Mutations in the cyclin-dependent kinase-like 5 gene(CDKL5)cause a severe neurodevelopmental disorder,yet the impact of truncating mutations remains unclear.Here,we introduce the Cdkl5^(492stop) mouse model,mimicking ...Mutations in the cyclin-dependent kinase-like 5 gene(CDKL5)cause a severe neurodevelopmental disorder,yet the impact of truncating mutations remains unclear.Here,we introduce the Cdkl5^(492stop) mouse model,mimicking C-terminal truncating mutations in patients.492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors,alongside other behavioral deficits.After creating cell lines with various Cdkl5 truncating mutations,we found that these mutations are regulated by the nonsense-mediated RNA decay pathway.Most truncating mutations result in CDKL5 protein loss,leading to multiple disease phenotypes,and offering new insights into the pathogenesis of CDKL5 disorder.展开更多
Acute kidney injury （AKI） is commonly seen amongst critically ill and hospitalized patients. Individuals with certain co-morbid diseases have an increased risk of developing AKI. Thus, recognizing the co-morbidities...Acute kidney injury （AKI） is commonly seen amongst critically ill and hospitalized patients. Individuals with certain co-morbid diseases have an increased risk of developing AKI. Thus, recognizing the co-morbidities that predispose patients to AKI is important in AKI prevention and treatment. Some of the most common co-morbid disease processes that increase the risk of AKI are diabetes, cancer, cardiac surgery and human immunodefciency virus （HIV） acquired immune defciency syndrome （AIDS）. This review article identifies the increased risk of acquiring AKI with given co-morbid diseases. Furthermore, the pathophysiological mechanisms underlying AKI in relation to co-morbid diseases are discussed to understand how the risk of acquiring AKI is increased. This paper reviews the effects of various co-morbid diseases including： Diabetes, cancer, cardiovascular disease and HIV AIDS, which all exhibit a significant increased risk of developing AKI. Amongst these co-morbid diseases, inflammation, the use of nephrotoxic agents, and hypoperfusion to the kidneys have been shown to be major pathological processes that predisposes individuals to AKI. The pathogenesis of kidney injury is complex, however, effective treatment of the co-morbid disease processes may reduce its risk. Therefore, improved management of co-morbid diseases may prevent some of the underlying pathology that contributes to the increased risk of developing AKI.展开更多
[Objective] Iron deficiency is one of the most important crop element deficiencies in the Loess Plateau of northwestern China. The selection for crop cultivars that are tolerant to low iron levels could be one of the ...[Objective] Iron deficiency is one of the most important crop element deficiencies in the Loess Plateau of northwestern China. The selection for crop cultivars that are tolerant to low iron levels could be one of the approaches to solving the problem and improving crop production. [Method] Three major apple root stock species （Malus prunifolia, Malus sieversii and Malus baccata） were selected to evaluate their tolerance to iron defciency in hydroponic system. A 3×2 factorial pot experiment was conducted with three replicates in a greenhouse at Gansu Agricultural University, Lanzhou, China. [Result] The SOD, POD and CAT activities in roots and stems of the 3 root stock species in Fe-defcient Hoagland solution decreased, however Malus sieversii got the less reduction and had better root architecture and growth than the other species. The aboveground biomass, plant height, chlorophyll content, total root length and lateral root number were correlated positively with iron-defciency stress tolerance. The species’ tolerance to iron-defciency from high to low was M. sieversii’s〉M. baccata’s〉M. prunifolia’s. Moreover, the improvement of some morphological features such as root length, above-ground biomass, plant height and lateral root number in apple could be conducive to breeding cultivars with tolerance to iron-defciency stress. [Conclusion] Malus sieversii had better tolerance to iron-defciency stress than the others in this study.展开更多
The clinical spectrum of human immunodeficiency virus （HIV） infection associated disease has changed significantly over the past decade, mainly due to the wide availability and improvement of combination antiretrovi...The clinical spectrum of human immunodeficiency virus （HIV） infection associated disease has changed significantly over the past decade, mainly due to the wide availability and improvement of combination antiretroviral therapy regiments. Serious complications associated with profound immunodeficiency are nowa-days fortunately rare in patients with adequate access to care and treatment. However, HIV infected patients, and particularly those with acquired immune defciency syndrome, are predisposed to a host of different water, electrolyte, and acid-base disorders （sometimes with opposite characteristics）, since they have a modified renal physiology （reduced free water clearance, and relatively increased fractional excretion of calcium and magnesium） and they are also exposed to infectious, inflammatory, endocrinological, oncological variables which promote clinical conditions （such as fever,tachypnea, vomiting, diarrhea, polyuria, and delirium）, and may require a variety of medical interventions （antiviral medication, antibiotics, antineoplastic agents）, whose combination predispose them to undermine their homeostatic capability. As many of these disturbances may remain clinically silent until reaching an advanced condition, high awareness is advisable, particularly in patients with late diagnosis, concomitant inflammatory conditions and opportunistic diseases. These disorders contribute to both morbidity and mortality in HIV infected patients.展开更多
We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud’s phenomenon, and hypermobility. She was found to have a 6074A 〉 T nucleotide transition in the TNXB gene causing...We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud’s phenomenon, and hypermobility. She was found to have a 6074A 〉 T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025Val classifed as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as disease-causing. This gene variant was reported previously in a different 36-year-old patient who shared our patient’s symptoms of joint hypermobility, skeletal and joint pain, skin elasticity and musculoskeletal problems, thereby causing a more severe presentation than seen in the hypermobility type of Ehlers-Danlos syndrome （EDS）. At the time of writing, a few mutations in the TNXB gene have been recognized as pathogenic causing EDS due to tenascin-X defciency, but the variant identifed in our patient has not been recognized as pathogenic in online genetic databases. Our case study in combination with peer-reviewed literature suggests that the 6074A 〉 T nucleotide transition in the TNXB gene may be classifed as disease-causing for EDS due to tenascin-X defciency.展开更多
Glucose transporter type 1 defciency syndrome(Glut1DS)is a rare neurometabolic disorder that afects the nervous system,primarily due to impaired glucose transport across the blood–brain barrier.This condition is caus...Glucose transporter type 1 defciency syndrome(Glut1DS)is a rare neurometabolic disorder that afects the nervous system,primarily due to impaired glucose transport across the blood–brain barrier.This condition is caused by mutations in the SLC2A1,which encodes the GLUT1 protein responsible for glucose transport into the brain[1].Zhang et al.recently published their study in World Journal of Pediatrics.The article is entitled as“Clinical and genetic characteristics of glucose transporter 1 defciency syndrome in a large cohort of Chinese patients”.Zhang et al.collected clinical and genetic data from 90 Chinese children with Glut1DS,making it the largest cohort analyzed to date in this population,provides a crucial and detailed analysis for clinicians to diagnosis and treat this rare disease[2].展开更多
Background The SLC2A1 gene plays a vital role in brain energy metabolism.SLC2A1 variants have been reported to be associated with early-onset refractory seizures.This study aims to explore the association between the ...Background The SLC2A1 gene plays a vital role in brain energy metabolism.SLC2A1 variants have been reported to be associated with early-onset refractory seizures.This study aims to explore the association between the SLC2A1 gene and late-onset epilepsy.Methods Trios-based whole-exome sequencing was performed on patients with epilepsy without acquired etiologies.The pathogenicity of the variants was assessed according to the American College of Medical Genetics and Genomics(ACMG)guidelines.Results A total of 14 heterozygous SLC2A1 variants were identifed in 16 unrelated families.The variants were evaluated as“pathogenic”or“likely pathogenic”according to the ACMG guidelines.Ten cases(62.5%)presented with infantile onset seizures and developmental delay/intellectual disability and were diagnosed with developmental and epileptic encephalopathy(DEE).The other six cases(37.5%)exhibited late-onset seizures and normal development.They were diagnosed with idiopathic partial epilepsy(n=2)or idiopathic generalized epilepsy(n=4).Further analysis showed that DEE-associated variants tended to cluster in the transmembrane region,whereas the mild epilepsyassociated variants tended to locate in regions outside the transmembrane region,suggesting a potential molecular sub-regional efect.A total of 15 cases had delayed diagnosis,with the longest delay being 22 years.The SLC2A1 expression stage,which is expressed at relatively high level throughout the whole life span,from the embryonic to adult stages with two peaks at approximately four and 14 years,is generally consistent with the seizure onset age.In addition,patients with early-onset age had variants that were potentially associated with severe damage,suggesting a potential correlation between the age of disease onset and the damaging efects of the variants.Conclusions SLC2A1 variants are associated with late-onset epilepsy,which is consistent with the genetic-dependent stage feature of SLC2A1.Early genetic diagnosis is important for treatment of patients with SLC2A1 variants.展开更多
基金supported by the Innovation of Science and Technology 2030-Major Project"Platform of Nonhuman Primate Models"(2021ZD0200900)the Ministry of Science and Technology(2018YFA0801404)+1 种基金the National Natural Science Foundation of China(82021001)the Shanghai Municipal Science and Technology Major Project.
文摘Mutations in the cyclin-dependent kinase-like 5 gene(CDKL5)cause a severe neurodevelopmental disorder,yet the impact of truncating mutations remains unclear.Here,we introduce the Cdkl5^(492stop) mouse model,mimicking C-terminal truncating mutations in patients.492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors,alongside other behavioral deficits.After creating cell lines with various Cdkl5 truncating mutations,we found that these mutations are regulated by the nonsense-mediated RNA decay pathway.Most truncating mutations result in CDKL5 protein loss,leading to multiple disease phenotypes,and offering new insights into the pathogenesis of CDKL5 disorder.
文摘Acute kidney injury （AKI） is commonly seen amongst critically ill and hospitalized patients. Individuals with certain co-morbid diseases have an increased risk of developing AKI. Thus, recognizing the co-morbidities that predispose patients to AKI is important in AKI prevention and treatment. Some of the most common co-morbid disease processes that increase the risk of AKI are diabetes, cancer, cardiac surgery and human immunodefciency virus （HIV） acquired immune defciency syndrome （AIDS）. This review article identifies the increased risk of acquiring AKI with given co-morbid diseases. Furthermore, the pathophysiological mechanisms underlying AKI in relation to co-morbid diseases are discussed to understand how the risk of acquiring AKI is increased. This paper reviews the effects of various co-morbid diseases including： Diabetes, cancer, cardiovascular disease and HIV AIDS, which all exhibit a significant increased risk of developing AKI. Amongst these co-morbid diseases, inflammation, the use of nephrotoxic agents, and hypoperfusion to the kidneys have been shown to be major pathological processes that predisposes individuals to AKI. The pathogenesis of kidney injury is complex, however, effective treatment of the co-morbid disease processes may reduce its risk. Therefore, improved management of co-morbid diseases may prevent some of the underlying pathology that contributes to the increased risk of developing AKI.
基金Supported by University Research Project of Education Dpartment(2018A-035)~~
文摘[Objective] Iron deficiency is one of the most important crop element deficiencies in the Loess Plateau of northwestern China. The selection for crop cultivars that are tolerant to low iron levels could be one of the approaches to solving the problem and improving crop production. [Method] Three major apple root stock species （Malus prunifolia, Malus sieversii and Malus baccata） were selected to evaluate their tolerance to iron defciency in hydroponic system. A 3×2 factorial pot experiment was conducted with three replicates in a greenhouse at Gansu Agricultural University, Lanzhou, China. [Result] The SOD, POD and CAT activities in roots and stems of the 3 root stock species in Fe-defcient Hoagland solution decreased, however Malus sieversii got the less reduction and had better root architecture and growth than the other species. The aboveground biomass, plant height, chlorophyll content, total root length and lateral root number were correlated positively with iron-defciency stress tolerance. The species’ tolerance to iron-defciency from high to low was M. sieversii’s〉M. baccata’s〉M. prunifolia’s. Moreover, the improvement of some morphological features such as root length, above-ground biomass, plant height and lateral root number in apple could be conducive to breeding cultivars with tolerance to iron-defciency stress. [Conclusion] Malus sieversii had better tolerance to iron-defciency stress than the others in this study.
文摘The clinical spectrum of human immunodeficiency virus （HIV） infection associated disease has changed significantly over the past decade, mainly due to the wide availability and improvement of combination antiretroviral therapy regiments. Serious complications associated with profound immunodeficiency are nowa-days fortunately rare in patients with adequate access to care and treatment. However, HIV infected patients, and particularly those with acquired immune defciency syndrome, are predisposed to a host of different water, electrolyte, and acid-base disorders （sometimes with opposite characteristics）, since they have a modified renal physiology （reduced free water clearance, and relatively increased fractional excretion of calcium and magnesium） and they are also exposed to infectious, inflammatory, endocrinological, oncological variables which promote clinical conditions （such as fever,tachypnea, vomiting, diarrhea, polyuria, and delirium）, and may require a variety of medical interventions （antiviral medication, antibiotics, antineoplastic agents）, whose combination predispose them to undermine their homeostatic capability. As many of these disturbances may remain clinically silent until reaching an advanced condition, high awareness is advisable, particularly in patients with late diagnosis, concomitant inflammatory conditions and opportunistic diseases. These disorders contribute to both morbidity and mortality in HIV infected patients.
基金Supported by The National Institute of Child Health and Human Development(NICHD),No.HD02528
文摘We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud’s phenomenon, and hypermobility. She was found to have a 6074A 〉 T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025Val classifed as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as disease-causing. This gene variant was reported previously in a different 36-year-old patient who shared our patient’s symptoms of joint hypermobility, skeletal and joint pain, skin elasticity and musculoskeletal problems, thereby causing a more severe presentation than seen in the hypermobility type of Ehlers-Danlos syndrome （EDS）. At the time of writing, a few mutations in the TNXB gene have been recognized as pathogenic causing EDS due to tenascin-X defciency, but the variant identifed in our patient has not been recognized as pathogenic in online genetic databases. Our case study in combination with peer-reviewed literature suggests that the 6074A 〉 T nucleotide transition in the TNXB gene may be classifed as disease-causing for EDS due to tenascin-X defciency.
文摘Glucose transporter type 1 defciency syndrome(Glut1DS)is a rare neurometabolic disorder that afects the nervous system,primarily due to impaired glucose transport across the blood–brain barrier.This condition is caused by mutations in the SLC2A1,which encodes the GLUT1 protein responsible for glucose transport into the brain[1].Zhang et al.recently published their study in World Journal of Pediatrics.The article is entitled as“Clinical and genetic characteristics of glucose transporter 1 defciency syndrome in a large cohort of Chinese patients”.Zhang et al.collected clinical and genetic data from 90 Chinese children with Glut1DS,making it the largest cohort analyzed to date in this population,provides a crucial and detailed analysis for clinicians to diagnosis and treat this rare disease[2].
基金supported by the National Natural Science Foundation of China(82271505 to W.L.)UCB Pharma Ltd.and the Joint Science Research Foundation of China Association Against Epilepsy(CU-2024-042 to B.L.).
文摘Background The SLC2A1 gene plays a vital role in brain energy metabolism.SLC2A1 variants have been reported to be associated with early-onset refractory seizures.This study aims to explore the association between the SLC2A1 gene and late-onset epilepsy.Methods Trios-based whole-exome sequencing was performed on patients with epilepsy without acquired etiologies.The pathogenicity of the variants was assessed according to the American College of Medical Genetics and Genomics(ACMG)guidelines.Results A total of 14 heterozygous SLC2A1 variants were identifed in 16 unrelated families.The variants were evaluated as“pathogenic”or“likely pathogenic”according to the ACMG guidelines.Ten cases(62.5%)presented with infantile onset seizures and developmental delay/intellectual disability and were diagnosed with developmental and epileptic encephalopathy(DEE).The other six cases(37.5%)exhibited late-onset seizures and normal development.They were diagnosed with idiopathic partial epilepsy(n=2)or idiopathic generalized epilepsy(n=4).Further analysis showed that DEE-associated variants tended to cluster in the transmembrane region,whereas the mild epilepsyassociated variants tended to locate in regions outside the transmembrane region,suggesting a potential molecular sub-regional efect.A total of 15 cases had delayed diagnosis,with the longest delay being 22 years.The SLC2A1 expression stage,which is expressed at relatively high level throughout the whole life span,from the embryonic to adult stages with two peaks at approximately four and 14 years,is generally consistent with the seizure onset age.In addition,patients with early-onset age had variants that were potentially associated with severe damage,suggesting a potential correlation between the age of disease onset and the damaging efects of the variants.Conclusions SLC2A1 variants are associated with late-onset epilepsy,which is consistent with the genetic-dependent stage feature of SLC2A1.Early genetic diagnosis is important for treatment of patients with SLC2A1 variants.
