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Polyethylene glycol has immunoprotective effects on sciatic allografts, but behavioral recovery and graft tolerance require neurorrhaphy and axonal fusion

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Neural Regeneration Research 2025年第4期20卷 1192-1206页

作者： Tyler A.Smith liwen Zhou cameron l.Ghergherehchi Michelle Mikesh Cathy Z.Yang Haley O.Tucker JuliAnne Allgood Jared S.Bushman George D.Bittner Department of Molecular Biosciences University of Texas at AustinAustinTXUSA Department of Neuroscience University of Texas at AustinAustinTXUSA Division of Pharmaceutical Sciences University of WyomingLaramieWYUSA

Behavioral recovery using(viable)peripheral nerve allografts to repair ablation-type(segmental-loss)peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal ***,such peripheral nerve allografts undergo immunological rejection by the host immune *** contrast,peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks,reduced immune responses,and many axons do not undergo Wallerian *** relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this *** hypothesized that polyethylene glycol might have some immune-protective effects,but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral *** examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal ***-type sciatic nerve injuries in outbred Sprague–Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts,but peripheral nerve allografts were loose-sutured(loose-sutured polyethylene glycol)with an intentional gap of 1–2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host *** to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts,animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days *** morphological signs of rejection,such as col

关键词： allograft rejection axotomy macrophage myelin nerve repair polyethylene glycol(PEG) sciatic nerve T cell transplantation Wallerian degeneration

Conundrums and confusions regarding how polyethylene glycol-fusion produces excellent behavioral recovery after peripheral nerve injuries

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Neural Regeneration Research 2018年第1期13卷 53-57页

作者： George D.Bittner Dale R.Sengelaub cameron l.Ghergherehchi Department of Neuroscience University of Texas at Austin Department of Psychological and Brain Sciences Indiana University Department of Molecular Biosciences University of Texas at Austin

Current Neuroscience dogma holds that transections or ablations of a segment of peripheral nerves produce：（1） Immediate loss of axonal continuity, sensory signaling, and motor control; （2） Wallerian rapid （1-3 days） degeneration of severed distal axons, muscle atrophy, and poor behavioral recovery after many months （if ever, after ablations） by slowly-regenerating （1 mm/d）, proximal-stump outgrowths that must specifically reinnervate denervated targets; （3） Poor acceptance of microsutured nerve allografts, even if tissue-matched and immune-suppressed. Repair of transections/ablations by neurorrhaphy and well-specified-sequences of PEG-fusion solutions （one containing polyethylene glycol, PEG） successfully address these problems. However, conundrums and confusions regarding unorthodox and dramatic results of PEG-fusion repair in animal model systems often lead to misunderstandings. For example, （1） Axonal continuity and signaling is re-established within minutes by non-specifically PEG-fusing （connecting） severed motor and sensory axons across each lesion site, but remarkable behavioral recovery to near-unoperated levels takes several weeks; （2） Many distal stumps of inappropriately-reconnected, PEG-fused axons do not ever （Wallerian） degenerate and continuously innervate muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers; （3） Host rats do not reject PEG-fused donor nerve allografts in a non-immuno-privileged environment with no tissue matching or immunosuppression; （4） PEG fuses apposed open axonal ends or seals each shut （thereby preventing PEG-fusion）, depending on the experimental protocol; （5） PEG-fusion protocols produce similar results in animal model systems and early human case studies. Hence, iconoclastic PEG-fusion data appropriately understood might provoke a re-thinking of some Neuroscience dogma and a paradigm shift in clinical treatment of peripheral nerve injuries.

关键词： axonal repair axotomy Wallerian degeneration polyethylene glycol allograft autograft nerve regeneration

Practical guide to improving diagnostic sensitivity of bile duct brushings

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Hepatobiliary & Pancreatic Diseases International 2021年第4期20卷 396-399页

作者： Ioannis C Varbobitis Jonathan C Booth cameron l Griffiths Nishchay Chandra Department of Gastroenterology Royal Berkshire HospitalReading RG15ANUK

Despite recent advances in hepatopancreatobiliary (HPB) endoscopy,pancreatobiliary (PB) tract brushing remains the first diagnostic approach in cases of indeterminate PB *** accurate cytological diagnosis is critical to establishing an early and definite diagnosis before proceeding to aggressive chemotherapy regimens or major operations like a Whipple’s procedure.

关键词： diagnosis chemotherapy regimen

Methylene blue enhances polyethylene glycol-fusion repair of completely severed rat sciatic nerves

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Neural Regeneration Research 2021年第10期16卷 2056-2063页

作者： cameron l.Ghergherehchi Jaimie T.Shores Joseph Alderete Erik K.Weitzel George D.Bittner Institute for Cellular and Molecular Biology University of Texas at AustinAustinTXUSA Department of Plastic and Reconstructive Surgery Johns Hopkins University School of MedicineBaltimoreMDUSA Department of Surgery RESTOR LaboratorySan AntonioTXUSA Department of Neuroscience University of Texas at AustinAustinTXUSA

Complete transection of peripheral mixed nerves immediately produces loss of sensory perception,muscle contractions and voluntary behavior mediated by the severed distal *** contrast to natural regeneration(~1 mm/d)of proximal axons that may eventually reinnervate denervated targets,re-innervation is restored within minutes by PEG-fusion that consists of neurorrhaphy and a sequence of well specified hypo-and isotonic calcium-free or calcium-containing solutions,the anti-oxidant methylene blue(MB)and the membrane fusogen polyethylene glycol(PEG).In this study,we examined the relative efficacy of PEG-fusion with no MB(0%),0.5%MB,or 1%MB on the recovery of voluntary behaviors by female Sprague-Dawley rats with a complete mid-thigh severance of their sciatic nerve bathed in extracellular fluid or calcium-containing isotonic *** recovery of voluntary behaviors is the most relevant measure of success of any technique to repair peripheral nerve *** assessed recovery by the sciatic functional index,a commonly used measure of voluntary hindlimb behaviors following complete sciatic *** reported that both 1%MB and 0.5%MB in sterile distilled water in our PEG-fusion protocol with neurorrhaphy significantly increased the rate and extent of behavioral recovery compared to PEG plus neurorrhaphy ***,0.5%MB was as effective as 1%MB in voluntary behavioral recovery as assessed by the sciatic functional *** sterile 1%MB is no longer clinically available,we therefore recommend that 0.5%MB be included in upcoming human clinical trials to evaluate the safety and efficacy of *** animal procedures were approved by the University of Texas Institutional Animal Care and Use Committee(AUP-2019-00225)on September 9,2020.

关键词： axotomy methylene blue nerve repair neurorrhaphy peripheral nerve injury polyethylene glycol fusion sciatic nerve

Optimizing oncolytic virus design:a“Swiss army knife”approach to create a systemically delivered therapeutic

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1791-1792页

作者： Carolina S.Ilkow John cameron Bell Ottawa Hospital Research Institute 501 Smyth RoadOttawaONK1H 8L6Canada

In a recent paper published in Nature Biotechnology,Chen et al.1 describe a multiplex oncolytic virus platform that coupled with adoptive T cell therapy could solve the problem of repeat,systemic delivery of virus based *** is widely accepted that multi-targeted therapeutic approaches attacking several facets of cancer biology are necessary to effectively deal with the tumor heterogeneity that exists within and between patients.

关键词： therapeutic al. targeted

Polymer graph neural networks for multitask property learning

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npj Computational Materials 2023年第1期9卷 1420-1429页

作者： Owen Queen Gavin A.McCarver Saitheeraj Thatigotla Brendan P.Abolins cameron l.Brown Vasileios Maroulas Konstantinos D.Vogiatzis Department of Mathematics University of TennesseeKnoxvilleTN 37996-1320USA Department of Electrical Engineering and Computer Science University of TennesseeKnoxvilleTN 37996-2250USA Department of Chemistry University of TennesseeKnoxvilleTN 37996-1600USA Eastman Chemical Company KingsportTN 37660USA

The prediction of a variety of polymer properties from their monomer composition has been a challenge for material informatics,and their development can lead to a more effective exploration of the material *** this work,POlYMERGNN,a multitask machine learning architecture that relies on polymeric features and graph neural networks has been developed towards this *** provides accurate estimates for polymer properties based on a database of complex and heterogeneous polyesters(linear/branched,homopolymers/copolymers)with experimentally refined *** POlYMERGNN,each polyester is represented as a set of monomer units,which are introduced as molecular graphs.A virtual screening of a large,computationally generated database with materials of variable composition was performed,a task that demonstrates the applicability of the POlYMERGNN on future studies that target the exploration of the polymer ***,a discussion on the explainability of the models is provided.

关键词： properties space polyester

Fire blight QTl analysis in a multi-family apple population identifies a reduced-susceptibility allele in ‘Honeycrisp’

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Horticulture Research 2021年第1期8卷 355-367页

作者： Sarah A.Kostick Soon li Teh John l.Norelli Stijn Vanderzande cameron Peace Kate M.Evans Tree Fruit Research and Extension Center Department of HorticultureWashington State UniversityWenatcheeWA 98801USA United States Department of Agriculture Agricultural Research ServiceAppalachian Fruit Research LaboratoryKearneysvilleWV 25430USA Department of Horticulture Washington State UniversityPullmanWA 99164USA

Breeding apple cultivars with resistance offers a potential solution to fire blight,a damaging bacterial disease caused by Erwinia *** resistance alleles at quantitative trait loci(QTls)were previously characterized in diverse Malus germplasm with poor fruit quality,which reduces breeding *** study utilized a pedigree-based QTl analysis approach to elucidate the genetic basis of resistance/susceptibility to fire blight from multiple genetic sources in germplasm relevant to *** breeding ***-seven important breeding parents(IBPs)were represented by 314 offspring from 32 full-sib families,with‘Honeycrisp’being the most highly represented *** resistance/susceptibility data from a two-year replicated field inoculation study and previously curated genome-wide single nucleotide polymorphism data,QTls were consistently mapped on chromosomes(Chrs.)6,7,and *** QTls together explained~28% of phenotypic *** Chr.6 and Chr.15 QTls colocalized with previously reported QTls,while the Chr.7 QTl is possibly novel.‘Honeycrisp’inherited a rare reduced-susceptibility allele at the Chr.6 QTl from its grandparent‘Frostbite’.The highly resistant IBP‘Enterprise’had at least one putative reduced-susceptibility allele at all three *** general,lower susceptibility was observed for individuals with higher numbers of reduced-susceptibility alleles across *** study highlighted QTl mapping and allele characterization of resistance/susceptibility to fire blight in complex pedigree-connected apple breeding *** gained will enable more informed parental selection and development of trait-predictive DNA tests for pyramiding favorable alleles and selection of superior apple cultivars with resistance to fire blight.

关键词： blight breeding cultivar

Summer monsoon and dust signals recorded in the Dasuopu firn core, central Himalayas

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Chinese Science Bulletin 1999年第21期44卷 2010-2015页

作者： cameron P.Wake Paul A.Mayewski Climate Change Research Center Institute for the Study of EarthOcean and Space(EOS)University of New Hampshire DurhamNH 03824USAClimate Change Research CenterInstitute for the Study of EarthOcean and Space(EOS)University of New Hampshire DurhamNH 03824USA

In September 1997, a 15-m firn core was recovered from an elevation of 7 000 m a. s.l. from the Dasuopu Glacier in the central Himalayas. The analysis of δ18O values and major ion (Ca2+ , Mg2+ , NH4+ , SO2- and NO3-) concentrations shows that average annual accumulation is 0.75 m (water equivalent) in the Dasuopu firn core. The seasonal variations of δ18O values and major ion concentrations in the core indicate that present summer monsoon and

关键词： firn core records of summer monsoon and dust signals central Himalayas.

Vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts

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Bone Research 2016年第3期4卷 164-173页

作者： Allahdad Zarei Alireza Morovat Kassim Javaid cameron P Brown Botnar Research Centre Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Science University of Oxford Oxford UK Clinical Biochemistry Oxford University Hospitals NHS Trust Oxford UK

The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor （VDR）, we examined their response to different concentrations of 25-hydroxy vitamin D3 [25（OH）D3] （100 or 500 nmol·l^-1） and 1,25-dihydroxy vitamin D3 [1,25（OH）2D3] （0.1 or 0.5 nmol·l^-1） metabolites in cell cultures. Specifically, CD14＋ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand （RANKl） and macrophage colony-stimulating factor （M-CSF）. Tartrate-resistant acid phosphatase （TRAP） histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue （ex vivo） by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR （qRT-PCR） was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·l^-1 of 25（OH）D3 and 0.1-0.5 nmol·l^-1 of 1,25（OH）2D3, upregulating cytochrome P450 family 27 subfamily B member I （CYP27B1） and cytochrome P450 family 24 subfamily A member I （CYP24A1）. Osteoclast fusion transcripts transmembrane 7 subfamily member 4 （tm7sf4） and nuclear factor of activated T-cell cytoplasmic 1 （nfatcl） where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25（OH）D3 and 1,25（OH）2D3 reduced osteoclast size and number when co-treated with RANKl and M-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25（OH）2D3 on osteoclasts in vitro may therefore provide

关键词： Vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts bone