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TLR2 and TLR4 in Parkinson’s disease pathogenesis:the environment takes a toll on the gut

Translational Neurodegeneration 2021年第4期10卷 611-629页

作者： Anastazja M.Gorecki Chidozie C.Anyaegbu ryan s.anderton school of Biological science University of Western AustraliaCrawleyWAAustralia Neurodegenerative Disorders Research Group Perron Institute for Neurological and Translational ScienceNedlandsWAAustralia Curtin Health Innovation Research Institute Ralph and Patricia Sarich Neuroscience Research InstituteCurtin UniversityNedlandsWAAustralia Faculty of Medicine Nursing and Midwifery and Faculty of Health SciencesUniversity of Notre Dame AustraliaFremantleWAAustralia school of Nursing MidwiferyHealth Sciences and PhysiotherapyUniversity of Notre Dame AustraliaFremantleWAAustralia

Parkinson's disease(PD)is an incurable,devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra.In recent years,growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD,especially in a subset of people who exhibit prodromal gastrointestinal dysfunction.specifically,perturbations of gut homeostasis are hypothesized to contribute toα-synuclein aggregation in enteric neurons,which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD,including neurodegeneration and motor impairments.However,the mechanisms linking gut disturbances andα-synuclein aggregation are still unclear.A plethora of research indicates that toll-like receptors(TLRs),especially TLR2 and TLR4;are critical mediators of gut homeostasis.Alongside their established role in innate immunity throughout the body,studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system.Notably,TLR2 and TLR4 are dysregulated in patients with PD,and may thus be central to early gut dysfunction in PD.To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to earlyα-synuclein aggregation and PD,we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD;by reviewing clinical,animal model and in vitro research.Growing evidence on the immunological aetiology ofα-synuclein aggregation is also discussed,with a focus on the interactions ofα-synuclein with TLR2 and TLR4.We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling,ultimately leading to a positive feedback loop of chronic gut dysfunction promotingα-synuclein aggregation in enteric and vagal neurons.In turn,α-synuclein aggregates m

关键词： Parkinson’s disease TLR2 TLR4 α-synuclein Gut-brain axis Gut barrier Gut homeostasis

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Direct-to-indirect mapping for optimal low-thrust trajectories

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Astrodynamics 2024年第1期8卷 27-46页

作者： David Ottesen ryan P.Russell Department of Aerospace Engineering and Engineering Mechanics The University of Texas at AustinAustinTexas78712USA

Optimal,many-revolution spacecraft trajectories are challenging to solve.A connection is made for a class of models between optimal direct and indirect solutions.For transfers that minimize thrust-acceleration-squared,primer vector theory maps direct,many-impulsive-maneuver trajectories to the indirect,continuous-thrust-acceleration equivalent.The mapping algorithm is independent of how the direct solution is obtained and requires only a solver for a boundary value problem and its partial derivatives.A Lambert solver is used for the two-body problem in this work.The mapping is simple because the impulsive maneuvers and co-states share the same linear space around an optimal trajectory.For numerical results,the direct coast-impulse solutions are demonstrated to converge to the indirect continuous solutions as the number of impulses and segments increases.The two-body design space is explored with a set of three many-revolution,many-segment examples changing semimajor axis,eccentricity,and inclination.The first two examples involve a small change to either semimajor axis or eccentricity,and the third example is a transfer to geosynchronous orbit.Using a single processor,the optimization runtime is seconds to minutes for revolution counts of 10 to 100,and on the order of one hour for examples with up to 500 revolutions.Any of these thrust-acceleration-squared solutions are good candidates to start a homotopy to a higher-fidelity minimization problem with practical constraints.

关键词： direct optimization indirect optimization impulsive maneuvers Lambert's problem two-body dynamics primer vectortheory

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Robotic-assisted retroperitoneal lymph node dissection for stage II testicular cancer

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Asian Journal of Urology 2024年第1期11卷 121-127页

作者： George McClintock Ahmed s.Goolam Don Perera ryan Downey scott Leslie Peter Grimison Henry Woo Peter Ferguson Nariman Ahmadi Department of Urology Chris O'Brien LifehouseSydneyNSWAustralia Department of Anaesthesia Chris O'Brien LifehouseSydneyNSWAustralia The University of sydney SydneyNSW2006Australia Department of Medical Oncology Chris O'Brien LifehouseSydneyNSWAustralia

Objective:To evaluate the perioperative as well as early oncological outcomes of patients undergoing robotic retroperitoneal lymph node dissection for treatment of testicular cancer.Methods:We conducted a prospective consecutive case series of patients undergoing robotic assisted retroperitoneal lymph node dissection for metastatic testicular cancer between May 2018 and July 2021 at our institution.Data were collected on patient and tumour characteristics,intraoperative and postoperative parameters,and functional and oncological outcomes.Descriptive statistics are presented.Results:Nineteen patients were identified;18(94.7%)completed the procedure robotically and one was converted to open surgery;78.9%of patients had stage≥IIB and 12(63.2%)patients had undergone prior chemotherapy.The median operative time was 300(interquartile range[IQR]240-315)min.Median blood loss was 100(IQR 50-175)mL.Median length of stay was 2(range 1-11)days.All robotically completed patients commenced diet and passed flatus on Day 1 and were discharged by Day 3.The median lymph node yield was 40.5(IQR 38-51)nodes.All patients undergoing nerve-sparing procedures recovered antegrade ejaculatory function.One patient had a Clavien-Dindo III complication(chylous ascites requiring drainage).At a median follow-up of 22.3(IQR 16.3-24.9)months,one patient developed retroperitoneal recurrence,which was successfully treated with second-line chemotherapy;no other patients have had recurrences.Conclusion:Robotic retroperitoneal lymph node dissection is a safe and feasible alternative to open surgery in appropriately selected patients,offering low morbidity.Early oncological outcomes are promising.Larger cohorts and longer follow-ups are required to validate our institution's findings.

关键词： Retroperitoneal lymph node dissection Robotic surgery Testicular cancer Retroperitoneal node dissection

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subsequent total joint arthroplasty: Are we learning from the first stage?

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World Journal of Orthopedics 2024年第3期15卷 230-237页

作者： Christine Jiang Wu Colin Penrose sean Patrick ryan Michael Paul Bolognesi Thorsten Markus seyler samuel secord Wellman Department of Orthopaedic surgery Duke University HospitalDurhamNC 27710United States Department of Orthopaedic surgery Midwest Center for Joint ReplacementIndianapolisIN 46241United States

BACKGROUND With the increasing incidence of total joint arthroplasty(TJA),there is a desire to reduce peri-operative complications and resource utilization.As degenerative conditions progress in multiple joints,many patients undergo multiple proce-dures.AIM To determine if both physicians and patients learn from the patient’s initial arth-roplasty,resulting in improved outcomes following the second procedure.METHODs The institutional database was retrospectively queried for primary total hip arth-roplasty(THA)and total knee arthroplasty(TKA).Patients with only unilateral THA or TKA,and patients undergoing same-day bilateral TJA,were excluded.Patient demographics,comorbidities,and implant sizes were collected at the time of each procedure and patients were stratified by first vs second surgery.Outcome metrics evaluated included operative time,length of stay(LOs),disposition,90-d readmissions and emergency department(ED)visits.REsULTs A total of 642 patients,including 364 undergoing staged bilateral TKA and 278 undergoing bilateral THA,were analyzed.There was no significant difference in demographics or comorbidities between the first and second procedure,which were separated by a mean of 285 d.For THA and TKA,LOs was significantly less for the second surgery,with 66%of patients having a shorter hospitalization(Ps had significantly decreased operative time only when the same sized implant was utilized(P=0.025).The vast majority(93.3%)of patients were discharged to the same type of location following their second surgery.However,when a change in disposition was present from the first surgery,patients were significantly more likely to be discharged to home after the second procedure(P=0.033).There was no difference between procedures for post-operative readmissions(P=0.438)or ED visits(P=0.915).CONCLUsION After gaining valuable experience recovering from the initial surgery,a patient’s perioperative outcomes are improved for their second TJA.This may be the result of increased confidence and decrea

关键词： staged total joint arthroplasty Asynchronous total joint arthroplasty subsequent total joint arthroplasty Contralateral total joint arthroplasty Perioperative outcomes

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The secondary injury cascade after spinal cord injury: an analysis of local cytokine/chemokine regulation

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Neural Regeneration Research 2024年第6期19卷 1308-1317页

作者： Daniel J.Hellenbrand Charles M.Quinn Zachariah J.Piper ryan T.Elder Raveena R.Mishra Taylor L.Marti Phoebe M.Omuro Rylie M.Roddick Jae sung Lee William L.Murphy Amgad s.Hanna Department of Neurosurgery University of Wisconsin-Madison School of Medicine and Public Health Department of Biomedical Engineering University of Wisconsin-Madison Department of Orthopedics and Rehabilitation University of Wisconsin-Madison Department of Materials science and Engineering University of Wisconsin-Madison Forward BIO Institute University of Wisconsin-Madison

After spinal cord injury, there is an extensive infiltration of immune cells, which exacerbates the injury and leads to further neural degeneration. Therefore, a major aim of current research involves targeting the immune response as a treatment for spinal cord injury. Although much research has been performed analyzing the complex inflammatory process following spinal cord injury, there remain major discrepancies within previous literature regarding the timeline of local cytokine regulation. The objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury, identify sexual dimorphisms in terms of cytokine levels, and determine local cytokines that significantly change based on the severity of spinal cord injury. Rats were inflicted with either a mild contusion, moderate contusion, severe contusion, or complete transection, 7 mm of spinal cord centered on the injury was harvested at varying times post-injury, and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex assay. Results demonstrated pro-inflammatory cytokines including tumor necrosis factor α, interleukin-1β, and interleukin-6 were all upregulated after spinal cord injury, but returned to uninjured levels within approximately 24 hours post-injury, while chemokines including monocyte chemoattractant protein-1 remained upregulated for days post-injury. In contrast, several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days post-injury. After spinal cord injury, tissue inhibitor of metalloproteinase-1, which specifically affects astrocytes involved in glial scar development, increased more than all other cytokines tested, reaching 26.9-fold higher than uninjured rats. After a mild injury, 11 cytokines demonstrated sexual dimorphisms; however, after a severe contusion only leptin levels were different between female and male rats. In conclusion, pro-inflammatory cytokines initiate the inf

关键词： astrocytes chemokines cytokines inflammation macrophages microglia secondary damage spinal cord injury

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Evaluation of hybrid closed-loop insulin delivery system in type 1 diabetes in real-world clinical practice:One-year observational study

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World Journal of Diabetes 2024年第3期15卷 455-462页

作者： Ahmed Eldib shilton Dhaver Karim Kibaa Astrid Atakov-Castillo Tareq salah Marwa Al-Badri Abdelrahman Khater ryan McCarragher Omnia Elenani Elena Toschi Osama Hamdy Department of Clinical Behavioral&Outcomes ResearchJoslin Diabetes CenterBostonMA 02215United States Department of Medicine Harvard Medical SchoolBostonMA 02115United States

BACKGROUND In 2016,the Food and Drug Administration approved the first hybrid closed-loop(HCL)insulin delivery system for adults with type 1 diabetes(T1D).There is limited information on the impact of using HCL systems on patient-reported outcomes(PROs)in patients with T1D in real-world clinical practice.In this independent study,we evaluated glycemic parameters and PROs over one year of continuous use of Medtronic’s 670G HCL in real-world clinical practice.AIM To assess the effects of hybrid closed loop system on glycemic control and quality of life in adults with T1D.METHODs We evaluated 71 patients with T1D(mean age:45.5±12.1 years;59%females;body weight:83.8±18.7 kg,body mass index:28.7±5.6 kg/m2,A1C:7.6%±0.8%)who were treated with HCL at Joslin Clinic from 2017 to 2019.We measured A1C and percent of glucose time-in-range(%TIR)at baseline and 12 months.We measured percent time in auto mode(%TiAM)for the last two weeks preceding the final visit and assessed PROs through several validated quality-of-life surveys related to general health and diabetes management.REsULTs At 12 mo,A1C decreased by 0.3%±0.1%(P=0.001)and%TIR increased by 8.1%±2.5%(P=0.002).The average%TiAM was only 64.3%±32.8%and was not associated with A1C,%TIR or PROs.PROs,provided at baseline and at the end of the study,showed that the physical functioning submodule of 36Item short-Form Health survey increased significantly by 22.9%(Psurvey/worry scale decreased significantly by 24.9%(Ps In Diabetes reduced significantly by-17.2%(P=0.002).The emotional burden submodules of dietary diversity score reduced significantly by-44.7%(P=0.001).Furthermore,analysis of Clarke questionnaire showed no increase in awareness of hypoglycemic episodes.WHO-5 showed no improvements in subject’s wellbeing among participants after starting the 670G HCL system.Finally,analysis of Pittsburgh sleep Quality Index showed no difference in sleep quality,sleep latency,or duration of sleep from baseline to 12 mo.CONCLUsION The us

关键词： Artificial pancreas Continuous blood glucose monitor Type 1 diabetes Hybrid closed-loop insulin delivery Quality of life

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Optical redox imaging of ANT1-de-cient muscles

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Journal of Innovative Optical Health sciences 2024年第1期17卷 135-140页

作者： He N.Xu ryan M.Morrow Min Feng Huaqing Zhao Douglas Wallace Lin Z.Li Britton Chance Laboratory of Redox Imaging Department of Radiology Perelman School of Medicine University of Pennsylvania PhiladelphiaPA 19104USA Center for Mitochondrial and Epigenomic Medicine Children's Hospital of Philadelphia Research Institute Philadelphia PA 19104USA Center for Biostatistics and Epidemiology Lewis Katz school of Medicine at Temple University Philadelphia PA 19140USA

Adenine nucleotide translocator(ANT)is a mitochondrial protein involved in the exchange of ADP and ATP across the mitochondrial inner membrane.It plays a crucial role in cellular energy metabolism by facilitating the transport of ATP synthesized within the mitochondria to the cytoplasm.The isoform ANT1 predominately expresses in cardiac and skeletal muscles.Mutations or dysregulation in ANT1 have been implicated in various mitochondrial disorders and neuromuscular diseases.We aimed to examine whether ANT1 deletion may affect mitochondrial redox state in our established ANT1-de-cient mice.Hearts and quadriceps resected from age-matched wild type(WT)and ANT1-de-cient mice were snap-frozen in liquid nitrogen.The Chance redox scanner was utilized to perform 3D optical redox imaging.Each sample underwent scanning across 3–5 sections.Global averaging analysis showed no signi-cant differences in the redox indices(NADH,flavin adenine dinucleotide containing-flavoproteins Fp,and the redox ratio Fp/(NADH+Fp)between WT and ANT1-de-cient groups.However,quadriceps had higher Fp than hearts in both groups(p¼0:0004 and 0.01,respectively).Furthermore,the quadriceps were also more oxidized(a higher redox ratio)than hearts in WT group(p¼0:004).NADH levels were similar in all cases.Our data suggest that under non-stressful physical condition,the ANT1-de-cient muscle cells were in the same mitochondrial state as WT ones and that the signi-cant difference in the mitochondrial redox state between quadriceps and hearts found in WT might be diminished in ANT1-de-cient ones.Redox imaging of muscles under physical stress can be conducted in future.

关键词： ANT1 redox ratio flavoproteins

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Lack of Evidence for Decreased Protein stability in the 2397 (Met) Haplotype of the Leucine Rich Repeat Kinase 2 Protein Implicated in Parkinson’s Disease

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Advances in Parkinson's Disease 2017年第4期6卷 113-123页

作者： ryan s. anderton Lauren Hill Rhiannon Morris Frank L. Mastaglia Wayne Greene sherif Boulos school of Health sciences and Institute for Health Research University of Notre Dame Australia Fremantle WA USA Perron Institute for Neurological and Translational sciences Nedlands WA USA Centre for Neuromuscular and Neurological Disorders University of Western Australia Nedlands WA USA Institute for Immunology and Infectious Diseases Murdoch University Perth WA USA school of Veterinary and Life sciences Murdoch University Perth WA USA

Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the leading genetic cause of autosomal dominant familial Parkinson’s disease. We previously reported that two mutations within the ROC domain, namely R1441C and A1442P, exhibit increased protein degradation leading to lowered steady state LRRK2 protein levels in HEK293 cells. More recently, the common WD40 domain LRRK2 haplotype, Met2397, which is a risk factor for Crohn’s disease, has been shown to lower steady state protein levels in HEK293 cells. In view of recent evidence implicating LRRK2 and inflamemation in PD, we investigated the effects of Met2397 on LRRK2 expression, and compared them to the Thr2397 variant and other LRRK2 mutants. In this study, we transfected HEK293 cells with plasmid constructs encoding the different LRRK2 variants, and analyzed the resulting protein levels by Western blot and flow cytometry. Here we found that both the Met2397 and Thr2397 haplotypes yield similar levels of LRRK2 protein expression and do not appear to impact cell viability in HEK293 cells, compared to other LRRK mutants. Thus, we have concluded that the Met2397 haplotype is unlikely to play a role in LRRK2 mediated or idiopathic PD.

关键词： Parkinson’s Disease LRRK2 Met2397 Thr2397 A1442P R1441C

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Exercised blood plasma promotes hippocampal neurogenesis in the Alzheimer's disease rat brain

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Journal of sport and Health science 2024年第2期13卷 245-255页

作者： Cecilie skarstad Norevik Aleksi M.Huuha Ragnhild N.RФsbjФrgen Linda Hildegard Bergersen Kamilla Jacobsen Rodrigo Miguel-dos-santos Liv ryan Belma skender Jose Bianco N.Moreira Asgeir Kobro-Flatmoen Menno P.Witter Nathan scrimgeour Atefe R.Tari Cardiac Exercise Research Group(CERG) Department of Circulation and Medical ImagingNorwegian University of Science and Technology7491TrondheimNorway Department of Neurology and Clinical Neurophysiology St.Olavs University Hospital7030TrondheimNorway Institute of Oral Biology University of Oslo0372OsloNorway Department of Physiology Federal University of SergipeS~ao Cristov~ao49100-000SergipeBrazil Centre of Molecular Inflammation Research Department of Clinical and Molecular MedicineNorwegian University of Science and Technology7491TrondheimNorway Kavli Institute for systems Neuroscience Centre for Neural Computationand Egil and Pauline Braathen and Fred Kavli Centre for Cortical MicrocircuitsNorwegian University of Science and Technology7030TrondheimNorway K.G.Jebsen Centre for Alzheimer’s Disease Norwegian University of Science and Technology7030TrondheimNorway

Background:Exercise training promotes brain plasticity and is associated with protection against cognitive impairment and Alzheimer’s disease(AD).These beneficial effects may be partly mediated by blood-borne factors.Here we used an in vitro model of AD to investigate effects of blood plasma from exercise-trained donors on neuronal viability,and an in vivo rat model of AD to test whether such plasma impacts cognitive function,amyloid pathology,and neurogenesis.Methods:Mouse hippocampal neuronal cells were exposed to AD-like stress using amyloid-βand treated with plasma collected from human male donors 3 h after a single bout of high-intensity exercise.For in vivo studies,blood was collected from exercise-trained young male Wistar rats(high-intensity intervals 5 days/week for 6 weeks).Transgenic AD rats(McGill-R-Thyl-APP)were inj ected 5 times/fortnight for 6 weeks at2 months or 5 months of age with either(a)plasma from the exercise-trained rats,(b)plasma from sedentary rats,or(c)saline.Cognitive function,amyloid plaque pathology,and neurogenesis were assessed.The plasma used for the treatment was analyzed for 23 cytokines.Results:Plasma from exercised donors enhanced cell viability by 44.1%(p=0.032)and reduced atrophy by 50.0%(ps.In vivo exercised plasma treatment did not alter cognitive function or amyloid plaque pathology but did increase hippocampal neurogenesis by~3 fold,regardless of pathological stage,when compared to saline-treated rats.Concentrations of 7 cytokines were significantly reduced in exercised plasma compared to sedentary plasma.Conclusion:Our proof-of-concept study demonstrates that plasma from exercise-trained donors can protect neuronal cells in culture and promote adult hippocampal neurogenesis in the AD rat brain.This effect may be partly due to reduced pro-inflammatory signaling molecules in exercised plasma.

关键词： Cytokines High-intensity interval training Inflammation Neurons Plasma transfusion

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Metabolic syndrome and the urinary microbiome of patients undergoing percutaneous nephrolithotomy

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Asian Journal of Urology 2024年第2期11卷 316-323页

作者： ryan A.Dornbier Chirag P.Doshi shalin C.Desai Petar Bajic Michelle Van Kuiken Mark Khemmani Ahmer V.Farooq Larissa Bresler Thomas M.T.Turk Alan J.Wolfe Kristin G.Baldea Loyola University Medical Center Department of UrologyMaywoodILUSA Loyola University Chicago Department of Microbiology and ImmunologyMaywoodILUSA

Objective:To identify possible stone-promoting microbes,we compared the profiles of microbes grown from stones of patients with and without metabolic syndrome(Mets).The association between Mets and urinary stone disease is well established,but the exact pathophysiologic relationship remains unknown.Recent evidence suggests urinary tract dysbiosis may lead to increased nephrolithiasis risk.Methods:At the time of percutaneous nephrolithotomy,bladder urine and stone fragments were collected from patients with and without Mets.Both sample types were subjected to expanded quantitative urine culture(EQUC)and 16 s ribosomal RNA gene sequencing.Results:Fifty-seven patients included 12 controls(21.1%)and 45 Mets patients(78.9%).Both cohorts were similar with respect to demographics and non-Mets comorbidities.No controls had uric acid stone composition.By EQUC,bacteria were detected more frequently in Mets stones(42.2%)compared to controls(8.3%)(p=0.041).Bacteria also were more abundant in stones of Mets patients compared to controls.To validate our EQUC results,we performed 16 s ribosomal RNA gene sequencing.In 12/16(75.0%)sequence-positive stones,EQUC reliably isolated at least one species of the sequenced genera.Bacteria were detected in both“infectious”and“non-infectious”stone compositions.Conclusion:Bacteria are more common and more abundant in Mets stones than control stones.Our findings support a role for bacteria in urinary stone disease for patients with Mets regardless of stone composition.

关键词： Nephrolithiasis Urolithiasis Metabolic syndrome Urinary microbiome Percutaneous nephrolithotomy

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