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Rizzi A,Murkli S,McNeill JN,Yao W,Sullivan M,Gilson MK,Chiu MW,Isaacs L,Gibb BC,Mobley DL,Chodera JD
Overview of the SAMPL6 host-guest binding affinity prediction challenge.
J Comput Aided Mol Des. 2018 Nov 10;
Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host-guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy.
PMID: 30415285
Bierma JC,Roskamp KW,Ledray AP,Kiss AJ,Christina Cheng CH,Martin RW
Controlling Liquid-Liquid Phase Separation of Cold-Adapted Crystallin Proteins from the Antarctic Toothfish.
J Mol Biol. 2018 Nov 08;
Liquid-liquid phase separation (LLPS) of proteins is important to a variety of biological processes both functional and deleterious, including the formation of membraneless organelles, molecular condensations that sequester or release molecules in response to stimuli, and the early stages of disease-related protein aggregation. In the protein-rich, crowded environment of the eye lens, LLPS manifests as cold cataract. We characterize the LLPS behavior of six structural ?-crystallins from theeye lens of the Antarctic toothfish Dissostichus mawsoni, whose intact lenses resist cold cataract in subzero waters. Phase separation of these proteins is not strongly correlated with thermal stability, aggregation propensity, or cross-species chaperone protection from heat denaturation. Instead, LLPS is driven by protein-protein interactions involving charged residues. The critical temperature of the phase transition can be tuned over a wide temperature range by selective substitution of surface residues, suggesting general principles for controlling this phenomenon, even in compactly folded proteins.
PMID: 30414964
Lee K,Pouldar D,Shiu J,Elsensohn A,de Feraudy S
The histological spectrum of Talimogene laherparepvec (TVEC) injections-neutrophilic and chronic granulomatous dermatitis.
J Cutan Pathol. 2018 Nov 09;
We read with interest the case series by Everett et al. (1) describing chronic granulomatous dermatitis at sites of Talimogene laherparepvec (TVEC) injections for advanced melanoma. This article is protected by copyright. All rights reserved.
PMID: 30414194
Di K,Lomeli N,Bota DA,Das BC
Magmas inhibition as a potential treatment strategy in malignant glioma.
J Neurooncol. 2018 Nov 09;
Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved, ubiquitously expressed in mammalian cells, and is essential for cell viability. Magmas expression levels are increased in prostate cancers and pituitary adenomas. Moreover, silencing Magmas by RNAi sensitizes pituitary adenoma cells to pro-apoptotic stimuli and induces a G0/G1 accumulation. The aim of this study was to examine whether inhibition of Magmas by small molecule inhibitors could be beneficial for the treatment of malignant gliomas.
PMID: 30414099
Okada Y,Sumioka T,Ichikawa K,Sano H,Nambu A,Kobayashi K,Uchida K,Suzuki Y,Tominaga M,Reinach PS,Hirai SI,Jester JV,Miyajima M,Shirai K,Iwanishi H,Kao WW,Liu CY,Saika S
Sensory nerve supports epithelial stem cell function in healing of corneal epithelium in mice: the role of trigeminal nerve transient receptor potential vanilloid 4.
Lab Invest. 2018 Nov 09;
In order to understand the pathobiology of neurotrophic keratopathy, we established a mouse model by coagulating the first branch of the trigeminal nerve (V1 nerve). In our model, the sensory nerve in the central cornea disappeared and remaining fibers were sparse in the peripheral limbal region. Impaired corneal epithelial healing in the mouse model was associated with suppression of both cell proliferation and expression of stem cell markers in peripheral/limbal epithelium as well as a reduction of transient receptor potential vanilloid 4 (TRPV4) expression in tissue. TRPV4 gene knockout also suppressed epithelial repair in mouse cornea, although it did not seem to directly modulate migration of epithelium. In a co-culture experiment, TRPV4-introduced KO trigeminal ganglion upregulated nerve growth factor (NGF) in cultured corneal epithelial cells, but ganglion with a control vector did not. TRPV4 gene introduction into a damaged V1 nerve rescues the impairment of epithelial healing in association with partial recovery of the stem/progenitor cell markers and upregulation of cell proliferation and of NGF expression in the peripheral/limbal epithelium. Gene transfer of TRPV4 did not accelerate the regeneration of nerve fibers. Sensory nerve TRPV4 is critical to maintain stemness of peripheral/limbal basal cells, and is one of the major mechanisms of homeostasis maintenance of corneal epithelium.
PMID: 30413814
Haensel D,Sun P,MacLean AL,Ma X,Zhou Y,Stemmler MP,Brabletz S,Berx G,Plikus MV,Nie Q,Brabletz T,Dai X
An Ovol2-Zeb1 transcriptional circuit regulates epithelial directional migration and proliferation.
EMBO Rep. 2018 Nov 09;
Directional migration is inherently important for epithelial tissue regeneration and repair, but how it is precisely controlled and coordinated with cell proliferation is unclear. Here, we report that Ovol2, a transcriptional repressor that inhibits epithelial-to-mesenchymal transition (EMT), plays a crucial role in adult skin epithelial regeneration and repair. -deficient mice show compromised wound healing characterized by aberrant epidermal cell migration and proliferation, as well as delayed anagen progression characterized by defects in hair follicle matrix cell proliferation and subsequent differentiation. Epidermal keratinocytes and bulge hair follicle stem cells (Bu-HFSCs) lacking Ovol2 fail to expand in culture and display molecular alterations consistent with enhanced EMT and reduced proliferation. Live imaging of wound explants and Bu-HFSCs reveals increased migration speed but reduced directionality, and post-mitotic cell cycle arrest. Remarkably, simultaneous deletion of encoding an EMT-promoting factor restores directional migration to -deficient Bu-HFSCs. Taken together, our findings highlight the important function of an Ovol2-Zeb1 EMT-regulatory circuit in controlling the directional migration of epithelial stem and progenitor cells to facilitate adult skin epithelial regeneration and repair.
PMID: 30413481
Chang Y,Moradi H,Kalantar-Zadeh K
Emerging paradigms of treating diabetic nephropathy.
Lancet Diabetes Endocrinol. 2018 Nov 06;
PMID: 30413395
Solomon BJ,Besse B,Bauer TM,Felip E,Soo RA,Camidge DR,Chiari R,Bearz A,Lin CC,Gadgeel SM,Riely GJ,Tan EH,Seto T,James LP,Clancy JS,Abbattista A,Martini JF,Chen J,Peltz G,Thurm H,Ignatius Ou SH,Shaw AT
Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
Lancet Oncol. 2018 Nov 06;
Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.
PMID: 30413378
Oakes MC,Porto M,Chung JH
Advances in prenatal and perinatal diagnosis and management of gastroschisis.
Semin Pediatr Surg. 2018 Oct;27(5):289-299
Gastroschisis is a congenital, ventral wall defect associated with bowel evisceration. The defect is usually to the right of the umbilical cord insertion and requires postnatal surgical correction. The fetus is at risk for complications such as intrauterine growth restriction, preterm delivery, and intrauterine fetal demise. In addition, complex cases, defined by the presence of intestinal complications such as bowel atresia, stenosis, perforation, or ischemia, occur in up to one third of pregnancies affected by gastroschisis. As complex gastroschisis is associated with increased morbidity and mortality, research has focused on the prenatal detection of this high risk subset of cases. The purpose of this review is to discuss the prenatal, diagnostic approach to the identification of gastroschisis, to describe potential signs of complex gastroschisis on prenatal ultrasound, to review current guidelines for antepartum management and delivery planning, and to summarize results of both past and current intervention trials in fetuses with gastroschisis.
PMID: 30413259
Rhee CM,Chou JA,Kalantar-Zadeh K
Dialysis Prescription and Sudden Death.
Semin Nephrol. 2018 Nov;38(6):570-581
In the United States, end-stage renal disease patients receiving hemodialysis have an exceedingly high risk of sudden cardiac death (SCD), accounting for 29% of death events, likely relating to their uremic milieu, recurring exposure to fluid and electrolyte fluxes, and underlying cardiovascular pathology. Furthermore, epidemiologic studies have shown that SCD events, as well as mortality and hospitalizations, occur most frequently on the first dialysis day after the long interdialytic gap, suggesting that abrupt fluctuations in the accumulation and removal of electrolytes, fluid, and uremic toxins over the dialysis cycle may be contributory. Some population-based observational studies have suggested that lower dialysate potassium concentrations appear to be associated with a heightened risk of postdialysis cardiac arrest in hemodialysis patients, although the optimal serum-to-dialysate potassium gradient remains unclear. Some observational studies have suggested that low dialysate calcium concentrations and high serum-to-dialysate calcium gradients may predispose patients to SCD. There is ongoing controversy about an association between higher dialysate bicarbonate concentrations and higher risk of cardiac arrest, likely owing to confounding by indication. Some observational studies also have shown that large interdialytic weight gains, fluid retention, and high ultrafiltration rates are linked with higher risk of SCD and mortality. However, there remains considerable controversy regarding the pros and cons of designating a specific upper ultrafiltration limit with extended treatment times as a clinical practice measure, and further studies are needed to define the optimal tools, metrics, targets, and implementation measures for volume control in the hemodialysis population. In this review, we highlight the epidemiology and pathophysiology of how specific aspects of the hemodialysis procedure may relate to the risk of SCD, as well as preventative strategies and future research directions that can address this risk.
PMID: 30413252
Wang B,Brewer PE,Shugart HH,Lerdau MT,Allison SD
Soil aggregates as biogeochemical reactors and implications for soil-atmosphere exchange of greenhouse gases-a concept.
Glob Chang Biol. 2018 Nov 09;
Soil-atmosphere exchange significantly influences the global atmospheric abundances of carbon dioxide (CO ), methane (CH ), and nitrous oxide (N O). These greenhouse gases (GHGs) have been extensively studied at the soil profile level and extrapolated to coarser scales (regional and global). However, finer scale studies of soil aggregation have not received much attention, even though elucidating the GHG activities at the full spectrum of scales rather than just coarse levels is essential for reducing the large uncertainties in the current atmospheric budgets of these gases. Through synthesizing relevant studies, we propose that aggregates, as relatively separate micro-environments embedded in a complex soil matrix, can be viewed as biogeochemical reactors of GHGs. Aggregate reactivity is determined by both aggregate size (which determines the reactor size) and the bulk soil environment including both biotic and abiotic factors (which further influence the reaction conditions). With a systematic, dynamic view of the soil system, implications of aggregate reactors for soil-atmosphere GHG exchange are determined by both an individual reactor's reactivity and dynamics in aggregate size distributions. Emerging evidence supports the contention that aggregate reactors significantly influence soil-atmosphere GHG exchange and may have global implications for carbon and nitrogen cycling. In the context of increasingly frequent and severe disturbances, we advocate more analyses of GHG activities at the aggregate scale. To complement data on aggregate reactors, we suggest developing bottom-up aggregate-based models (ABMs) that apply a trait-based approach and incorporate soil system heterogeneity. This article is protected by copyright. All rights reserved.
PMID: 30412646
Bagallab I,Mauricio Reyes-Ruiz J,Abulnaja K,Huwait E,Glabe C
Epitomic Characterization of the Specificity of the Anti-Amyloid Aß Monoclonal Antibodies 6E10 and 4G8.
J Alzheimers Dis. 2018 Nov 05;
The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aß and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aß target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.
PMID: 30412489
Abe K,Akutsu R,Ali A,Amey J,Andreopoulos C,Anthony L,Antonova M,Aoki S,Ariga A,Ashida Y,Azuma Y,Ban S,Barbi M,Barker GJ,Barr G,Barry C,Batkiewicz M,Bench F,Berardi V,Berkman S,Berner RM,Berns L,Bhadra S,Bienstock S,Blondel A,Bolognesi S,Bourguille B,Boyd SB,Brailsford D,Bravar A,Bronner C,Buizza Avanzini M,Calcutt J,Campbell T,Cao S,Cartwright SL,Catanesi MG,Cervera A,Chappell A,Checchia C,Cherdack D,Chikuma N,Christodoulou G,Coleman J,Collazuol G,Coplowe D,Cudd A,Dabrowska A,De Rosa G,Dealtry T,Denner PF,Dennis SR,Densham C,Di Lodovico F,Dokania N,Dolan S,Drapier O,Duffy KE,Dumarchez J,Dunne P,Emery-Schrenk S,Ereditato A,Fernandez P,Feusels T,Finch AJ,Fiorentini GA,Fiorillo G,Francois C,Friend M,Fujii Y,Fujita R,Fukuda D,Fukuda Y,Gameil K,Giganti C,Gizzarelli F,Golan T,Gonin M,Hadley DR,Haegel L,Haigh JT,Hamacher-Baumann P,Hansen D,Harada J,Hartz M,Hasegawa T,Hastings NC,Hayashino T,Hayato Y,Hiramoto A,Hogan M,Holeczek J,Hosomi F,Ichikawa AK,Ikeda M,Imber J,Inoue T,Intonti RA,Ishida T,Ishii T,Ishitsuka M,Iwamoto K,Izmaylov A,Jamieson B,Jiang M,Johnson S,Jonsson P,Jung CK,Kabirnezhad M,Kaboth AC,Kajita T,Kakuno H,Kameda J,Karlen D,Katori T,Kato Y,Kearns E,Khabibullin M,Khotjantsev A,Kim H,Kim J,King S,Kisiel J,Knight A,Knox A,Kobayashi T,Koch L,Koga T,Koller PP,Konaka A,Kormos LL,Koshio Y,Kowalik K,Kubo H,Kudenko Y,Kurjata R,Kutter T,Kuze M,Labarga L,Lagoda J,Lamoureux M,Lasorak P,Laveder M,Lawe M,Licciardi M,Lindner T,Liptak ZJ,Litchfield RP,Li X,Longhin A,Lopez JP,Lou T,Ludovici L,Lu X,Magaletti L,Mahn K,Malek M,Manly S,Maret L,Marino AD,Martin JF,Martins P,Maruyama T,Matsubara T,Matveev V,Mavrokoridis K,Ma WY,Mazzucato E,McCarthy M,McCauley N,McFarland KS,McGrew C,Mefodiev A,Metelko C,Mezzetto M,Minamino A,Mineev O,Mine S,Missert A,Miura M,Moriyama S,Morrison J,Mueller TA,Murphy S,Nagai Y,Nakadaira T,Nakahata M,Nakajima Y,Nakamura KG,Nakamura K,Nakamura KD,Nakanishi Y,Nakayama S,Nakaya T,Nakayoshi K,Nantais C,Nielsen C,Niewczas K,Nishikawa K,Nishimura Y,Nonnenmacher TS,Novella P,Nowak J,O'Keeffe HM,O'Sullivan L,Okumura K,Okusawa T,Oryszczak W,Oser SM,Owen RA,Oyama Y,Palladino V,Palomino JL,Paolone V,Paudyal P,Pavin M,Payne D,Pickering L,Pidcott C,Pinzon Guerra ES,Pistillo C,Popov B,Porwit K,Posiadala-Zezula M,Pritchard A,Quilain B,Radermacher T,Radicioni E,Ratoff PN,Reinherz-Aronis E,Riccio C,Rondio E,Rossi B,Roth S,Rubbia A,Ruggeri AC,Rychter A,Sakashita K,Sánchez F,Sasaki S,Scantamburlo E,Scholberg K,Schwehr J,Scott M,Seiya Y,Sekiguchi T,Sekiya H,Sgalaberna D,Shah R,Shaikhiev A,Shaker F,Shaw D,Shiozawa M,Smirnov A,Smy M,Sobczyk JT,Sobel H,Sonoda Y,Steinmann J,Stewart T,Stowell P,Suda Y,Suvorov S,Suzuki A,Suzuki SY,Suzuki Y,Sztuc AA,Tacik R,Tada M,Takeda A,Takeuchi Y,Tamura R,Tanaka HK,Tanaka HA,Thakore T,Thompson LF,Toki W,Touramanis C,Tsui KM,Tsukamoto T,Tzanov M,Uchida Y,Uno W,Vagins M,Vallari Z,Vasseur G,Vilela C,Vladisavljevic T,Volkov VV,Wachala T,Walker J,Wang Y,Wark D,Wascko MO,Weber A,Wendell R,Wilking MJ,Wilkinson C,Wilson JR,Wilson RJ,Wret C,Yamada Y,Yamamoto K,Yamasu S,Yanagisawa C,Yang G,Yano T,Yasutome K,Yen S,Yershov N,Yokoyama M,Yoshida T,Yu M,Zalewska A,Zalipska J,Zaremba K,Zarnecki G,Ziembicki M,Zimmerman ED,Zito M,Zsoldos S,Zykova A,
Search for CP Violation in Neutrino and Antineutrino Oscillations by the T2K Experiment with 2.2×10^{21} Protons on Target.
Phys Rev Lett. 2018 Oct 26;121(17):171802
The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of 14.7(7.6)×10^{20} protons on target in the neutrino (antineutrino) mode, 89 ?_{e} candidates and seven anti-?_{e} candidates are observed, while 67.5 and 9.0 are expected for d_{CP}=0 and normal mass ordering. The obtained 2s confidence interval for the CP-violating phase, d_{CP}, does not include the CP-conserving cases (d_{CP}=0, p). The best-fit values of other parameters are sin^{2}?_{23}=0.526_{-0.036}^{+0.032} and ?m_{32}^{2}=2.463_{-0.070}^{+0.071}×10^{-3}??eV^{2}/c^{4}.
PMID: 30411920
Chang HH,Yeh JC,Mao J,Ginsberg DA,Ghoniem G,Rodriguez LV
Spinal cord stimulation ameliorates detrusor over-activity and visceromotor pain responses in rats with cystitis.
Neurourol Urodyn. 2018 Nov 09;
Interstitial cystitis/painful bladder syndrome/(IC/PBS) results in recurring pain in the bladder and surrounding pelvic region caused by abnormal excitability of micturition reflexes. Spinal cord stimulation (SCS) is currently clinically used for the attenuation of neuropathic and visceral pain. The present study examined whether SCS at upper lumbar segments modulates detrusor overactivity and visceral hyperalgesia associated with cystitis in a rat model of cyclophosphamide (CYP)-induced cystitis.
PMID: 30411810
Lee CC,Hu Y,Ribbe MW
Reduction and Condensation of Aldehydes by the Isolated Cofactor of Nitrogenase.
ACS Cent Sci. 2018 Oct 24;4(10):1430-1435
Isolated nitrogenase cofactors can reduce CO, CN, and CO to short-chain hydrocarbons in reactions driven by a strong reductant. Here, we use activity analyses and isotope labeling experiments to show that formaldehyde and acetaldehydes can be reduced as-is or reductively condensed into alkanes and alkenes by the isolated cofactor of Mo-nitrogenase in the presence of Eu-diethylenetriamine pentaacetate (DTPA). Further, we demonstrate that aldehydes can be condensed with CO by the isolated cofactor under the same reaction conditions, pointing to aldehyde-derived species as possible intermediates of nitrogenase-catalyzed CO reduction. Our deuterium labeling experiments suggest the formation of a cofactor-bound hydroxymethyl intermediate upon activation of the formaldehyde, as well as the release of CH as a product upon ß-hydride elimination of an acetaldehyde-derived hydroxyethyl intermediate. These findings establish the reductive condensation of aldehydes as a previously unobserved reactivity of a biogenic catalyst while at the same time shed light on the mechanism of enzymatic CO reduction and C-C bond formation, thereby providing a useful framework for further exploration of the unique reactivity and potential applications of nitrogenase-based reactions.
PMID: 30410981
Juhász MLW,Atanaskova Mesinkovska N
Does Complement Have a Role in the Pathogenesis of Alopecia Areata?
Skin Appendage Disord. 2018 Oct;4(4):261-263
Alopecia areata (AA) is an autoimmune disorder in which immune attack of the anagen follicle causes hair loss in approximately 2% of the population. Although the pathogenesis of AA has not been fully determined, most likely it is mediated by a variety of factors including cellular/humoral immunity and genetic predisposition. Researchers have been interested in the possible role of the complement pathway in AA since the 1970s. Given recent evidence suggesting that complement plays a role in many immunologic and inflammatory dermatologic diseases including systemic lupus erythematosus, bullous diseases, angioedema, lipodystrophy, and skin infections, it is likely that complement also contributes to AA pathogenesis. Although early serum studies and immunohistochemical staining have been unimpressive, recent genetics studies may provide evidence that complement does indeed contribute to AA. By determining if complement plays a role in AA, options for novel targeted treatments will become available for those patients with refractory disease.
PMID: 30410892
Yu V,Juhász M,Chiang A,Atanaskova Mesinkovska N
Alopecia and Associated Toxic Agents: A Systematic Review.
Skin Appendage Disord. 2018 Oct;4(4):245-260
There are a number of toxic agents that can cause alopecia. In this review we summarize the known substances that cause alopecia as one of the clinical signs of overdose or toxicity.
PMID: 30410891
Bender MT,Vo CD,Jiang B,Campos JK,Zarrin DA,Xu R,Westbroek EM,Caplan JM,Huang J,Tamargo RJ,Lin LM,Colby GP,Coon AL
Pipeline Embolization for Salvage Treatment of Previously Stented Residual and Recurrent Cerebral Aneurysms.
Interv Neurol. 2018 Oct;7(6):359-369
This study assessed the safety and effectiveness of the Pipeline embolization device (PED) for persistent and recurrent aneurysms previously treated with either a vascular reconstruction device (VRD) or a flow diverter (FD).
PMID: 30410513
Sparks TN,Thao K,Lianoglou BR,Boe NM,Bruce KG,Datkhaeva I,Field NT,Fratto VM,Jolley J,Laurent LC,Mardy AH,Murphy AM,Ngan E,Rangwala N,Rottkamp CAM,Wilson L,Wu E,Uy CC,Valdez Lopez P,Norton ME,
Nonimmune hydrops fetalis: identifying the underlying genetic etiology.
Genet Med. 2018 Nov 09;
Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes.
PMID: 30410095
Corva M,Ferrari A,Rinaldi M,Feng Z,Roiaz M,Rameshan C,Rupprechter G,Costantini R,Dell'Angela M,Pastore G,Comelli G,Seriani N,Vesselli E
Vibrational fingerprint of localized excitons in a two-dimensional metal-organic crystal.
Nat Commun. 2018 Nov 08;9(1):4703
Long-lived excitons formed upon visible light absorption play an essential role in photovoltaics, photocatalysis, and even in high-density information storage. Here, we describe a self-assembled two-dimensional metal-organic crystal, composed of graphene-supported macrocycles, each hosting a single FeN center, where a single carbon monoxide molecule can adsorb. In this heme-like biomimetic model system, excitons are generated by visible laser light upon a spin transition associated with the layer 2D crystallinity, and are simultaneously detected via the carbon monoxide ligand stretching mode at room temperature and near-ambient pressure. The proposed mechanism is supported by the results of infrared and time-resolved pump-probe spectroscopies, and by ab initio theoretical methods, opening a path towards the handling of exciton dynamics on 2D biomimetic crystals.
PMID: 30409974
McLean L,Connor CM
Relations between third grade teachers' depressive symptoms and their feedback to students, with implications for student mathematics achievement.
Sch Psychol Q. 2018 06;33(2):272-282
Recent studies have observed connections among teachers' depressive symptoms and student outcomes; however, the specific mechanisms through which teachers' mental health characteristics operate in the classroom remain largely unknown. The present study used student-level observation methods to examine the relations between third-grade teachers' (N = 32) depressive symptoms and their academic feedback to students (N = 310) and sought to make inferences about how these factors might influence students' mathematics achievement. A novel observational tool, the Teacher Feedback Coding System-Academic (TFCS-A), was used that assesses feedback across 2 dimensions-teacher affect and instructional strategy, which have been shown to be important to student learning. Multilevel exploratory factor analysis of TFCS-A data suggested 2 primary factors: positive feedback and neutral/negative feedback. Hierarchical linear modeling revealed that positive feedback was related to higher math achievement among students who began the year with weaker math skills and that teachers who reported more depressive symptoms less frequently provided this positive feedback. Results offer new information about a type of instruction that may be affected by teachers' depressive symptoms and inform efforts aimed at improving teachers' instructional interactions with students. (PsycINFO Database Record
PMID: 28857586
Delli Pizzi S,Punzi M,Sensi SL,
Functional signature of conversion of patients with mild cognitive impairment.
Neurobiol Aging. 2018 Oct 12;74:21-37
The entorhinal-hippocampal circuit is a strategic hub for cognition and the first site affected by Alzheimer's disease (AD). We investigated magnetic resonance imaging patterns of brain atrophy and functional connectivity in an Alzheimer's Disease Neuroimaging Initiative data set that included healthy controls, mild cognitive impairment (MCI), and patients with AD. Individuals with MCI were clinically evaluated 24 months after the first magnetic resonance imaging scan, and the cohort subdivided into sets of individuals who either did or did not convert to AD. The MCI group was also divided into patients who did show or not the presence of AD-related alterations in the cerebrospinal fluid. Patients with AD exhibited the collapse of the long-range hippocampal/entorhinal connectivity, pronounced cortical/subcortical atrophy, and a dramatic decline in cognitive performances. Patients with MCI who converted to AD or patients with MCI who showed the presence of AD-related alterations in the cerebrospinal fluid showed memory deficits, entorhinal/hippocampal hypoconnectivity, and concomitant atrophy of the two regions. Patients with MCI who did not convert to AD or patients with MCI who did not show the presence of AD-related alterations in the cerebrospinal fluid had no atrophy but showed hippocampal/entorhinal hyperconnectivity with selected neocortical/subcortical regions involved in memory processing and brain metastability. This hyperconnectivity may represent a compensatory strategy against the progression of cognitive impairment.
PMID: 30408719
Tadir Y,Iglesia C,Alexiades M,Davila GW,Guerette N,Gaspar A
Energy-based treatment for gynecologic conditions including genitourinary syndrome of menopause: Consensus, controversies, recommendations, and FDA clearance.
Lasers Surg Med. 2018 Nov 08;
PMID: 30408203
Kim JH,Jang SJ,Yun JW,Jung MH,Woo SH
Effects of pepsin and pepstatin on reflux tonsil hypertrophy in vitro.
PLoS One. 2018;13(11):e0207090
There is evidence that pepsin can aggravate tonsil hypertrophy. Pepstatin is a potent inhibitor of pepsin activity and could protect patients against reflux tonsil hypertrophy by inhibiting pepsin. We examined the effects of pepstatin on the development of tonsil hypertrophy to investigate pepsin's role in the pathogenesis of tonsil lesions. We investigated whether pepstatin suppresses pepsin-mediated lymphocyte proliferation in tonsil hypertrophy. Forty-nine children with tonsil hypertrophy and twenty-two adults with tonsillitis were recruited to the study prior to surgery. Tonsil tissue from each patient was harvested and assessed for changes in the number of lymphocytes and macrophages in the presence of pepsin and pepstatin. We found that the proportions of CD4- and CD14-positive cells were significantly lower (p < 0.05), but that the proportions of CD19- and CD68-positive cells were significantly higher (p < 0.05), in children than in adults. There were significantly more CD4-positive cells after pepsin treatment, but these numbers were reduced by pepstatin. The levels of both interleukin-2 (IL-2) and interferon gamma (IFN-?) increased significantly in response to pepsin, but were reduced when pepsin was inhibited by pepstatin. The level of IL-10 is reduced in pepsin-treated CD4 cells and the level is restored by pepstatin. IL-2 blocking reduced the increased CD4 cell number by pepsin. But, an additive or a synergic effect is not founded in combined with IL-2 blocking and pepstatin. Pepsin-positive cells did not co-localize with CD20 and CD45 cells, but they were found surrounding CD20- and CD45-positive hypertrophic tonsil cells. Pepsin-positive cells co-localized with CD68-positive cells. It is probable that pepsin from extraesophageal reflux aggravates tonsil hypertrophy and pepstatin exerts a protective effect by inhibiting pepsin activity.
PMID: 30408092
Wang PZT,Abdelhalim A,Walia A,Wehbi E,Dave S,Khoury A
Avoiding routine postoperative voiding cystourethrogram: Predicting radiologic success for endoscopically treated vesicoureteral reflux.
Can Urol Assoc J. 2018 Nov 05;
Variability in the success rates for the endoscopic correction of vesicoureteral reflux (VUR) has prompted a debate regarding the use of routine postoperative voiding cystourethrogram (VCUG). This study examines the predictive performance of intraoperative mound morphology (IMM) and the presence of a postoperative ultrasound mound (PUM) on radiologic success, as well as investigates the role of using these two predictive factors as a composite tool to predict VUR resolution after endoscopic treatment.
PMID: 30407152
Overview of the SAMPL6 host-guest binding affinity prediction challenge.
J Comput Aided Mol Des. 2018 Nov 10;
Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host-guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy.
PMID: 30415285
Bierma JC,Roskamp KW,Ledray AP,Kiss AJ,Christina Cheng CH,Martin RW
Controlling Liquid-Liquid Phase Separation of Cold-Adapted Crystallin Proteins from the Antarctic Toothfish.
J Mol Biol. 2018 Nov 08;
Liquid-liquid phase separation (LLPS) of proteins is important to a variety of biological processes both functional and deleterious, including the formation of membraneless organelles, molecular condensations that sequester or release molecules in response to stimuli, and the early stages of disease-related protein aggregation. In the protein-rich, crowded environment of the eye lens, LLPS manifests as cold cataract. We characterize the LLPS behavior of six structural ?-crystallins from theeye lens of the Antarctic toothfish Dissostichus mawsoni, whose intact lenses resist cold cataract in subzero waters. Phase separation of these proteins is not strongly correlated with thermal stability, aggregation propensity, or cross-species chaperone protection from heat denaturation. Instead, LLPS is driven by protein-protein interactions involving charged residues. The critical temperature of the phase transition can be tuned over a wide temperature range by selective substitution of surface residues, suggesting general principles for controlling this phenomenon, even in compactly folded proteins.
PMID: 30414964
Lee K,Pouldar D,Shiu J,Elsensohn A,de Feraudy S
The histological spectrum of Talimogene laherparepvec (TVEC) injections-neutrophilic and chronic granulomatous dermatitis.
J Cutan Pathol. 2018 Nov 09;
We read with interest the case series by Everett et al. (1) describing chronic granulomatous dermatitis at sites of Talimogene laherparepvec (TVEC) injections for advanced melanoma. This article is protected by copyright. All rights reserved.
PMID: 30414194
Di K,Lomeli N,Bota DA,Das BC
Magmas inhibition as a potential treatment strategy in malignant glioma.
J Neurooncol. 2018 Nov 09;
Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved, ubiquitously expressed in mammalian cells, and is essential for cell viability. Magmas expression levels are increased in prostate cancers and pituitary adenomas. Moreover, silencing Magmas by RNAi sensitizes pituitary adenoma cells to pro-apoptotic stimuli and induces a G0/G1 accumulation. The aim of this study was to examine whether inhibition of Magmas by small molecule inhibitors could be beneficial for the treatment of malignant gliomas.
PMID: 30414099
Okada Y,Sumioka T,Ichikawa K,Sano H,Nambu A,Kobayashi K,Uchida K,Suzuki Y,Tominaga M,Reinach PS,Hirai SI,Jester JV,Miyajima M,Shirai K,Iwanishi H,Kao WW,Liu CY,Saika S
Sensory nerve supports epithelial stem cell function in healing of corneal epithelium in mice: the role of trigeminal nerve transient receptor potential vanilloid 4.
Lab Invest. 2018 Nov 09;
In order to understand the pathobiology of neurotrophic keratopathy, we established a mouse model by coagulating the first branch of the trigeminal nerve (V1 nerve). In our model, the sensory nerve in the central cornea disappeared and remaining fibers were sparse in the peripheral limbal region. Impaired corneal epithelial healing in the mouse model was associated with suppression of both cell proliferation and expression of stem cell markers in peripheral/limbal epithelium as well as a reduction of transient receptor potential vanilloid 4 (TRPV4) expression in tissue. TRPV4 gene knockout also suppressed epithelial repair in mouse cornea, although it did not seem to directly modulate migration of epithelium. In a co-culture experiment, TRPV4-introduced KO trigeminal ganglion upregulated nerve growth factor (NGF) in cultured corneal epithelial cells, but ganglion with a control vector did not. TRPV4 gene introduction into a damaged V1 nerve rescues the impairment of epithelial healing in association with partial recovery of the stem/progenitor cell markers and upregulation of cell proliferation and of NGF expression in the peripheral/limbal epithelium. Gene transfer of TRPV4 did not accelerate the regeneration of nerve fibers. Sensory nerve TRPV4 is critical to maintain stemness of peripheral/limbal basal cells, and is one of the major mechanisms of homeostasis maintenance of corneal epithelium.
PMID: 30413814
Haensel D,Sun P,MacLean AL,Ma X,Zhou Y,Stemmler MP,Brabletz S,Berx G,Plikus MV,Nie Q,Brabletz T,Dai X
An Ovol2-Zeb1 transcriptional circuit regulates epithelial directional migration and proliferation.
EMBO Rep. 2018 Nov 09;
Directional migration is inherently important for epithelial tissue regeneration and repair, but how it is precisely controlled and coordinated with cell proliferation is unclear. Here, we report that Ovol2, a transcriptional repressor that inhibits epithelial-to-mesenchymal transition (EMT), plays a crucial role in adult skin epithelial regeneration and repair. -deficient mice show compromised wound healing characterized by aberrant epidermal cell migration and proliferation, as well as delayed anagen progression characterized by defects in hair follicle matrix cell proliferation and subsequent differentiation. Epidermal keratinocytes and bulge hair follicle stem cells (Bu-HFSCs) lacking Ovol2 fail to expand in culture and display molecular alterations consistent with enhanced EMT and reduced proliferation. Live imaging of wound explants and Bu-HFSCs reveals increased migration speed but reduced directionality, and post-mitotic cell cycle arrest. Remarkably, simultaneous deletion of encoding an EMT-promoting factor restores directional migration to -deficient Bu-HFSCs. Taken together, our findings highlight the important function of an Ovol2-Zeb1 EMT-regulatory circuit in controlling the directional migration of epithelial stem and progenitor cells to facilitate adult skin epithelial regeneration and repair.
PMID: 30413481
Chang Y,Moradi H,Kalantar-Zadeh K
Emerging paradigms of treating diabetic nephropathy.
Lancet Diabetes Endocrinol. 2018 Nov 06;
PMID: 30413395
Solomon BJ,Besse B,Bauer TM,Felip E,Soo RA,Camidge DR,Chiari R,Bearz A,Lin CC,Gadgeel SM,Riely GJ,Tan EH,Seto T,James LP,Clancy JS,Abbattista A,Martini JF,Chen J,Peltz G,Thurm H,Ignatius Ou SH,Shaw AT
Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
Lancet Oncol. 2018 Nov 06;
Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.
PMID: 30413378
Oakes MC,Porto M,Chung JH
Advances in prenatal and perinatal diagnosis and management of gastroschisis.
Semin Pediatr Surg. 2018 Oct;27(5):289-299
Gastroschisis is a congenital, ventral wall defect associated with bowel evisceration. The defect is usually to the right of the umbilical cord insertion and requires postnatal surgical correction. The fetus is at risk for complications such as intrauterine growth restriction, preterm delivery, and intrauterine fetal demise. In addition, complex cases, defined by the presence of intestinal complications such as bowel atresia, stenosis, perforation, or ischemia, occur in up to one third of pregnancies affected by gastroschisis. As complex gastroschisis is associated with increased morbidity and mortality, research has focused on the prenatal detection of this high risk subset of cases. The purpose of this review is to discuss the prenatal, diagnostic approach to the identification of gastroschisis, to describe potential signs of complex gastroschisis on prenatal ultrasound, to review current guidelines for antepartum management and delivery planning, and to summarize results of both past and current intervention trials in fetuses with gastroschisis.
PMID: 30413259
Rhee CM,Chou JA,Kalantar-Zadeh K
Dialysis Prescription and Sudden Death.
Semin Nephrol. 2018 Nov;38(6):570-581
In the United States, end-stage renal disease patients receiving hemodialysis have an exceedingly high risk of sudden cardiac death (SCD), accounting for 29% of death events, likely relating to their uremic milieu, recurring exposure to fluid and electrolyte fluxes, and underlying cardiovascular pathology. Furthermore, epidemiologic studies have shown that SCD events, as well as mortality and hospitalizations, occur most frequently on the first dialysis day after the long interdialytic gap, suggesting that abrupt fluctuations in the accumulation and removal of electrolytes, fluid, and uremic toxins over the dialysis cycle may be contributory. Some population-based observational studies have suggested that lower dialysate potassium concentrations appear to be associated with a heightened risk of postdialysis cardiac arrest in hemodialysis patients, although the optimal serum-to-dialysate potassium gradient remains unclear. Some observational studies have suggested that low dialysate calcium concentrations and high serum-to-dialysate calcium gradients may predispose patients to SCD. There is ongoing controversy about an association between higher dialysate bicarbonate concentrations and higher risk of cardiac arrest, likely owing to confounding by indication. Some observational studies also have shown that large interdialytic weight gains, fluid retention, and high ultrafiltration rates are linked with higher risk of SCD and mortality. However, there remains considerable controversy regarding the pros and cons of designating a specific upper ultrafiltration limit with extended treatment times as a clinical practice measure, and further studies are needed to define the optimal tools, metrics, targets, and implementation measures for volume control in the hemodialysis population. In this review, we highlight the epidemiology and pathophysiology of how specific aspects of the hemodialysis procedure may relate to the risk of SCD, as well as preventative strategies and future research directions that can address this risk.
PMID: 30413252
Wang B,Brewer PE,Shugart HH,Lerdau MT,Allison SD
Soil aggregates as biogeochemical reactors and implications for soil-atmosphere exchange of greenhouse gases-a concept.
Glob Chang Biol. 2018 Nov 09;
Soil-atmosphere exchange significantly influences the global atmospheric abundances of carbon dioxide (CO ), methane (CH ), and nitrous oxide (N O). These greenhouse gases (GHGs) have been extensively studied at the soil profile level and extrapolated to coarser scales (regional and global). However, finer scale studies of soil aggregation have not received much attention, even though elucidating the GHG activities at the full spectrum of scales rather than just coarse levels is essential for reducing the large uncertainties in the current atmospheric budgets of these gases. Through synthesizing relevant studies, we propose that aggregates, as relatively separate micro-environments embedded in a complex soil matrix, can be viewed as biogeochemical reactors of GHGs. Aggregate reactivity is determined by both aggregate size (which determines the reactor size) and the bulk soil environment including both biotic and abiotic factors (which further influence the reaction conditions). With a systematic, dynamic view of the soil system, implications of aggregate reactors for soil-atmosphere GHG exchange are determined by both an individual reactor's reactivity and dynamics in aggregate size distributions. Emerging evidence supports the contention that aggregate reactors significantly influence soil-atmosphere GHG exchange and may have global implications for carbon and nitrogen cycling. In the context of increasingly frequent and severe disturbances, we advocate more analyses of GHG activities at the aggregate scale. To complement data on aggregate reactors, we suggest developing bottom-up aggregate-based models (ABMs) that apply a trait-based approach and incorporate soil system heterogeneity. This article is protected by copyright. All rights reserved.
PMID: 30412646
Bagallab I,Mauricio Reyes-Ruiz J,Abulnaja K,Huwait E,Glabe C
Epitomic Characterization of the Specificity of the Anti-Amyloid Aß Monoclonal Antibodies 6E10 and 4G8.
J Alzheimers Dis. 2018 Nov 05;
The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aß and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aß target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.
PMID: 30412489
Abe K,Akutsu R,Ali A,Amey J,Andreopoulos C,Anthony L,Antonova M,Aoki S,Ariga A,Ashida Y,Azuma Y,Ban S,Barbi M,Barker GJ,Barr G,Barry C,Batkiewicz M,Bench F,Berardi V,Berkman S,Berner RM,Berns L,Bhadra S,Bienstock S,Blondel A,Bolognesi S,Bourguille B,Boyd SB,Brailsford D,Bravar A,Bronner C,Buizza Avanzini M,Calcutt J,Campbell T,Cao S,Cartwright SL,Catanesi MG,Cervera A,Chappell A,Checchia C,Cherdack D,Chikuma N,Christodoulou G,Coleman J,Collazuol G,Coplowe D,Cudd A,Dabrowska A,De Rosa G,Dealtry T,Denner PF,Dennis SR,Densham C,Di Lodovico F,Dokania N,Dolan S,Drapier O,Duffy KE,Dumarchez J,Dunne P,Emery-Schrenk S,Ereditato A,Fernandez P,Feusels T,Finch AJ,Fiorentini GA,Fiorillo G,Francois C,Friend M,Fujii Y,Fujita R,Fukuda D,Fukuda Y,Gameil K,Giganti C,Gizzarelli F,Golan T,Gonin M,Hadley DR,Haegel L,Haigh JT,Hamacher-Baumann P,Hansen D,Harada J,Hartz M,Hasegawa T,Hastings NC,Hayashino T,Hayato Y,Hiramoto A,Hogan M,Holeczek J,Hosomi F,Ichikawa AK,Ikeda M,Imber J,Inoue T,Intonti RA,Ishida T,Ishii T,Ishitsuka M,Iwamoto K,Izmaylov A,Jamieson B,Jiang M,Johnson S,Jonsson P,Jung CK,Kabirnezhad M,Kaboth AC,Kajita T,Kakuno H,Kameda J,Karlen D,Katori T,Kato Y,Kearns E,Khabibullin M,Khotjantsev A,Kim H,Kim J,King S,Kisiel J,Knight A,Knox A,Kobayashi T,Koch L,Koga T,Koller PP,Konaka A,Kormos LL,Koshio Y,Kowalik K,Kubo H,Kudenko Y,Kurjata R,Kutter T,Kuze M,Labarga L,Lagoda J,Lamoureux M,Lasorak P,Laveder M,Lawe M,Licciardi M,Lindner T,Liptak ZJ,Litchfield RP,Li X,Longhin A,Lopez JP,Lou T,Ludovici L,Lu X,Magaletti L,Mahn K,Malek M,Manly S,Maret L,Marino AD,Martin JF,Martins P,Maruyama T,Matsubara T,Matveev V,Mavrokoridis K,Ma WY,Mazzucato E,McCarthy M,McCauley N,McFarland KS,McGrew C,Mefodiev A,Metelko C,Mezzetto M,Minamino A,Mineev O,Mine S,Missert A,Miura M,Moriyama S,Morrison J,Mueller TA,Murphy S,Nagai Y,Nakadaira T,Nakahata M,Nakajima Y,Nakamura KG,Nakamura K,Nakamura KD,Nakanishi Y,Nakayama S,Nakaya T,Nakayoshi K,Nantais C,Nielsen C,Niewczas K,Nishikawa K,Nishimura Y,Nonnenmacher TS,Novella P,Nowak J,O'Keeffe HM,O'Sullivan L,Okumura K,Okusawa T,Oryszczak W,Oser SM,Owen RA,Oyama Y,Palladino V,Palomino JL,Paolone V,Paudyal P,Pavin M,Payne D,Pickering L,Pidcott C,Pinzon Guerra ES,Pistillo C,Popov B,Porwit K,Posiadala-Zezula M,Pritchard A,Quilain B,Radermacher T,Radicioni E,Ratoff PN,Reinherz-Aronis E,Riccio C,Rondio E,Rossi B,Roth S,Rubbia A,Ruggeri AC,Rychter A,Sakashita K,Sánchez F,Sasaki S,Scantamburlo E,Scholberg K,Schwehr J,Scott M,Seiya Y,Sekiguchi T,Sekiya H,Sgalaberna D,Shah R,Shaikhiev A,Shaker F,Shaw D,Shiozawa M,Smirnov A,Smy M,Sobczyk JT,Sobel H,Sonoda Y,Steinmann J,Stewart T,Stowell P,Suda Y,Suvorov S,Suzuki A,Suzuki SY,Suzuki Y,Sztuc AA,Tacik R,Tada M,Takeda A,Takeuchi Y,Tamura R,Tanaka HK,Tanaka HA,Thakore T,Thompson LF,Toki W,Touramanis C,Tsui KM,Tsukamoto T,Tzanov M,Uchida Y,Uno W,Vagins M,Vallari Z,Vasseur G,Vilela C,Vladisavljevic T,Volkov VV,Wachala T,Walker J,Wang Y,Wark D,Wascko MO,Weber A,Wendell R,Wilking MJ,Wilkinson C,Wilson JR,Wilson RJ,Wret C,Yamada Y,Yamamoto K,Yamasu S,Yanagisawa C,Yang G,Yano T,Yasutome K,Yen S,Yershov N,Yokoyama M,Yoshida T,Yu M,Zalewska A,Zalipska J,Zaremba K,Zarnecki G,Ziembicki M,Zimmerman ED,Zito M,Zsoldos S,Zykova A,
Search for CP Violation in Neutrino and Antineutrino Oscillations by the T2K Experiment with 2.2×10^{21} Protons on Target.
Phys Rev Lett. 2018 Oct 26;121(17):171802
The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of 14.7(7.6)×10^{20} protons on target in the neutrino (antineutrino) mode, 89 ?_{e} candidates and seven anti-?_{e} candidates are observed, while 67.5 and 9.0 are expected for d_{CP}=0 and normal mass ordering. The obtained 2s confidence interval for the CP-violating phase, d_{CP}, does not include the CP-conserving cases (d_{CP}=0, p). The best-fit values of other parameters are sin^{2}?_{23}=0.526_{-0.036}^{+0.032} and ?m_{32}^{2}=2.463_{-0.070}^{+0.071}×10^{-3}??eV^{2}/c^{4}.
PMID: 30411920
Chang HH,Yeh JC,Mao J,Ginsberg DA,Ghoniem G,Rodriguez LV
Spinal cord stimulation ameliorates detrusor over-activity and visceromotor pain responses in rats with cystitis.
Neurourol Urodyn. 2018 Nov 09;
Interstitial cystitis/painful bladder syndrome/(IC/PBS) results in recurring pain in the bladder and surrounding pelvic region caused by abnormal excitability of micturition reflexes. Spinal cord stimulation (SCS) is currently clinically used for the attenuation of neuropathic and visceral pain. The present study examined whether SCS at upper lumbar segments modulates detrusor overactivity and visceral hyperalgesia associated with cystitis in a rat model of cyclophosphamide (CYP)-induced cystitis.
PMID: 30411810
Lee CC,Hu Y,Ribbe MW
Reduction and Condensation of Aldehydes by the Isolated Cofactor of Nitrogenase.
ACS Cent Sci. 2018 Oct 24;4(10):1430-1435
Isolated nitrogenase cofactors can reduce CO, CN, and CO to short-chain hydrocarbons in reactions driven by a strong reductant. Here, we use activity analyses and isotope labeling experiments to show that formaldehyde and acetaldehydes can be reduced as-is or reductively condensed into alkanes and alkenes by the isolated cofactor of Mo-nitrogenase in the presence of Eu-diethylenetriamine pentaacetate (DTPA). Further, we demonstrate that aldehydes can be condensed with CO by the isolated cofactor under the same reaction conditions, pointing to aldehyde-derived species as possible intermediates of nitrogenase-catalyzed CO reduction. Our deuterium labeling experiments suggest the formation of a cofactor-bound hydroxymethyl intermediate upon activation of the formaldehyde, as well as the release of CH as a product upon ß-hydride elimination of an acetaldehyde-derived hydroxyethyl intermediate. These findings establish the reductive condensation of aldehydes as a previously unobserved reactivity of a biogenic catalyst while at the same time shed light on the mechanism of enzymatic CO reduction and C-C bond formation, thereby providing a useful framework for further exploration of the unique reactivity and potential applications of nitrogenase-based reactions.
PMID: 30410981
Juhász MLW,Atanaskova Mesinkovska N
Does Complement Have a Role in the Pathogenesis of Alopecia Areata?
Skin Appendage Disord. 2018 Oct;4(4):261-263
Alopecia areata (AA) is an autoimmune disorder in which immune attack of the anagen follicle causes hair loss in approximately 2% of the population. Although the pathogenesis of AA has not been fully determined, most likely it is mediated by a variety of factors including cellular/humoral immunity and genetic predisposition. Researchers have been interested in the possible role of the complement pathway in AA since the 1970s. Given recent evidence suggesting that complement plays a role in many immunologic and inflammatory dermatologic diseases including systemic lupus erythematosus, bullous diseases, angioedema, lipodystrophy, and skin infections, it is likely that complement also contributes to AA pathogenesis. Although early serum studies and immunohistochemical staining have been unimpressive, recent genetics studies may provide evidence that complement does indeed contribute to AA. By determining if complement plays a role in AA, options for novel targeted treatments will become available for those patients with refractory disease.
PMID: 30410892
Yu V,Juhász M,Chiang A,Atanaskova Mesinkovska N
Alopecia and Associated Toxic Agents: A Systematic Review.
Skin Appendage Disord. 2018 Oct;4(4):245-260
There are a number of toxic agents that can cause alopecia. In this review we summarize the known substances that cause alopecia as one of the clinical signs of overdose or toxicity.
PMID: 30410891
Bender MT,Vo CD,Jiang B,Campos JK,Zarrin DA,Xu R,Westbroek EM,Caplan JM,Huang J,Tamargo RJ,Lin LM,Colby GP,Coon AL
Pipeline Embolization for Salvage Treatment of Previously Stented Residual and Recurrent Cerebral Aneurysms.
Interv Neurol. 2018 Oct;7(6):359-369
This study assessed the safety and effectiveness of the Pipeline embolization device (PED) for persistent and recurrent aneurysms previously treated with either a vascular reconstruction device (VRD) or a flow diverter (FD).
PMID: 30410513
Sparks TN,Thao K,Lianoglou BR,Boe NM,Bruce KG,Datkhaeva I,Field NT,Fratto VM,Jolley J,Laurent LC,Mardy AH,Murphy AM,Ngan E,Rangwala N,Rottkamp CAM,Wilson L,Wu E,Uy CC,Valdez Lopez P,Norton ME,
Nonimmune hydrops fetalis: identifying the underlying genetic etiology.
Genet Med. 2018 Nov 09;
Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes.
PMID: 30410095
Corva M,Ferrari A,Rinaldi M,Feng Z,Roiaz M,Rameshan C,Rupprechter G,Costantini R,Dell'Angela M,Pastore G,Comelli G,Seriani N,Vesselli E
Vibrational fingerprint of localized excitons in a two-dimensional metal-organic crystal.
Nat Commun. 2018 Nov 08;9(1):4703
Long-lived excitons formed upon visible light absorption play an essential role in photovoltaics, photocatalysis, and even in high-density information storage. Here, we describe a self-assembled two-dimensional metal-organic crystal, composed of graphene-supported macrocycles, each hosting a single FeN center, where a single carbon monoxide molecule can adsorb. In this heme-like biomimetic model system, excitons are generated by visible laser light upon a spin transition associated with the layer 2D crystallinity, and are simultaneously detected via the carbon monoxide ligand stretching mode at room temperature and near-ambient pressure. The proposed mechanism is supported by the results of infrared and time-resolved pump-probe spectroscopies, and by ab initio theoretical methods, opening a path towards the handling of exciton dynamics on 2D biomimetic crystals.
PMID: 30409974
McLean L,Connor CM
Relations between third grade teachers' depressive symptoms and their feedback to students, with implications for student mathematics achievement.
Sch Psychol Q. 2018 06;33(2):272-282
Recent studies have observed connections among teachers' depressive symptoms and student outcomes; however, the specific mechanisms through which teachers' mental health characteristics operate in the classroom remain largely unknown. The present study used student-level observation methods to examine the relations between third-grade teachers' (N = 32) depressive symptoms and their academic feedback to students (N = 310) and sought to make inferences about how these factors might influence students' mathematics achievement. A novel observational tool, the Teacher Feedback Coding System-Academic (TFCS-A), was used that assesses feedback across 2 dimensions-teacher affect and instructional strategy, which have been shown to be important to student learning. Multilevel exploratory factor analysis of TFCS-A data suggested 2 primary factors: positive feedback and neutral/negative feedback. Hierarchical linear modeling revealed that positive feedback was related to higher math achievement among students who began the year with weaker math skills and that teachers who reported more depressive symptoms less frequently provided this positive feedback. Results offer new information about a type of instruction that may be affected by teachers' depressive symptoms and inform efforts aimed at improving teachers' instructional interactions with students. (PsycINFO Database Record
PMID: 28857586
Delli Pizzi S,Punzi M,Sensi SL,
Functional signature of conversion of patients with mild cognitive impairment.
Neurobiol Aging. 2018 Oct 12;74:21-37
The entorhinal-hippocampal circuit is a strategic hub for cognition and the first site affected by Alzheimer's disease (AD). We investigated magnetic resonance imaging patterns of brain atrophy and functional connectivity in an Alzheimer's Disease Neuroimaging Initiative data set that included healthy controls, mild cognitive impairment (MCI), and patients with AD. Individuals with MCI were clinically evaluated 24 months after the first magnetic resonance imaging scan, and the cohort subdivided into sets of individuals who either did or did not convert to AD. The MCI group was also divided into patients who did show or not the presence of AD-related alterations in the cerebrospinal fluid. Patients with AD exhibited the collapse of the long-range hippocampal/entorhinal connectivity, pronounced cortical/subcortical atrophy, and a dramatic decline in cognitive performances. Patients with MCI who converted to AD or patients with MCI who showed the presence of AD-related alterations in the cerebrospinal fluid showed memory deficits, entorhinal/hippocampal hypoconnectivity, and concomitant atrophy of the two regions. Patients with MCI who did not convert to AD or patients with MCI who did not show the presence of AD-related alterations in the cerebrospinal fluid had no atrophy but showed hippocampal/entorhinal hyperconnectivity with selected neocortical/subcortical regions involved in memory processing and brain metastability. This hyperconnectivity may represent a compensatory strategy against the progression of cognitive impairment.
PMID: 30408719
Tadir Y,Iglesia C,Alexiades M,Davila GW,Guerette N,Gaspar A
Energy-based treatment for gynecologic conditions including genitourinary syndrome of menopause: Consensus, controversies, recommendations, and FDA clearance.
Lasers Surg Med. 2018 Nov 08;
PMID: 30408203
Kim JH,Jang SJ,Yun JW,Jung MH,Woo SH
Effects of pepsin and pepstatin on reflux tonsil hypertrophy in vitro.
PLoS One. 2018;13(11):e0207090
There is evidence that pepsin can aggravate tonsil hypertrophy. Pepstatin is a potent inhibitor of pepsin activity and could protect patients against reflux tonsil hypertrophy by inhibiting pepsin. We examined the effects of pepstatin on the development of tonsil hypertrophy to investigate pepsin's role in the pathogenesis of tonsil lesions. We investigated whether pepstatin suppresses pepsin-mediated lymphocyte proliferation in tonsil hypertrophy. Forty-nine children with tonsil hypertrophy and twenty-two adults with tonsillitis were recruited to the study prior to surgery. Tonsil tissue from each patient was harvested and assessed for changes in the number of lymphocytes and macrophages in the presence of pepsin and pepstatin. We found that the proportions of CD4- and CD14-positive cells were significantly lower (p < 0.05), but that the proportions of CD19- and CD68-positive cells were significantly higher (p < 0.05), in children than in adults. There were significantly more CD4-positive cells after pepsin treatment, but these numbers were reduced by pepstatin. The levels of both interleukin-2 (IL-2) and interferon gamma (IFN-?) increased significantly in response to pepsin, but were reduced when pepsin was inhibited by pepstatin. The level of IL-10 is reduced in pepsin-treated CD4 cells and the level is restored by pepstatin. IL-2 blocking reduced the increased CD4 cell number by pepsin. But, an additive or a synergic effect is not founded in combined with IL-2 blocking and pepstatin. Pepsin-positive cells did not co-localize with CD20 and CD45 cells, but they were found surrounding CD20- and CD45-positive hypertrophic tonsil cells. Pepsin-positive cells co-localized with CD68-positive cells. It is probable that pepsin from extraesophageal reflux aggravates tonsil hypertrophy and pepstatin exerts a protective effect by inhibiting pepsin activity.
PMID: 30408092
Wang PZT,Abdelhalim A,Walia A,Wehbi E,Dave S,Khoury A
Avoiding routine postoperative voiding cystourethrogram: Predicting radiologic success for endoscopically treated vesicoureteral reflux.
Can Urol Assoc J. 2018 Nov 05;
Variability in the success rates for the endoscopic correction of vesicoureteral reflux (VUR) has prompted a debate regarding the use of routine postoperative voiding cystourethrogram (VCUG). This study examines the predictive performance of intraoperative mound morphology (IMM) and the presence of a postoperative ultrasound mound (PUM) on radiologic success, as well as investigates the role of using these two predictive factors as a composite tool to predict VUR resolution after endoscopic treatment.
PMID: 30407152
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