroxylation of benzoic acid with R. eutrophus B9 provided enantiomerically pure diene diol 6. Elaboration of the carboxylate moiety to the alkyl side chain was followed by singlet oxygen cycloaddition to furnish an endoperoxide whose reduction with thiourea led to cyclitol 19. Several protective operations were required before oxidation and the final extension of the side chain by a Wittig reaction. After final deprotection of the acetonide functionality the desired pleiogenone A (1) was obtained in 14 operations from benzoic acid.

trihydroxyalkylcyclohexenones
Pleiogynium timorense
enzymatic dihydroxylation
singlet oxygen cycloaddition
anticancer activity


Discovery and Functional Prediction of Long Non-Coding RNAs Common to Ischemic Stroke and Myocardial Infarction.

Abstract:
Objective
Ischemic stroke and myocardial infarction are 2 of the leading causes of mortality. Both conditions are caused by arterial occlusion, resulting in ischemic necrosis of the cells in the cortex and heart. Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs longer than 200 nucleotides without protein-coding potential. Thousands of lncRNAs have been identified but their involvement in ischemic stroke and myocardial infarction has not been studied extensively. Therefore, this study aimed to identify the role of lncRNAs, particularly those that are commonly altered in these two ischemic injuries.

Methods
We combined diverse RNA sequencing data obtained from public databases and performed extensive bioinformatics analyses to determine reliable lncRNAs commonly identified from these datasets. Using sequence analysis, we also detected the lncRNAs that may act as microRNA (miRNA) regulators.

Results
We found several altered lncRNAs that were common in ischemic stroke and myocardial infarction models. Some of these lncRNAs, including zinc finger NFX1-type containing 1 antisense RNA 1 and small nucleolar RNA host gene 1, were previously reported to be involved in the pathogenesis of each of these models. Interestingly, several lncRNAs had binding sites for miRNAs that were previously reported to be involved in the hypoxic response, suggesting the possible role of these lncRNAs as regulators in ischemic responses.

Conclusion
The lncRNAs identified in this study will be useful in determining the regulatory networks in ischemic stroke and myocardial infarction and in identifying potential specific markers for each of these ischemic diseases.

Long non-coding RNA
Stroke
Myocardial infarction
MicroRNAs


JCL Roundtable: is inflammation a future target in preventing arteriosclerotic cardiovascular disease.

Abstract: It has been a long developing concept that inflammatory infiltration by white blood cells from the blood plasma is an important part of the atherosclerotic process. However, we have thought of this as a secondary phenomenon resulting from the causative insults of high concentrations of apolipoprotein B (apoB)-containing lipoproteins, toxins such as those from cigarette smoke, high blood pressure, and high blood glucose. Much research has provided evidence as to how the invading cells interact with the basic components of the arterial structure to produce the damage observed throughout the vessel wall. We have focused our preventive efforts on the clinical risk factors with significant but partial success in patients with active disease. It is a relatively new concept that suppressing the inflammation itself, as an adjunct to risk factor modification, could help reduce the clinical manifestations of atherosclerosis. This concept is now being tested in randomized clinical trials. Our discussants in this Roundtable are Dr Alan Remaley, a Senior Investigator in the Lipoprotein Metabolism Section of the National Heart Lung and Blood Institute and Dr Paul Ridker, a cardiologist at the Brigham and Women's Hospital and a Professor at the Harvard Medical School. Both have made very significant contributions to our understanding of the signaling process that drives this inflammatory aspect of the disease.

Brown|W Virgil|WV|
Remaley|Alan T|AT|
Ridker|Paul M|PM|

Inflammation
Prevention
Apolipoprotein B
Atherosclerosis
ASCVD


Advice on chemical weapons sample stability and storage provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons to increase investigative capabilities worldwide.

Abstract: The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice on the long-term storage and stability of samples collected in the context of chemical weapons investigations. The information they compiled and reviewed is beneficial to all laboratories that carry out analysis of samples related to chemical warfare agents and is described herein. The preparation of this report was undertaken on request from the OPCW Director-General. The main degradation products for chemicals on the Schedules in the Annex on Chemicals of the Chemical Weapons Convention are tabulated. The expertise of the 25 scientists comprising the SAB, a review of the scientific literature on environmental and biomedical sample analysis, and answers to a questionnaire from chemists of nine OPCW Designated Laboratories, were drawn upon to provide the advice. Ten recommendations to ensure the long-term storage and stability of samples collected in relation to the potential use of chemical weapons were provided and are repeated here for the consideration of all laboratories worldwide.

Timperley|Christopher M|CM|
Forman|Jonathan E|JE|
Abdollahi|Mohammad|M|
Al-Amri|Abdullah Saeed|AS|
Alonso|Isel Pascual|IP|
Baulig|Augustin|A|
Borrett|Veronica|V|
Cariño|Flerida A|FA|
Curty|Christophe|C|
Berrutti|David González|DG|
Kovarik|Zrinka|Z|
Martínez-Álvarez|Roberto|R|
Mikulak|Robert|R|
Mourão|Nicia Maria Fusaro|NMF|
Ponnadurai|Ramasami|R|
Neffe|Slawomir|S|
Raza|Syed K|SK|
Rubaylo|Valentin|V|
Takeuchi|Koji|K|
Tang|Cheng|C|
Trifirò|Ferruccio|F|
van Straten|Francois Mauritz|FM|
Vanninen|Paula S|PS|
Zaitsev|Volodymyr|V|
Waqar|Farhat|F|
Zina|Mongia Saïd|MS|
Blum|Marc-Michael|MM|
Gregg|Hugh|H|
Fischer|Elena|E|
Sun|Siqing|S|
Yang|Pei|P|


An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA.

Abstract: Helicobacter pylori is a specific gastric pathogen that colonizes the stomach in more than 50% of the world's human population. Infection with this bacterium can induce several types of gastric pathology, ranging from chronic gastritis to peptic ulcers and even adenocarcinoma. Virulent H. pylori isolates encode components of a type IV secretion system (T4SS), which form a pilus for the injection of virulence proteins such as CagA into host target cells. This is accomplished by a specialized adhesin on the pilus surface, the protein CagL, a putative VirB5 ortholog, which binds to host cell β(1) integrin, triggering subsequent delivery of CagA across the host cell membrane. Like the human extracellular matrix protein fibronectin, CagL contains an RGD (Arg-Gly-Asp) motif and is able to trigger intracellular signaling pathways by RGD-dependent binding to integrins. While CagL binding to host cells is mediated primarily by the RGD motif, we identified an auxiliary binding motif for CagL-integrin interaction. Here, we report on a surface exposed FEANE (Phe-Glu-Ala-Asn-Glu) interaction motif in spatial proximity to the RGD sequence, which enhances the interactions of CagL with integrins. It will be referred to as RGD helper sequence (RHS). Competitive cell adhesion assays with recombinant wild type CagL and point mutants, competition experiments with synthetic cyclic and linear peptides, and peptide array experiments revealed amino acids essential for the interaction of the RHS motif with integrins. Infection experiments indicate that the RHS motif plays a role in the early interaction of H. pylori T4SS with integrin, to trigger signaling and to inject CagA into host cells. We thus postulate that CagL is a versatile T4SS surface protein equipped with at least two motifs to promote binding to integrins, thereby causing aberrant signaling within host cells and facilitating translocation of CagA into host cells, thus contributing directly to H. pylori pathogenesis.

Conradi|Jens|J|
Tegtmeyer|Nicole|N|
Woźna|Marta|M|
Wissbrock|Marco|M|
Michalek|Carmela|C|
Gagell|Corinna|C|
Cover|Timothy L|TL|
Frank|Ronald|R|
Sewald|Norbert|N|
Backert|Steffen|S|

D020816:Amino Acid Motifs
D000942:Antigens, Bacterial
D001422:Bacterial Adhesion
D001426:Bacterial Proteins
D002460:Cell Line
D004847:Epithelial Cells
D016480:Helicobacter pylori
D054884:Host-Pathogen Interactions
D006801:Humans
D016023:Integrins
D050505:Mutant Proteins
D017354:Point Mutation
D011485:Protein Binding
D025941:Protein Interaction Mapping
D021381:Protein Transport

CagL
binding motifs
ERK kinase
cortactin
integrin interaction
α5β1


WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors.

Abstract: Here we present WIDOCK, a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity towards cysteine residues into AutoDock4. WIDOCK applies the reactive docking method (Backus et al. in Nature 534:570-574, 2016) and extends it into a virtual screening tool by introducing facile experimental or computational parametrization and a ligand focused evaluation scheme together with a retrospective and prospective validation against various therapeutically relevant targets. Parameters accounting for ligand reactivity are derived from experimental reaction kinetic data or alternatively from computed reaction barriers. The performance of this docking protocol was first evaluated by investigating compound series with diverse warhead chemotypes against KRASG12C, MurA and cathepsin B. In addition, WIDOCK was challenged on larger electrophilic libraries screened against OTUB2 and NUDT7. These retrospective analyses showed high sensitivity in retrieving experimental actives, by also leading to superior ROC curves, AUC values and better enrichments than the standard covalent docking tool available in AutoDock4 when compound collections with diverse warheads were investigated. Finally, we applied WIDOCK for the prospective identification of covalent human MAO-A inhibitors acting via a new mechanism by binding to Cys323. The inhibitory activity of several predicted compounds was experimentally confirmed and the labelling of Cys323 was proved by subsequent MS/MS measurements. These findings demonstrate the usefulness of WIDOCK as a warhead-sensitive, covalent virtual screening protocol.

Scarpino|Andrea|A|
Petri|László|L|
Knez|Damijan|D|
Imre|Tímea|T|
Ábrányi-Balogh|Péter|P|
Ferenczy|György G|GG|
Gobec|Stanislav|S|
Keserű|György M|GM|0000-0003-1039-7809

Virtual screening
Covalent inhibitors
Covalent docking
Warhead reactivity


Simultaneous determination of various bioactive redox components in Shuang-Huang-Lian preparations using a novel three-channel isocratic elution liquid chromatography with electrochemical detection system.

Abstract: A novel three-channel isocratic elution high performance liquid chromatography with electrochemical detection (3LC-ECD) system was developed for the simultaneous determination of various bioactive redox components in Shuang-Huang-Lian (SHL) preparations. This 3LC-ECD system consists of three isocratic elution flow ways, two switching valves, four columns, and three electrochemical detectors. Through alternately rotating switching valves to change the elution flow way, six caffeoylquinic acids, four flavonoids, and one phenylethanoid glycoside compound were simultaneously determined within 70 min by the present 3LC-ECD method, in which three compounds of protocatechuic aldehyde, propyl gallate, and kaempferol were used as internal standards. The results demonstrated that the present 3LC-ECD method has achieved desired linearity (r>0.999), precision (relative standard deviation <2.5%), accuracy (recovery, 95.6-103.6%), and high sensitivity (limit of detection, 0.11-0.90 ng/mL). In addition, we successfully determined the contents of these 11 bioactive redox components in 14 batches of SHL oral liquid and 12 batches of SHL lyophilized powder for injection produced by different manufacturers in China.

Chen|Liangmian|L| Hakamata|Hideki|H| Kusu|Fumiyo|F| Wang|Zhimin|Z| Gao|Huimin|H| Kotani|Akira|A|

D002851:Chromatography, High Pressure Liquid

Electrochemical detection
Caffeoylquinic acids
Flavonoids
Phenylethanoid glycosides
Shuang–Huang–Lian (SHL)