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SAR of tricyclic sulfones as γ-secretase inhibitors

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Science China Chemistry 2011年第11期54卷 1688-1701页

作者： COLE David ASBEROM Ted BARA Tom BENNETT Chad BURNETT Duane A. CLADER j.hn DOMALSKI Martin GREENLEE William j. HYDE Lynn j.SIEN Hubert McBRIAR Mark McKITTRICK brian PISSARNITSKI Dmitri RAj.GOPALAN Murali SASIKUMAR Thavalakulamgara Merck Research Laboratories 2015 Galloping Hill RoadKenilworth New Jersey 07033 USA

Novel tricyclic sulfones as γ-secretase inhibitors have been reported by this laboratory for the treatment of Alzheimer's disease. Compounds in this series have comparable or better in vitro activities and in vivo efficacies than sulfonamide analogues re- ported previously by this laboratory. Based on the previously reported tricyclic sulfone scaffold, additional SAR studies of C ring were carried out. Various C-ring structures including cyclohexane, pyran, and piperidine were tolerated. Additionally, the 7- and 8- positions of the C-ring were identified as the best sites to introduce substituent for modulating the pharmacokinetic properties of compounds from this series.

关键词： tricyclic sulfones T-secretase Alzheimer's disease inhibitors

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Variability of cell proliferation in the proximal and distal colon of normal rats and rats with dimethylhydrazine induced carcinogenesis

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World j.urnal of Gastroenterology 2002年第5期8卷 847-852页

作者： Kate E Williamson brian j.Rowlands Department of Surgery Institute of Clinical ScienceThe Queen's University of BelfastBelfastUK

AIM：To investigate the patterns of cell proliferation in proximal and distal colons in normal rats and rats with1,2-dimethylhydrazine(DMH)induced carcinogenesis using the thymidine analogue ***:Colonic crypt cell proliferation was immunohistochemically detected using the anti-bromodeoxyuridine Bu20a monoclonal ***:Marked regional differences were found in both *** labelling index(LI)and proliferative zone size in both normal(8.65±0.34vs7.2±0.45,27.74±1.07vs16.75±1.45)andDMH groups(13.13±0.46vs11.55±0.45,39.60±1.32vs35.52±1.58)were significantly higher in distal than in proximal colon(P<0.05).although the number of cells per proxmal crypt was greater(31.45±0.20vs34.45±0.39,42.68±0.53vs49.09±0.65,P<0.001).Crypt length,total LT and proliferative zone size all increased in both proximal and distal regions of DMH rats compared to normal controls(P<0.0001).In DMH-treated rat colon a shift of labelled cells to higher crypt cell positions was demonstrated distally whist a bi-directional shift was evident proximally(P<0.05).CONCLUSION:Our results show that changes in cell proliferation patterns,as assessed by bromodeoxyuridine uptake,can act as a reliable intermediate marker of colonic cancer *** differences between proliferation patterns in distal and proximal colon may be associated with the higher incidence of tumors in t he distal colon.

关键词：溴脱氧尿嘧啶二甲肼细胞增殖致癌机制动物实验

Angling of hybrid sunfish from a hatchery pond with potential implications for community fisheries

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Aquaculture and Fisheries 2023年第1期8卷 91-95页

作者： brian G.Blackwell Matthew j.Ward Todd M.Kaufman South Dakota Department of Game Fish and Parks603 East 8th AvenueWebsterSD57274USA South Dakota Department of Game Fish and Parks44437139A StreetWaubaySD57273USA

Hatcheries are frequently called upon to produce catchable-sized fish for stocking community fishing *** attributes of fish selected for stocking into community ponds are that they are easy to produce in a hatchery system to sizes anglers are interested in catching and they provide anglers with high catch rates once *** sunfish[male Bluegill(Lepomis macrochirus)×female Green Sunfish(***)]have attributes that potentially make them attractive for use in community fishing *** assessed initial angler catch rates of 100 stocked hybrid sunfish in a 0.12-ha hatchery pond and after being subj.cted to angling(four,1-hr catch-and-release fishing events with five anglers).We also investigated whether catch rates would change following a supplemental stocking of an additional 100 hybrid sunfish(four,1-hr catch-and-release fishing events with five anglers).The anal fin of each fish in the second stocking was hole punched to differentiate them from those of the first stocking and fish caught by anglers were hole punched in the caudal fin each time they were caught before being released back into the *** catch rates were highest during initial fishing events that followed stocking(9.2 fish/angler hr and 18.0 fish/angler hr)and substantially declined in subsequent events(≤3.4 fish/angler hr).Catches of the newly stocked fish and previously stocked fish contributed to the high catch following the supplemental ***(80%)of the fish were caught in the first 30 min of each event and 45%were caught during the first 10 *** were able to catch 88%of the fish from the first stocking and 67%from the second stocking at least *** mortality occurred during the study as all fish were recovered when the pond was *** results suggest that hybrid sunfish will potentially provide high initial catch rates following stocking into community ponds,but managers should expect reduced catch rates following initial fishing even without h

关键词： Hybrid sunfish Angling Community fishing ponds

Photonic waveguide to free-space Gaussian beam extreme mode converter

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Light(Science & Applications) 2018年第1期7卷 346-358页

作者： Sangsik Kim Daron A.Westly brian j.Roxworthy Qing Li Alexander Yulaev Kartik Srinivasan Vladimir A.Aksyuk Center for Nanoscale Science and Technology National Institute of Standards and TechnologyGaithersburgMD 20899USA Maryland Nanocenter University of MarylandCollege ParkMD 20742USA Department of Electrical and Computer Engineering Texas Tech UniversityLubbockTX 79409USA

Integration of photonic chips with millimeter-scale atomic,micromechanical,chemical,and biological systems can advance science and enable new miniaturized hybrid devices and *** interaction via small evanescent volumes restricts performance in applications such as gas spectroscopy,and a general ability to photonically access optical fields in large free-space volumes is ***,conventional inverse tapers and grating couplers do not directly scale to create wide,high-quality collimated beams for low-loss diffraction-free propagation over many millimeters in free space,necessitating additional bulky collimating optics and expensive ***,we develop an extreme mode converter,which is a compact planar photonic structure that efficiently couples a 300 nm×250 nm silicon nitride high-index single-mode waveguide to a well-collimated near surface-normal Gaussian beam with an≈160μm waist,which corresponds to an increase in the modal area by a factor of>*** beam quality is thoroughly characterized,and propagation over 4mm in free space and coupling back into a single-mode photonic waveguide with low loss via a separate identical mode converter is *** achieve low phase error over a beam area that is>100×larger than that of a typical grating coupler,our approach separates the two-dimensional mode expansion into two sequential separately optimized stages,which create a fully expanded and well-collimated Gaussian slab mode before out-coupling it into free *** at 780 nm for integration with chip-scale atomic vapor cell cavities,our design can be adapted for visible,telecommunication,or other *** technique can be expanded to more arbitrary phase and intensity control of both large-diameter,free-space optical beams and wide photonic slab modes.

关键词： waveguide millimeter mode

When Interfaces Interfere:Crashlands,Cancer,and Embodied Gaming

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j.urnal of Foreign Languages and Cultures 2019年第2期3卷 33-40页

作者： brian Reed University of Washington

In Gameworld Interfaces,Kristine j.rgensen maintains that the best interfaces provide an optimal amount of useful information about a gameworld without becoming *** games are,however,complex obj.cts,and sometimes they serve purposes other than entertaining users through facilitating immersive *** can,for instance,promote educational and aesthetic ends that are not inhibited but advanced by making an interface the focus of player *** essay offers one example of a game that cannot be fully appreciated by prioritizing efficient interface *** Coster first conceived the broad outlines of Butterscotch Shenanigans’s Crashlands after being diagnosed with stage four *** game,as finally released,is partially a statement about and in response to“all the bone pain,chemo nausea,anxiety,depression,stab wounds,tape rips and hair loss”that he *** specifically,by occasionally and obstructively spotlighting the physical,fleshly contact between a player,a screen,and an imagined landscape,it explores the problem of embodiment in video *** teaches the phenomenological lesson that a body’s boundaries are not so easily *** the philosopher Maurice Merleau-Ponty would put it,players’“flesh”necessarily provides the medium through which they gain access to and inhabit a *** other words,you take your body with you,sick or healthy,even when voyaging to another planet.

关键词： video game studies interface medicine embodiment phenomenology

Advances in Home Photo Printing

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仪器仪表学报 2004年第S3期 116-120页

作者： brian Atkins Hewlett-Packard Laboratories CA 94304 USA Palo Alto

With digital camera adoptions going main stream, consumers capture a record number of photos. Currently, the maj.rity of the digital photos are printed at home. One of the key enablers of this transformation is the advancement of home photo printing technologies. In the past few years, inkj.t printing technologies have continued to deliver smaller drop size, larger number of inks, and longer-lasting prints. In the mean time, advanced image processing automatically enhances captured digital photos while being printed. The combination of the above two forces has closed the gap between the home photo prints and AgX prints. It will give an overview of the home photo printing market and technology trends, and discuss maj.r advancements in automatic image processing.

关键词： Image processing Printing Automatic enhancement

The Lost and the Found:Memories of Donald ***

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Earthquake Science 2022年第1期35卷 51-53页

作者： brian Savage University of Rhode Island KingstonRI02879USA

My first exposure to Don Helmberger’s work was during a seismology class in my 2nd year in college where several students,including myself,were to present on Grand and Helmberger(1984).It was over my head,but seeing the beauty of the seismograms,tracking the upper mantle triplication,and what it revealed about the Earth was j.st *** my time as an undergraduate at Berkeley,I also digitized(Dreger and Savage,1999)and forward modeled seismic data under the advisement of *** Dreger(a Helmberger student)for about two years,had an academic advisor who went to Caltech(*** Richards)and took a couple of courses from *** j.hnson(Don's friend from Minnesota).Little did I know the path I needed to take was already laid out-I j.st had to follow it.

关键词： mantle Berkeley Grand

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Fetal Head Compression: Its Possible Role in Neurologic Inj.ry

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Open j.urnal of Obstetrics and Gynecology 2024年第1期14卷 124-143页

作者： Barry S. Schifrin brian j. Koos Wayne R. Cohen Department of Obstetrics and Gynecology The Western University of Health Sciences Pomona USA The David Geffen School of Medicine at UCLA Los Angeles USA The University of Arizona College of Medicine Tucson USA

It is widely assumed that fetal ischemic brain inj.ry during labor derives almost exclusively from severe, systemic hypoxemia with marked neonatal depression and acidemia. Severe asphyxia, however, is one of several causes of perinatal neurological inj.ry and may not be the most common;most neonates diagnosed with hypoxic-ischemic encephalopathy do not have evidence of severe asphyxia. Sepsis, direct brain trauma, and drug or toxin exposure account for some cases, while mechanical forces of labor and delivery that increase fetal intracranial pressure sufficiently to impair brain perfusion may also contribute. Because of bony compliance and mobile suture lines, the fetal skull changes shape and redistributes cerebrospinal fluid during labor according to constraints imposed by contractions, and bony and soft tissue elements of the birth canal as the head descends. These accommodations, including the increase in intracranial pressure, are adaptive and necessary for efficient descent of the head while safeguarding cerebral blood flow. Autonomic reflexes mediated through central receptors normally provide ample protection of the brain from the considerable pressure exerted on the skull. On occasion, those forces, which are transmitted intracranially, may overcome the various adaptive anatomical, cardiovascular, metabolic, and neurological mechanisms that maintain cerebral perfusion and oxygen availability, resulting in ischemic brain inj.ry. Accepting the notion of a potentially adverse impact of fetal head compression suggests that avoidance of excessive uterine activity and of relentless pushing without steady progress in descent may offer protection for the fetal brain during parturition. Excessive head compression should be considered in the differential diagnosis of ischemic encephalopathy.

关键词： Fetal Brain Inj.ry Fetal Head Compression Ischemic Encephalopathy Neonatal Encephalopathy

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中国与澳大利亚胃溃疡的比较研究

中华消化杂志 1993年第1期13卷 61-62页

作者：李增烈 piper,DW 710068 澳大利亚，悉尼大学内科及皇家北岸医院消化科