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Molecular overview of progressive familial intrahepatic cholestasis

World Journal of Gastroenterology 2020年第47期26卷 7470-7484页

作者： Sriram Amirneni Nils Haep Mohammad A Gad alejandro soto-gutierrez James E Squires Rodrigo MFlorentino Department of Pathology University of PittsburghPittsburghPA 15213United States Pittsburgh Liver Research Center University of PittsburghPittsburghPA 15213United States Division of Gastroenterology Hepatologyand NutritionUPMC Children's Hospital of PittsburghPittsburghPA 15224United States

Cholestasis is a clinical condition resulting from the imapairment of bile flow.This condition could be caused by defects of the hepatocytes,which are responsible for the complex process of bile formation and secretion,and/or caused by defects in the secretory machinery of cholangiocytes.Several mutations and pathways that lead to cholestasis have been described.Progressive familial intrahepatic cholestasis(PFIC)is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes.PFIC 1,also known as Byler’s disease,is caused by mutations of the ATP8B1 gene,which encodes the familial intrahepatic cholestasis 1 protein.PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump(BSEP)expression via variations in the ABCB11 gene.Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein,leading to the third type of PFIC.Newer variations of this disease have been described.Loss of function of the tight junction protein 2 protein results in PFIC 4,while mutations of the NR1H4 gene,which encodes farnesoid X receptor,an important transcription factor for bile formation,cause PFIC 5.A recently described type of PFIC is associated with a mutation in the MYO5B gene,important for the trafficking of BSEP and hepatocyte membrane polarization.In this review,we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.

关键词： Progressive familial intrahepatic cholestasis ATP8B1/familial intrahepatic cholestasis 1 ABCB11/bile salt export pump ABCB4/multidrug resistance class 3 Intrahepatic cholestasis Bile

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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

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Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats withα-synucleinopathy

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Neural Regeneration Research 2024年第9期19卷 2057-2067页

作者： Bismark Gatica-Garcia Michael J.Bannon Irma Alicia Martínez-Dávila Luis O.soto-Rojas David Reyes-Corona Lourdes Escobedo Minerva Maldonado-Berny ME gutierrez-Castillo Armando J.Espadas-Alvarez Manuel A.Fernandez-Parrilla Juan U.Mascotte-Cruz CP Rodríguez-Oviedo Irais E.Valenzuela-Arzeta Claudia Luna-Herrera Francisco E.Lopez-Salas Jaime Santoyo-Salazar Daniel Martinez-Fong Departamento de Fisiología Biofísica y NeurocienciasCentro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico Department of Pharmacology Wayne State University School of MedicineDetroitMIUSA Laboratorio de Patogénesis Molecular Carrera Médico CirujanoFacultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla de BazMéxico Red de Medicina para la Educación y Desarrollo y la Investigación Científica de Iztacala(Red MEDICI) Carrera Médico CirujanoFacultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla de BazMéxico Nanoparticle Therapy Institute AguascalientesMéxico Departamento de Biociencias e Ingeniería Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y DesarrolloInstituto Politécnico NacionalCiudad de MéxicoMéxico Escuela Nacional de Medicina y Homeopatía Instituto Politécnico NacionalCiudad de MéxicoMéxico Departamento de Fisiología Escuela Nacional de Ciencias BiológicasInstituto Politécnico NacionalCiudad de MéxicoMéxico Departamento de Biología Molecular y Biotecnología Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoCiudad de MéxicoMéxico Departamento de Física Centro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico Programa de Nanociencias y Nanotecnología Centro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico

Parkinsonism by unilateral,intranigralβ-sitosterolβ-D-glucoside administration in rats is distinguished in that theα-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time,thus replicating several clinical features of Parkinson’s disease,a typicalα-synucleinopathy.As Nurr1 repressesα-synuclein,we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateralβ-sitosterolβ-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection.This study found that rNurr1-V5 expression but not that of the green fluorescent protein(the negative control)reducedβ-sitosterolβ-D-glucoside-induced neuropathology.Accordingly,a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum.In addition,tyrosine hydroxylase-positive cells displayed less senescence markerβ-galactosidase and more neuron-cytoskeleton markerβIII-tubulin and brain-derived neurotrophic factor.A significant decrease in activated microglia(positive to ionized calcium-binding adaptor molecule 1)and neurotoxic astrocytes(positive to glial fibrillary acidic protein and complement component 3)and increased neurotrophic astrocytes(positive to glial fibrillary acidic protein and S100 calcium-binding protein A10)also occurred in the substantia nigra.These effects followed the bilateral reduction inα-synuclein aggregates in the nigrostriatal system,improving sensorimotor behavior.Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration(senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells),neuroinflammation(activated microglia,neurotoxic astrocytes),α-synuclein aggregation,and sensorimotor deficits.Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate t

关键词： A1 astrocytes A2 astrocytes gene therapy microglia motor deficits nanoparticles neurodegeneration neuroinflammation senescence α-synuclein aggregates

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Utilization of RNA sequencing to investigate olfactory dysfunction in chronic rhinosinusitis without nasal polyps:A pilot study

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2024年第1期10卷 29-36页

作者： Jorge A.gutierrez III Jeremy L.Barth Rodney J.Schlosser Thomas S.Edwards Timothy L.Smith Zachary M.Soler Department of Otolaryngology-Head and Neck Surgery Medical University of South CarolinaCharlestonSouth CarolinaUSA Department of Regenerative Medicine&Cell Biology Medical University of South CarolinaCharlestonSouth CarolinaUSA Department of Otolaryngology-Head and Neck Surgery Oregon Health&Science UniversityPortlandOregonUSA

Objectives:Prior research on olfactory dysfunction in chronic rhinosinusitis(CRS)has focused on patients with polyps and suggests that direct inflammation of the olfactory cleft mucosa plays a contributory role.The purpose of this study was to evaluate gene expression in superior turbinate mucosal specimens,comparing normosmic and dysosmic CRS patients without polyps(CRSsNP).Methods:Tissue samples were obtained from the superior turbinates of patients with CRSsNP at the time of endoscopic sinus surgery.Samples subsequently underwent RNA sequencing and functional analysis to investigate biological pathways associated with differentially expressed genes between dysosmic(n=7)and normosmic(n=4)patients.Results:Differential gene expression analysis comparing dysosmic and normosmic CRSsNP patients showed upregulation of 563 genes and downregulation of 327 genes.Using stringent criteria for multiple comparisons,one upregulated gene(Immediate Early Response 3[IER3])had an false discovery rate(FDR)correction adjustedP value considered statistically significant(P<0.001,fold change 2.69).Reactome functional analysis revealed eight biological pathways significantly different between dysosmic and normosmic patients(P<0.05,FDR correction)including IL-4 and IL-13 signaling,IL-10 signaling,and rhodopsin-like receptors.Conclusions:RNA sequencing of the superior turbinates in patients with CRSsNP can provide valuable information regarding biological pathways and genes involved in olfactory dysfunction.This study supports literature suggesting that Type 2 inflammation may play a role in olfactory dysfunction in at least some patients with CRSsNP.This study also prompts questions regarding the role of IL-10,rhodopsin-like receptors,andIER3 in the pathogenesis of olfactory dysfunction.

关键词： chronic rhinosinusitis without nasal polyps olfactory dysfunction RNA sequencing

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Vertical Displacement Measurement in a Slow-Moving Sinkhole Using BOTDA

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Photonic Sensors 2024年第1期14卷 23-39页

作者： Pascual SEVILLANO Javier PRECIADO-GARBAYO Jorge SEVIL Francisco gutierrez Juan JMARTiNEZ Sonia MARTiN-LOPEZ Miguel GONZALEZ-HERRAEZ Aragon Institute of Engineering Research(I3A) Universidad de ZaragozaZaragoza 50018Spain Electronic Enginering and Communicaton Dpartment EINAUniversidad de ZaragzaZaragza 50018Spain Aragon Photonics Labs. Zaragoza 50009Spain Department of Earth Sciences Universidad de ZaragozaZaragoza 50009Spain Department of Electronics Escuela Politecnica SuperiorUniversidad de AlcalaMadrid 28805Spain

The effectiveness of monitoring and early-warning systems for ground deformation phenomena,such as sinkholes,depends on their ability to accurately resolve the ongoing ground displacement and detect the subtle deformation preceding catastrophic failures.Sagging sinkholes with a slow subsidence rate and diffuse edges pose a significant challenge for subsidence monitoring due to the low deformation rates and limited lateral strain gradients.In this work,we satisfactorily illustrate the practicality of the Brillouin optical time domain analysis(BOTDA)to measure the spatial-temporal patterns of the vertical displacement in such challenging slow-moving sagging sinkholes.To assess the performance of the approach,we compare the strain recorded by the distributed optical fiber sensor with the vertical displacement measured by high-precision leveling.The results show a good spatial correlation with the ability to identify the maximum subsidence point.There is also a good temporal correlation with the detection of an acceleration phase in the subsidence associated with a flood event.

关键词： Distributed fiber optic sensing(DFOS) vertical displacement measurement slow subsidence rate sinkhole hazard early-warning system

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Systemic Inflammation Response Index and weight loss as prognostic factors in metastatic pancreatic cancer: A concept study from the PANTHEIA-SEOM trial

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World Journal of Gastrointestinal Oncology 2024年第2期16卷 386-397页

作者： Vilma Pacheco-Barcia Sara Custodio-Cabello Fatima Carrasco-Valero Magda Palka-Kotlowska Axel Mariño-Mendez Alberto Carmona-Bayonas Javier Gallego A J Muñoz Martín Paula Jimenez-Fonseca Luis Cabezon-gutierrez Department of Medical Oncology Hospital Universitario de TorrejonMadrid 28850Spain Department of Internal Medicine Hospital Universitario de TorrejonMadrid 28850Spain Department of Medical Oncology Hospital Universitario Central de AsturiasOviedo 33011Spain Department of Medical Oncology Hospital Universitario Morales MeseguerUniversity of MurciaMurcia 30001Spain Department of Medical Oncology Hospital General Universitario de ElcheElche 03202Spain Department of Medical Oncology Hospital General Universitario Gregorio MarañónUniversidad Complutense MadridMadrid 28007Spain Universidad Francisco de Vitoria Madrid 28223Spain

BACKGROUND The prognostic value of the Systemic Inflammation Response Index(SIRI)in advanced pancreatic cancer is recognized,but its correlation with patients´nutritional status and outcomes remains unexplored.AIM To study the prognostic significance of SIRI and weight loss in metastatic pancreatic cancer.METHODS The PANTHEIA-Spanish Society of Medical Oncology(SEOM)study is a multicentric(16 Spanish hospitals),observational,longitudinal,non-interventional initiative,promoted by the SEOM Real World-Evidence work group.This pilot study sought to analyze the association between weight loss and inflammatory status as defined by SIRI.The cohort stems from a proof-of-concept pilot study conducted at one of the coordinating centers.Patients with pathologically confirmed metastatic pancreatic adenocarcinoma,treated from January 2020 to January 2023,were included.The index was calculated using the product of neutrophil and monocyte counts,divided by lymphocyte counts,obtained within 15 days before initiation chemotherapy.This study evaluated associations between overall survival(OS),SIRI and weight loss.RESULTS A total of 50 patients were included.66%of these patients were male and the median age was 66 years.Metastasis sites:36%liver,12%peritoneal carcinomatosis,10%lung,and 42%multiple locations.Regarding the first line palliative chemotherapy treatments:50%received gemcitabine plus nab-paclitaxel;28%,modified fluorouracil,leucovorin,irinotecan and oxaliplatin,and 16%were administered gemcitabine.42%had a weight loss>5%in the three months(mo)preceding diagnosis.21 patients with a SIRI≥2.3×10^(3)/L exhibited a trend towards a lower median OS compared to those with a SIRI5%weight loss before diagnosis,the median OS was 6 mo,in contrast to 19 mo for those who did not experience such weight loss(P=0.003).Patients with a weight loss>5%showed higher SIRI levels.This difference was statistically significant(P<0.000).For patients with a SIRI<2.3×10^(3)/L,those who did not

关键词： Pancreatic cancer Nutrition Prognostic factor Inflammation Advanced cancer Systemic inflammatory response index Weight loss

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Histopathological impact of SARS-CoV-2 on the liver:Cellular damage and long-term complications

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World Journal of Gastroenterology 2024年第22期30卷 2866-2880页

作者： Alfonso Rodriguez-Espada Moises Salgado-de la Mora Briana Mariette Rodriguez-Paniagua Nathaly Limonde la Rosa Monica Itzel Martinez-gutierrez Santiago Pastrana-Brandes Nalu Navarro-Alvarez Department of Molecular Biology Universidad Panamericana School of MedicineCampus MéxicoMexico 03920Mexico Department of Internal Medicine Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico 14080Mexico Department of Surgery University of Colorado Anschutz Medical CampusDenverCO 80045United States PECEM Facultad de MedicinaUniversidad Nacional Autónoma de MéxicoMexico 04360Mexico Department of Gastroenterology Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico 14080Mexico

Coronavirus disease 2019(COVID-19),caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome,multiple organ failure,and death.Despite extensive studies on the pathogenicity of SARS-CoV-2,its impact on the hepatobiliary system remains unclear.While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels,the exact source of this damage is not fully understood.Proposed mechanisms for injury include direct cytotoxicity,collateral damage from inflammation,drug-induced liver injury,and ischemia/hypoxia.However,evidence often relies on blood tests with liver enzyme abnormalities.In this comprehensive review,we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients,drawing from liver biopsies,complete autopsies,and in vitro liver analyses.We present evidence of the direct impact of SARS-CoV-2 on the liver,substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes,including mitochondrial swelling,endoplasmic reticulum dilatation,and hepatocyte apoptosis.Additional ly,we describe the diverse liver pathology observed during COVID-19 infection,encompassing necrosis,steatosis,cholestasis,and lobular inflammation.We also discuss the emergence of long-term complications,notably COVID-19-related secondary sclerosing cholangitis.Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.

关键词： Liver SARS-CoV-2 COVID-19 Angiotensin-converting enzyme 2 Histopathology Liver biopsies Liver autopsy In vitro

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Multi-omic study to unmask genes involved in prostate cancer development in amulti-case family

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Cancer Communications 2024年第3期44卷 443-447页

作者： Lucia Chica-Redecillas Sergio Cuenca-Lopez Eduardo Andres-Leon Laura Carmen Terron-Camero Blanca Cano-gutierrez Jose Manuel Cozar Jose Antonio Lorente Fernando Vazquez-Alonso Luis Javier Martinez-Gonzalez Maria Jesus Alvarez-Cubero GENYO Centre for Genomics and Oncological ResearchPfizerUniversity of GranadaAndalusian Regional GovernmentPTS GranadaGranadaGranadaSpain Department of Biochemistry Molecular Biology III and ImmunologyFaculty of MedicineUniversity of GranadaPTS GranadaGranadaGranadaSpain Bioinformatics Unit Institute of Parasitology and Biomedicine“López-Neyra”Spanish National Research CouncilGranadaGranadaSpain Nursery Service.University Hospital Clínico San Cecilio GranadaGranadaSpain Urology Department University Hospital Virgen de las NievesGranadaGranadaSpain Legal Medicine and Toxicology Department Faculty of MedicineUniversity of GranadaPTS GranadaGranadaGranadaSpain Ibs Biosanitary Research InstituteGranadaGranadaSpain

Dear Editor,Hereditary prostate cancer(PC)comprises 5%-10%of all PC cases.The increased risk of PC in menwith a family his-tory of the disease is well known and is commonly caused by germline mutations,leading to clinical guidelines men-tioning various genes for identifying high-risk individuals.However,the complex inheritance patterns involvingmul-tiple single nucleotide polymorphisms(SNPs)make it a genetically heterogeneous disease,with genetic testing still in its early stages.

关键词： cancer clinical cases

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Uremic Bleeding in 2 Patients with Dieulafoy’s Lesion: Case Report and Literature Review

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Open Journal of Gastroenterology 2024年第5期14卷 167-173页

作者： Gustavo Adolfo Hernández Valdez Diana Estefanía Ibarra García Juan Antonio Contreras Escamilla Janette Alejandra Gamiño gutierrez Francisco Manuel Tonatiuh Carrillo Beltran Ulises Solis Gomez Jocelyn Nataly Quintero Meléndez Ivan alejandro Medina Jimenez Marco Antonio González Villar Jorge Rojas Morales Department of Internal Medicine ISSSTE APP General Hospital of Tepic Tepic Nayarit Mexico Hospital Civil de Guadalajara Fray Antonio Alcalde Guadalajara Jalisco M&#233xico

Dieulafoy’s lesions are rare vascular malformations of the gastrointestinal tract. A Dieulafoy’s lesion is an aberrant vessel that does not reduce in caliber when it extends from the submucosa to the mucosa. Damage to this artery can cause severe and intermittent arterial bleeding from small vascular stumps that are difficult to visualize. Furthermore, these catastrophic bleeding episodes frequently result in hemodynamic instability and the need for transfusion of multiple blood products. Recently, uremic syndrome has been identified as a risk factor for gastric mucosal lesions. We present two clinical cases of acute digestive bleeding due to Dielafoy lesion with chronic kidney disease as the main cause, where two different therapies were performed endoscopically. We concluded with the results of our patients that the best therapy was the application of the hemostatic hemoclip on the injury vs the injection with adrenaline on the wound site. Uremia is identified as a risk factor for upper gastrointestinal bleeding in patients with pre-existing Dieulafoy’s lesion, as well as a higher incidence of new bleeding.

关键词： Dieulafoy’s Lesion Gastrointestinal Bleeding Endoscopy Endoscopy Hemostatic Clips Kidney Disease Adrenaline Thermal Coagulation Dieulafoy

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Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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Neural Regeneration Research 2025年第5期20卷 1324-1335页

作者： Hassan Saad Bachar El Baba Ali Tfaily Firas Kobeissy Juanmarco gutierrez Gonzalez Daniel Refai Gerald R.Rodts Christian Mustroph David Gimbel Jonathan Grossberg Daniel L.Barrow Matthew F.Gary Ali M.Alawieh Department of Neurosurgery Emory University School of MedicineAtlantaGAUSA Department of Neurology Yale UniversityNew HavenCTUSA Center for Neurotrauma Multiomics&Biomarkers(CNMB)Morehouse School of MedicineAtlantaGAUSA

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

关键词： complement neuroinflammation neuroplasticity regeneration spinal cord injury targeted therapy

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