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Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations:lessons from recent clinical trials

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Neural Regeneration Research 2023年第8期18卷 1679-1683页

作者： Bruno P.Imbimbo Viviana Triaca Camillo Imbimbo robert nisticò Department of Research&Development Chiesi FarmaceuticiParmaItaly Institute of Biochemistry and Cell Biology National Research CouncilRomeItaly Department of Brain and Behavioral Sciences University of PaviaPaviaItaly School of Pharmacy Department of BiologyUniversity of Tor Vergataand European Brain Research Institute(EBRI)RomeItaly

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type var

关键词： Alzheimer's disease amyotrophic lateral sclerosis amyloid precursor protein glucocerebrosidase huntingtin Huntington's disease Parkinson's disease presenilin 1 presenilin 2 superoxide dismutase 1

Acid-sensing ion channel 1a:a novel target in Alzheimer's disease?

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Neural Regeneration Research 2023年第2期18卷 324-324页

作者： Dalila Mango robert nisticò School of Pharmacy University of Rome“Tor Vergata”Laboratory of Pharmacology of Synaptic PlasticityEuropean Brain Research InstituteRomeItaly

Alzheimer's disease(AD)represents the most common form of dementia and is characterized by a progressive decline of cognitive functions.Complex multifactorial processes underlie AD pathophysiology,including amyloid-beta(Aβ)toxicity,tau protein hyperphosphorylation,syna ptic dysfunction,oxidative stress,and neuroinflammation(J u and Tam,2022).

关键词： Alzheimer Aβ tau

Necrotic enteritis and antibiotic-free production of broiler chickens:Challenges in testing and using alternative products

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Animal Nutrition 2024年第1期16卷 288-298页

作者： robert J.Moore School of Science RMIT University

The global trend towards raising broiler chickens without the use of in-feed antibiotics(IFAs) means that there is an ongoing need to develop alternative treatments capable of delivering the benefits that IFAs previously provided. IFAs supported the productivity performance of chickens and played a key role in maintaining their health. Necrotic enteritis(NE) is an important disease of broilers that affects health,productivity, and welfare, and was previously well controlled by IFAs. However, with the reduction in IFA use, NE is resurgent in some countries. Vaccines and various feed additives, including pre-, pro-, and postbiotics, phytobiotics, fatty acids, and phage therapies have been introduced as alternative methods of NE control. While some of these feed additives have specific activity against the NE pathogen, Clostridium perfringens, most have the more general goal of reinforcing gut health. Extensive reviews of the effects of many of these feed additives on gut health have been published recently. Hence, rather than cover previously well reviewed areas of research this review focuses on the challenges and pitfalls in undertaking experimental assessment of alternative NE treatments and translating laboratory research to real world commercial production settings. The review is based on the author's particular experience,reading, thoughts, and analysis of the available information and inevitably presents a particular understanding that is likely to be at odds with others thinking on these issues. It is put forward to stimulate thinking and discussion on the issues covered.

关键词： Necrotic enteritis

Predicting the coefficient of friction in a sliding contact by applying machine learning to acoustic emission data

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Friction 2024年第6期12卷 1299-1321页

作者： robert GUTIERREZ Tianshi FANG robert MAINWARING Tom REDDYHOFF Tribology Group Department of Mechanical EngineeringImperial College LondonExhibition RoadLondon SW72AZUK Shell Global Solutions(US)Inc.Shell Technology Center Houston 3333 Highway 6 SouthHoustonTX 77082USA Shell International Petroleum Company Limited Shell CentreYork RoadLondon SE17NAUK

It is increasingly important to monitor sliding interfaces within machines,since this is where both energy is lost,and failures occur.Acoustic emission(AE)techniques offer a way to monitor contacts remotely without requiring transparent or electrically conductive materials.However,acoustic data from sliding contacts is notoriously complex and difficult to interpret.Herein,we simultaneously measure coefficient of friction(with a conventional force transducer)and acoustic emission(with a piezoelectric sensor and high acquisition rate digitizer)produced by a steel‒steel rubbing contact.Acquired data is then used to train machine learning(ML)algorithms(e.g.,Gaussian process regression(GPR)and support vector machine(SVM))to correlated acoustic emission with friction.ML training requires the dense AE data to first be reduced in size and a range of processing techniques are assessed for this(e.g.,down-sampling,averaging,fast Fourier transforms(FFTs),histograms).Next,fresh,unseen AE data is given to the trained model and the resulting friction predictions are compared with the directly measured friction.There is excellent agreement between the measured and predicted friction when the GPR model is used on AE histogram data,with root mean square(RMS)errors as low as 0.03 and Pearson correlation coefficients reaching 0.8.Moreover,predictions remain accurate despite changes in test conditions such as normal load,reciprocating frequency,and stroke length.This paves the way for remote,acoustic measurements of friction in inaccessible locations within machinery to increase mechanical efficiency and avoid costly failure/needless maintenance.

关键词： acoustic emission condition monitoring friction machine learning Gaussian process regression support vector machine

A detailed rock density model of the Hong Kong territories

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Geodesy and Geodynamics 2024年第1期15卷 75-81页

作者： Albertini Nsiah Ababio robert Tenzer Department of Land Surveying and Geo-Informatics Hong Kong Polytechnic UniversityHong KongChina

We used the geological map and published rock density measurements to compile the digital rock density model for the Hong Kong territories.We then estimated the average density for the whole territory.According to our result,the rock density values in Hong Kong vary from 2101 to 2681 kg·m^(-3).These density values are typically smaller than the average density of 2670 kg·m^(-3),often adopted to represent the average density of the upper continental crust in physical geodesy and gravimetric geophysics applications.This finding reflects that the geological configuration in Hong Kong is mainly formed by light volcanic formations and lava flows with overlying sedimentary deposits at many locations,while the percentage of heavier metamorphic rocks is very low(less than 1%).This product will improve the accuracy of a detailed geoid model and orthometric heights.

关键词： Density model Rock types Gravimetric modeling Hong Kong

The concept of gene therapy for glaucoma:the dream that has not come true yet

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Neural Regeneration Research 2024年第1期19卷 92-99页

作者： robert Sulak Xiaonan Liu Adrian Smedowski Department of Physiology Faculty of Medical Sciences in KatowiceMedical University of Silesia in KatowiceKatowicePoland Institute of Biotechnology HiLIFEUniversity of HelsinkiHelsinkiFinland GlaucoTech Co. KatowicePoland

Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent manner.The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic profile.The gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model.Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.

关键词： adeno-associated virus gene editing gene therapy glaucoma IOP lowering IOP-independent mechanisms neuroprotection optic nerve optic neuropathy retinal ganglion cells

Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B:A comprehensive review of phases II and III therapeutic agents

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World Journal of Hepatology 2024年第3期16卷 331-343页

作者： robert Lam Joseph K Lim Section of Digestive Diseases Yale University School of MedicineNew HavenCT 06520United States

Chronic hepatitis B virus(HBV)infection affects over 295 million people globally and an estimated 1.6 million people in the United States.It is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver cancer.Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver complications.However,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver events.Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen(HBsAg)loss and suppression of HBV DNA.Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HBsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

关键词： Hepatitis B virus Treatment Clinical trials RNA interference Entry inhibitors Core inhibitors Immunomodulators

Glycolysis and glucose metabolism as a target for bioenergetic and neuronal protection in glaucoma

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Neural Regeneration Research 2024年第8期19卷 1637-1638页

作者： Pete A.Williams robert J.Casson Department of Clinical Neuroscience Division of Eye and VisionSt.Erik Eye HospitalKarolinska InstitutetStockholmSweden Ophthalmic Research Laboratories Discipline of Ophthalmology and Visual SciencesUniversity of AdelaideAdelaideAustralia

Vision is arguably our most valued sense,yet approximately 340 million people globally suffer blindness or moderate visual impairment,highlighting the need to further develop and advance treatments for ophthalmic diseases.Glaucoma refers to a group of ocular disorders united by a clinically characteristic optic neuropathy with associated retinal ganglion cell loss.

关键词： metabolism glaucoma globally

Optimization of product characteristics of porous carbon agglomerates using a design of experiments in fluidized bed agglomeration

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Particuology 2024年第6期89卷 258-269页

作者： Martin Oelofse robert Rack Marcelle Hilden Peter Langguth Department of Pharmaceutical Technology and Biopharmaceutics Johannes Gutenberg UniversityMainzGermany Carbon Advanced Solutions GmbH HeuchelheimGermany

Spraying parameters during particle agglomeration processes can affect the agglomeration kinetics and particle growth.This study was conducted to better understand the influence of the spraying parameters in a fluidized bed wet agglomeration process,and the influence on the stability characteristics of carbon tablets.A formulation based on fine carbon and peroxide powder,as well as carboxymethyl cellulose as a binder,was used to produce agglomerates in a first production step.Thereafter in a second production step carbon tablets with a high porosity were molded for the customer goods industry.The optimization of the compressive strength of these carbon tablets was the goal of the trials.Carbon agglomerates were produced with a laboratory scale granulator called“ProCell”and were compressed with a five-cavity mechanical press.The screening of the agglomeration process parameters and their influence on the agglomerates quality,as well as the performance characteristics of the carbon tablets,were investigated using a multilevel factorial design.The experimental runs were done by varying atomized air pressure and feed rate of the fluid.This was determined by the design model.The findings of the statistical trials showed that low atomized air pressure and a low feed rate lead to a higher tablet compressive strength.

关键词： Wet agglomeration Fluidized bed Design of experiments Carbon agglomerates and tablets