bluuebunny/crossref_metadata_2025 huggingface dataset:
Metachromatic leukodystrophy: Molecular genetics and an animal model
Authors: Gieselmann V. , Matzner U. , Hess B. , Lüllmann‐Rauch R. , Coenen R. , Hartmann D. , D'Hooge R. , Dedeyn P. , Nagels G.
Published: December 2002

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulphatase A (ASA; EC 3.1.6.8). Deficiency of this enzyme causes intralysosomal storage of the sphingolipid cerebroside sulphate. This lipid is abundant in myelin and it may thus not be surprising that storage mainly affects oligodendrocytes. Patients suffer from a progressive demyelination causing various neurological symptoms. The disease is fatal and treatment is not available. The human ASA gene has been cloned and more than 40 mutations have been analysed that cause metachromatic leukodystrophy. Few of these alleles are frequent among patients, whereas most mutant alleles have only been found in single families. Since MLD has only been described in humans and no naturally occurring animal model has been described, ASA‐deficient mice have been generated by homologous recombination. The ASA knockout mice are unable to degrade sulphatide and store the lipid intralysosomally. The pattern of lipid storage in neuronal and nonneuronal tissues resembles that described for patients. In the nervous system, lipid storage is found in oligodendrocytes, astrocytes and some neurons. Animals display an astrogliosis and a decreased average axonal diameter. Purkinje cells and Bergmann glia of the cerebellum are morphologically aberrant. Demyelination is seen in the acoustic ganglion and occurs between the ages of 6 and 12 months. The animals are deaf at this age and display various neuromotor abnormalities. However, compared to humans the mice have a surprisingly mild phenotype, since they have a normal life span and do not develop widespread demyelination. ASA‐deficient mice have been transplanted with bone marrow, which was transduced with a retroviral vector expressing arylsulphatase A. The majority of transplanted animals display sustained expression of arylsulphatase A from the retroviral construct up to 5 months after transplantation. However, preliminary data suggest that this therapeutic approach does not reduce storage material.
The spectrum of mutations of the aspartoacylase gene in Canavan disease in non‐Jewish patients
Authors: Elpeleg O. N. , Shaag A.
Published: December 2002

Canavan disease is an infantile neurodegenerative disease that is caused by mutations in the gene encoding the enzyme aspartoacylase. It has mainly been reported in Jewish families. Genotyping of newly diagnosed patients is essential for the carrier identification and prenatal diagnosis. The sequence of the coding region was determined in 15 non‐Jewish patients and 9 new mutations were identified: Y109X, P183H, V186F, M195R, P280L, P280S, A287T, 245insA, and a tentative missplicing mutation which leads to skipping of exon 5. The common pan‐European mutation, A305E, was identified in 40% of the alleles and the overall detection rate was 93%.
Nutritional deficiencies in a patient with glycogen storage disease type Ib
Authors: Kishnani P. S. , Boney A. , Chen Y.‐T.
Published: December 2002

The current mainstay of treatment in glycogen storage disease type I (GSD I) is dietary management that includes providing a frequent source of glucose to prevent hypoglycaemia. To ensure compliance, routine follow‐up by a health care team, including a dietitian, experienced in the treatment of GSD is necessary. We describe an adolescent patient with GSD Ib in good metabolic control who was admitted with a 3‐month history of weakness, depression, vomiting, decreased appetite and a 11.4‐kg weight loss. He had a recent onset of unsteady gait, inability to write, and sore mouth. After an extensive work‐up, the patient was found to have vitamin B12, folate, iron and other nutritional deficiencies, which explained his symptoms. The patient improved within 72h of initiation of total parenteral nutrition and therapeutic doses of deficient micronutrients, with a complete recovery in 2 months. Dietary restrictions, dependence on non‐food products (e.g. cornstarch in GSD I), and social and developmental issues place individuals with metabolic disorders at a high risk for developing an array of nutritional deficiencies. This case highlights the importance of both close follow‐up of the metabolic control and close monitoring of growth and nutritional intake in individuals with inborn errors of metabolism. This case also illustrates the importance of daily supplementation with appropriate multivitamins, calcium and other minerals needed to meet the Recommended Dietary Allowances (RDAs) in these patients.
Defects in activation and transport of fatty acids
Authors: Brivet M. , Boutron A. , Slama A. , Costa C. , Thuillier L. , Demaugre F. , Rabier D. , Saudubray J. M. , Bonnefont J. P.
Published: December 2002

The oxidation of long‐chain fatty acids in mitochondria plays an important role in energy production, especially in skeletal muscle, heart and liver. Long‐chain fatty acids, activated to their CoA esters in the cytosol, are shuttled across the barrier of the inner mitochondrial membrane by the carnitine cycle. This pathway includes four steps, mediated by a plasma membrane carnitine transporter, two carnitine palmitoyltransferases (CPT I and CPT II) and a carnitine‐acylcarnitine translocase. Defects in activation and uptake of fatty acids affect these four steps: CPT II deficiency leads to either exercise‐induced rhabdomyolysis in adults or hepatocardiomuscular symptoms in neonates and children. The three other disorders of the carnitine cycle have an early onset. Hepatic CPT I deficiency is characterized by recurrent episodes of Reye‐like syndrome, whereas severe muscular and cardiac signs are associated with episodes of fasting hypoglycaemia in defects of carnitine transport and translocase. Convenient metabolic investigations for reaching the diagnosis of carnitine cycle disorders are determination of plasma free and total carnitine concentrations, determination of plasma acylcarnitine profile by tandem mass spectrometry and in vitro fatty acid oxidation studies, particularly in fresh lymphocytes. Application of the tools of molecular biology has greatly aided the understanding of the carnitine palmitoyltransferase enzyme system and confirmed the existence of different related genetic diseases. Mutation analysis of CPT II defects has given some clues for correlation of genotype and phenotype. The first molecular analyses of hepatic CPT I and translocase deficiencies were recently reported.
Muscle carnitine acetyltransferase and carnitine deficiency in a case of mitochondrial encephalomyopathy
Authors: Melegh B. , Seress L. , Bedekovics T. , Kispál G. , Sümegi B. , Trombitás K. , Méhes K.
Published: December 2002

Profound decrease of the carnitine acetyltransferase activity (0.08 U/g wet weight; 1.67% of control) and carnitine deficiency (total carnitine was 230 nmol/g wet weight in the patient vs 2730 in the controls) was detected in the skeletal muscle of a female paediatric patient. She died of her illness, which included cerebellar symptoms and slight muscle spasticity affecting mainly the lower extremities, at 1 year of age. Histological examination of the autopsy specimens revealed a selective Purkinje cell degeneration in the cerebellum: the cells had abnormal position, were shrunken and decreased in number, and displayed abnormal dendritic trees and fragmented, disorganized axons. Electron microscopy revealed mitochondrial abnormalities in skeletal and cardiac muscle and also in the Purkinje cells. Deletions of the mitochondrial DNA were detected in the muscle in heteroplasmic form (up to 7%). Mainly the ND4‐ND4L region was affected, as evidenced by the PCR; however, other regions of the mitochondrial genome also showed deletions of varying size and extent, suggesting multiple deletions of the mitochondrial DNA.
Neurochemistry and defects of biogenic amine neurotransmitter metabolism
Authors: Hyland K.
Published: December 2002

The purpose of the current review is to present a brief background examining the mechanisms controlling synthesis, storage, release and action of the biogenic amine neurotransmitters and to provide examples of newly defined conditions that expand our awareness of the diversity and complexity of the inherited diseases that affect these important regulators of central and peripheral homeostasis.
Ceramide accumulation is associated with increased apoptotic cell death in cultured fibroblasts of sphingolipid activator protein‐deficient mouse but not in fibroblasts of patients with Farber disease
Authors: Tohyama J. , Oya Y. , Ezoe T. , Vanier M. T. , Nakayasu H. , Fujita N. , Suzuki K.
Published: December 2002

Ceramide is recognized as an intracellular mediator of cell growth, differentiation and apoptosis. Tumour necrosis factor, anti‐fas antibody, radiation and anticancer drugs such as actinomycin D are known to induce apoptosis in several cell types through generation of ceramide by activation of the sphingomyelinase pathway or ceramide synthetase. In this study, we examined the occurrence of apoptosis in fibroblasts from patients with Farber disease and from sphingolipid activator protein‐deficient (sap−/−) mouse. These cells accumulate ceramide as the result of genetic deficiency of acid ceramidase and the ceramidase activator (sap‐D), respectively. Amounts of ceramide in fibroblasts from Farber patients and in fibroblasts from sap−/− mouse were increased 2.9‐fold and 2.8‐fold, respectively, over the level of controls. Despite the similar degree of ceramide accumulation, cells exhibiting apoptotic features were increased only in fibroblasts from the sap−/− mouse but not those from the Farber patients. Thymidine uptake of Farber fibroblasts was normal while that of sap−/− mouse fibroblasts was twice normal, consistent with the apparently normal growth and the different rates of apoptotic cell death in these two cell lines. These data suggest that intralysosomal accumulation of ceramide due to defective acid ceramidase or its activator may not play an important role as a mediator of apoptosis. The increased apoptosis in the cultured fibroblasts from the sap−/− mouse may be caused by mechanisms other than the ceramide accumulation. Although more frequent than normal, significant apoptotic cell death was not observed in sap−/− mouse brain in vivo.
Successful pregnancy in severe methylmalonic acidaemia
Authors: Wasserstein M. P. , Gaddipati S. , Snyderman S. E. , Eddleman K. , Desnick R. J. , Sansaricq C.
Published: December 2002

Methylmalonic acidaemia is an inborn error of metabolism characterized by recurrent episodes of life‐threatening ketoacidosis. With improved and intensive treatment, these patients are living into adulthood, but many experience late‐onset disease complications such as chronic renal failure, chronic pancreatitis and osteopenia. We report the successful delivery of a healthy baby to a 20‐year‐old woman with vitamin B12‐unresponsive methylmalonic acidaemia who has these late‐onset manifestations of the disease and had plasma methylmalonic acid concentrations of 1900μmol/L during the first trimester of pregnancy.
Survival of two patients with severe δ‐aminolaevulinic acid dehydratase deficiency porphyria
Authors: Gross U. , Sassa S. , Arndt T. , Doss M. O.
Published: December 2002

The course of δ‐aminolaevulinic acid dehydratase activity was studied over the 23 years in erythrocytes of two male patients. The enzyme activity was originally 1–2%, which then increased to ∼8% of normal levels several years after clinical manifestation of the acute hepatic porphyria syndrome. Urinary excretions of δ‐aminolaevulinic acid and coproporphyrin III were excessively increased in the two patients with compound‐heterozygous δ‐aminolaevulinic acid dehydratase deficiency porphyria.
Isolation and characterization of the normal canine β‐galactosidase gene and its mutation in a dog model of GM1‐gangliosidosis
Authors: Wang Z. H. , Zeng B. , Shibuya H. , Johnson G. S. , Alroy J. , Pastores G. M. , Raghavan S. , Kolodny E. H.
Published: December 2002

The acid β‐galactosidase cDNA of Portuguese Water dogs was isolated and sequenced. The entire coding region of the gene consists of 2004 nucleotides encoding a protein of 668 amino acids. Its encoding sequence indicates approximately 86.5% identity at the nucleotide level and about 81% identity at the amino acid level with the encoding region of the human acid β‐galactosidase gene. The deduced amino acid sequence contains a 24‐amino‐acid putative signal sequence, six possible glycosylation sites, and seven cysteine residues. A homozygous recessive mutation, causing canine GM1‐gangliosidosis, was identified at nucleotide G200→A in exon 2 resulting in an Arg60→His (mutation R60H) amino acid substitution. The mutation creates a new restriction enzyme site for Pml1. Genotyping 115 dog samples for this acid β‐galactosidase gene alteration readily distinguished affected homozygous recessives (n=5), heterozygous carriers (n=50) and normal homozygotes (n=60). DNA mutation analysis provided a method more specific than enzyme assay of β‐galactosidase for determination of carriers.
Lovastatin does not correct the accumulation of very long‐chain fatty acids in tissues of adrenoleukodystrophy protein‐deficient mice
Authors: Yamada T. , Shinnoh N. , Taniwaki T. , Ohyagi Y. , Asahara H. , Horiuchi I. , Kira J.
Published: December 2002

Lovastatin, an inhibitor of 3‐hydroxy‐3‐methylglutarylcoenzyme A reductase, normalizes the very long‐chain fatty acids (VLCFA) concentrations in fibroblasts and plasma from patients with X‐linked adrenoleukodystrophy (X‐ALD). The effects of lovastatin on the accumulation of VLCFA in tissues of adrenoleukodystrophy protein (ALDP)‐deficient mice were assessed. ALDP‐deficient mice were fed chow with 0.01–0.1% lovastatin for 4–8 weeks. The VLCFA concentrations in the plasma, brain, spinal cord, liver and kidneys were measured. Treatment with 0.1% lovastatin significantly reduced body weight and total cholesterol in the plasma of ALDP‐deficient mice. Treatment with lovastatin, however, did not correct the accumulation of VLCFA in the plasma or tissues, including the brain and spinal cord. Lovastatin does not affect the accumulation of VLCFA in ALDP‐deficient tissues in mice.
Effect of sodium benzoate in the treatment of atypical nonketotic hyperglycinaemia
Authors: Neuberger J. M. , Schweitzer S. , Rolland M.‐O. , Burghard R.
Published: December 2002

A 6‐month‐old girl presented with hypotonia and mild psychomotor retardation. Subsequently, an atypical manifestation of a nonketotic hyperglycinaemia was diagnosed, confirmed by significantly reduced activity of the glycine cleavage system in the liver tissue. After the patient developed hypsarrhythmia and had a single cerebral seizure, treatment with both sodium benzoate and dextromethorphan was started. During the following year, the girl was free of seizures with improvement of the EEG activity and showed retarded but continuously progressing psychomotor development. At the age of 20 months she began to walk freely but had generalized muscular hypotonia and moderate mental retardation. Discontinuation of dextromethorphan medication after one year of treatment did not change the clinical and electroencephalographic status. However, after cessation of sodium benzoate therapy, epileptic activity in the EEG and behavioural changes occurred. These changes disappeared promptly after sodium benzoate therapy was reinstituted. Thus, this case of mild atypical nonketotic hyperglycinaemia with only moderate psychomotor retardation and without epilepsy benefited from treatment with sodium benzoate in terms of electroencephalographic and behavioural changes.
Mitochondrial respiratory chain defects are not accompanied by an increase in the activities of lactate dehydrogenase or manganese superoxide dismutase in paediatric skeletal muscle biopsies
Authors: Hargreaves I. P. , Heales S. J. R. , Land J. M.
Published: December 2002

Both the activity of lactate dehydrogenase (LDH) and the quantity of manganese superoxide dismutase (MnSOD) protein have been reported to be increased in fibroblasts from individuals with mitochondrial electron transport chain defects. To ascertain whether this is a general phenomenon, we have determined the specific activities of these enzymes in skeletal muscle biopsies from control individuals and patients with defined electron transport chain defects. On investigation, both LDH and MnSOD activities were not found to be elevated. These findings suggest a possible fundamental difference between skeletal muscle preparations and fibroblasts with regard to their metabolic response to an electron transport chain defect.
Erythropoietic and hepatic porphyrias
Authors: Gross U. , Hoffmann G. F. , Doss M. O.
Published: December 2002

Porphyrias are divided into erythropoietic and hepatic manifestations. Erythropoietic porphyrias are characterized by cutaneous symptoms and appear in early childhood. Erythropoietic protoporphyria is complicated by cholestatic liver cirrhosis and progressive hepatic failure in 10% of patients. Acute hepatic porphyrias (δ‐aminolaevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) are characterized by variable extrahepatic gastrointestinal, neurological–psychiatric and cardiovascular manifestations requiring early diagnosis to avoid life‐threatening complications. Acute hepatic porphyrias are pharmacogenetic and molecular regulatory diseases (without porphyrin accumulation) mainly induced by drugs, sex hormones, fasting or alcohol. The disease process depends on the derepression of hepatic δ‐aminolaevulinic acid synthase following haem depletion. In contrast to the acute porphyrias, nonacute, chronic hepatic porphyrias such as porphyria cutanea tarda are porphyrin accumulation disorders leading to cutaneous symptoms associated with liver disease, especially caused by alcohol or viral hepatitis. Alcohol, oestrogens, haemodialysis, hepatitis C and AIDS are triggering factors. Porphyria cutanea tarda is the most common porphyria, followed by acute intermittent porphyria and erythropoietic protoporphyria. The molecular genetics of the porphyrias is very heterogenous. Nearly every family has its own mutation. The mutations identified account for the corresponding enzymatic deficiencies, which may remain clinically silent throughout life. Thus, the recognition of the overt disorder with extrahepatic manifestations depends on the demonstration of biochemical abnormalities due to these primary defects and compensatory hepatic overexpression of hepatic δ‐aminolaevulinic acid synthase in the acute porphyrias. Consequently, haem precursors are synthesized in excess. The increased metabolites upstream of the enzymatic defect are excreted into urine and faeces. The diagnosis is based on their evaluation. Primary enzymatic or molecular analyses are noncontributary and may be misleading. Acute polysymptomatic exacerbations accompany a high excretory constellation of porphyrin precursors δ‐aminolaevulinic acid and porphobilinogen. Homozygous or compound heterozygous variants of acute hepatic porphyrias may already manifest in childhood.
The natural course of Gaucher disease in The Netherlands: Implications for monitoring of disease manifestations
Authors: Maaswinkel‐Mooij P. , Hollak C. , Van Eysden‐Plaisier M. , Prins M. , Aerts H. , Pöll R.
Published: December 2002

This retrospective study in 20 untreated type I Gaucher disease patients shows that in Dutch patients clinical manifestations of Gaucher disease type I are progressive in the majority of patients, children as well as adults. This is in contrast with studies among Jewish patients. Our results emphasize the need for a regular follow‐up to enable timely initiation of enzyme therapy.
Isolated and contiguous glycerol kinase gene disorders: A review
Authors: Sjarif D. R. , Ploos van Amstel J. K. , Duran M. , Beemer F. A. , Poll‐The B. T.
Published: December 2002

Glycerol kinase deficiency (GKD) is an X‐linked recessive disorder. There are two types, an isolated form and a complex form. We review the clinical, biochemical and molecular genetic features of GKD. The clinical and biochemical phenotype of isolated GKD may vary from a life‐threatening childhood metabolic crisis to asymptomatic adult ‘pseudohypertriglyceridaemia’, resulting from hyperglycerolaemia. To date 38 patients from 24 families with isolated GKD have been reported. At least 7 of these patients had a metabolic crisis during a catabolic condition. The complex GKD is an Xp21 contiguous gene syndrome involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Clinical features of a patient with complex GKD depend on the loci that are involved. Approximately 100 patients from 78 families with a complex GKD have been reported. Seventeen patients with complex GKD (AHC‐GKD‐DMD or AHC‐GKD) died in the neonatal period or early childhood because of unrecognized or inappropriate management of adrenal dysfunction. Since the outcome of the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis. From molecular genetic investigations of isolated GKD, 7 missense mutations, 2 splice site mutations, 1 nonsense mutation, 1 Alu Sx insertion and 2 small deletions were reported for isolated GKD in 13 unrelated families. In 4 families consisting of more than one patient with the same biochemical and genetic defect, the phenotypic, variability, of, the, isolated GKD was remarkable. The clinical variability, in, isolated, GKD, cannot, be, explained, by, biochemical, or, by molecular heterogeneity. Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further.
Tripeptidyl‐peptidase I deficiency in classical late‐infantile neuronal ceroid lipofuscinosis brain tissue. Evidence for defective peptidase rather than proteinase activity
Authors: Warburton M. J. , Bernardini F.
Published: December 2002

Brain tissue from patients with classical late‐infantile neuronal ceroid lipofuscinosis (LINCL, an infantile form of Batten disease) is deficient in the lysosomal enzyme tripeptidyl‐peptidase I (EC 3.4.14.9). The activities of other lysosomal enzymes are either increased or decreased. Tripeptidyl‐peptidase I is a pepstatin‐insensitive exo‐tripeptidase, with little or no endo‐proteolytic activity, that is active on small peptides but not on large proteins. Using haemoglobin and casein as substrates for proteolytic activity, we were unable to demonstrate any significant defect in pepstatin‐sensitive or pepstatin‐insensitive proteinase activity in brain tissue or cultured skin fibroblasts of LINCL patients. These observations suggest that the lysosomal storage of undegraded, small peptides in LINCL results from the absence of peptidase rather than proteinase activity.
Therapy of X‐linked adrenoleukodystrophy: Prognosis based upon age and MRI abnormality and plans for placebo‐controlled trials
Authors: Moser H. W. , Bezman L. , Lu S. E. , Raymond G. V.
Published: December 2002

Evaluation of the therapy of X‐linked adrenoleukodystrophy (X‐ALD) is hampered by its rarity and by the striking and unpredictable variation in phenotypic expression. We present two approaches that may facilitate therapy evaluation. (1) We have analysed data on 377 X‐ALD patients who have been followed at the Kennedy Krieger Institute for a mean period of 38 months and have subdivided them into 18 subgroups on the basis of age and the degree of abnormality in brain magnetic resonance imaging (MRI) as assessed by the Loes score (Am. J. Neuroradiol 1994; 15: 1761). We find that grouping on the basis of age and MRI score provides information that is of significant prognostic value. (2) We present plans for the development of a placebo‐controlled multicentre international study that will have sufficient biostatistical power to provide objective evaluation of new therapeutic interventions.
Phenylketonuria: Tyrosine beyond the phenylalanine‐restricted diet
Authors: van Spronsen F. J. , Smit P. G. A. , Koch R.
Published: December 2002

Controversies exist on the role of tyrosine in the pathogenesis of phenylketonuria (PKU) and, consequently, on the therapeutic role of tyrosine. This review examines data and theoretical considerations on the role of tyrosine in the pathogenesis and treatment of PKU. It is concluded that treatment with tyrosine alone to replace the phenylalanine‐restricted diet cannot be justified. A treatment with large neutral amino acids (LNAA) including tyrosine to restore the balance in the transport of phenylalanine and other LNAA across the blood–brain barrier deserves further investigation. Such studies should prove the safety and the efficacy of such a treatment, finding the optimal dose of all LNAA, disclosing the correct age to start and the way to monitor treatment biochemically.
Treatment of late‐onset nonketotic hyperglycinaemia: Effectiveness of imipramine and benzoate
Authors: Wiltshire E. J. , Poplawski N. K. , Harrison J. R. , Fletcher J. M.
Published: December 2002

We report a patient with late‐onset nonketotic hyperglycinaemia managed with a sequential approach to drug therapy in placebo‐controlled therapeutic trials. Partial response to low‐protein diet and sodium benzoate and dramatic response to imipramine are demonstrated, with parental scores on the Developmental Behavioural Checklist falling from the 86th centile before treatment to normal with combined benzoate and imipramine therapy.
Adaptive trajectory tracking control for VTOL UAVs with unknown time‐varying mass using an extended I&I estimator
Authors: Han Qi , Liu Zhitao , Su Hongye , Liu Xiangbin
Published: January 2024

This article presents an adaptive control scheme for vertical takeoff and landing unmanned aerial vehicles subject to time‐varying mass based on the immersion and invariance scheme in an extended form. For the varying mass parameter in the position control, a generalized I&I adaptive law is proposed with higher dimension to estimate the mass and its derivatives. The stability of the resulting estimation error manifold, which is in a cascade form, is guaranteed by introducing smooth saturation functions in the position control law. The attitude control is designed by employing a smooth function with positive integrable time‐varying function to compensate unknown time‐varying moment of inertia to achieve asymptotic attitude tracking. Simulation and experimental results verify the effectiveness of the proposed method under different cases, and the robustness to time‐varying parameter is assured.
1‐Naphthaleneacetic Acid Improved the In Vitro Cell Culturing by Inhibiting Apoptosis
Authors: Wang Zhongyi , Li Fengqi , Feng Chunjing , Zheng Dongpeng , Pang Zhaojun , Ma Yue , Xu Ying , Yang Ce , Li Xueren , Peng Shouchun , Liu Zichuan , Mu Xin
Published: January 2024

In vitro cell culturing witnessed its applications in scientific research and industrial activities. Attempts to shorten the doubling time of cultured cells have never ceased. In plants, auxin is applied to promote plant growth, the synthetic derivative 1‐Naphthaleneacetic acid (NAA) is a good example. Despite the auxin's naturally occurring receptors are not present in mammalian cells, studies suggested they may affect cell culturing. Yet the effects and mechanisms are still unclear. Here, an up to 2‐fold increase in the yield of in vitro cultured human cells is observed. Different types of human cell lines and primary cells are tested and found that NAA is effective in all the cells tested. The PI staining followed by FACS suggested that NAA do not affect the cell cycling. Apoptosis‐specific dye staining analysis implicated that NAA rescued cell death. Further bulk RNA sequencing is done and it is identified that the lipid metabolism‐engaging and anti‐apoptosis gene, ANGPTL4, is enhanced in expression upon NAA treatment. Studies on ANGPTL4 knockout cells indicated that ANGPTL4 is required for NAA‐mediated response. Thus, the data identified a beneficial role of NAA in human cell culturing and highlighted its potency in in vitro cell culturing.
Highly Circularly Polarized Light‐Sensitive Chiral One‐Dimensional Perovskites Enabled by Antisolvent Engineering
Authors: Yang Seongyeon , Jang Gyumin , Lee Chan Uk , Son Jaehyun , Lee Junwoo , Jeong Wooyong , Roe Dong Gue , Cho Jeong Ho , Moon Jooho
Published: January 2024

Chiral perovskites have emerged as promising next‐generation materials for polarization detection due to their excellent circularly polarized light (CPL) detection capabilities. However, they suffer from a low chiroptical response when fabricated as a polycrystalline thin film, limiting their potential range of applications. Herein, it is demonstrated that antisolvent dripping during the spin‐coating process can effectively improve the chiroptical properties of polycrystalline chiral perovskite thin films. Systematic analysis with different antisolvents reveals that the highly polar antisolvent chloroform interacts with dimethyl sulfoxide molecules via hydrogen bonding. This strong hydrogen bonding suppresses the formation of intermediate and secondary phases and accelerates the crystallization of chiral 1D perovskites, thus reducing the density of the iodine vacancies inside the perovskite thin films. The lower density of iodine vacancies also intensifies the asymmetric tilting inorganic distortion of PbI6 octahedrons, enhancing the chiroptical response of the fabricated chiral perovskite material. Photodetectors based on the chloroform‐treated chiral perovskite films achieve a remarkably high distinguishability of 0.31, outperforming previously reported photodetectors based on the chiral perovskites. The fabricated photodetectors also exhibit outstanding responsivity and detectivity with enhanced operational stability.
Selenoprotein‐Regulated Hydrogel for Ultrasound‐Controlled Microenvironment Remodeling to Promote Bone Defect Repair
Authors: Xu Renhao , You Yuanyuan , Zheng Wenyi , Ma Li , Chang Yanzhou , Pan Shuya , He Yanni , Zhou Meijun , Xu Zhili , Chen Tianfeng , Liu Hongmei
Published: January 2024

Abnormal levels of reactive oxygen species (ROS) and the hypoxic microenvironment within bone defects are important factors that impede bone repair processes. Herein, an innovative ultrasound‐modulatable hydrogel platform with selenoprotein‐mediated antioxidant effects to promote bone injury repair is presented. This hydrogel platform encapsulates oxygen‐enriched selene‐incorporated thin‐shell silicon within methacrylate gelatin (O2‐PSSG). The resultant construct orchestrates the modulation of the bone‐defect microenvironment, thereby expediting the course of bone regeneration. Ultrasound (US) is used to regulate the pore size of the hydrogel to release selenium‐containing nanoparticles and promote the in situ synthesis of efficient intracellular selenoproteins and hydrogen peroxide consumption. As expected, O2‐PSSG rapidly releases selenocystine ([Sec]2) under US control to scavenge reactive oxygen species and maintain the homeostasis of bone marrow mesenchymal stem cells (BMSCs). Over time, the action of the system by selenoprotein increases the activation of Wnt/β‐catenin pathways and promotes the differentiation of BMSCs. Consequently, O2‐PSSG potentiates the antioxidant proficiency of BMSCs both in vitro and in vivo, alleviates hypoxic environments, promotes osteogenic differentiation, and expedites cranial bone repair in rat models. In summary, this study suggests that the designed and constructed US‐responsive antioxidant hydrogel is a promising prospective strategy for addressing bone defects and fostering bone regeneration.
Hydrogen‐Bonding Organocatalysis Enabled Photocatalytic Intramolecular [2+2]‐Cycloaddition Reaction
Authors: Perulli Stefania , Desai Om , Ardevines Sandra , Uygur Mustafa , Delgado‐Hernández Samuel , García Mancheño Olga
Published: January 2024

The combination of organocatalytic activation and photocatalysis for enabling the intramolecular [2+2]‐cycloaddition of enone‐ene substrates bearing one Lewis base binding site is reported. While in a variety of solvents a poor conversion or no reaction takes place in the absence of a hydrogen bonding catalyst, the corresponding ring‐fused cyclobutane products could be built in moderate to good yields using a synergistic dual iridium‐urea co‐catalytic system. Control and mechanistic studies supported the postulated interaction between the organocatalyst and the substrate, which proved essential for an efficient energy transfer from the photosensitizer.
An Algorithm of Complete Coverage Path Planning for Deep‐Sea Mining Vehicle Clusters Based on Reinforcement Learning
Authors: Xing Bowen , Wang Xiao , Liu Zhenchong
Published: January 2024

This paper proposes a deep reinforcement learning algorithm to achieve complete coverage path planning for deep‐sea mining vehicle clusters. First, the mining vehicles and the deep‐sea mining environment are modeled. Then, this paper implements a series of algorithm designs and optimizations based on Deep Q Networks (DQN). The map fusion mechanism can integrate the grid matrix data from multiple mining vehicles to get the state matrix of the complete environment. In this paper, a preprocessing method for the state matrix is also designed to provide suitable training data for the neural network. The reward function and action selection mechanism of the algorithm are also optimized according to the requirements of cluster cooperative operation. Furthermore, the algorithm uses distance constraints to prevent the entanglement of underwater hoses. To improve the training efficiency of the neural network, the algorithm filters and extracts training samples for training through the sample quality score. Considering the requirement of cluster complete coverage mission, this paper introduces Long Short‐Term Memory (LSTM) based on the neural network to achieve a better training effect. After completing the above optimization and design, the algorithm proposed in this paper is verified through simulation experiments.
Single‐Component Dual‐Functional Autoboost Strategy by Dual Photodynamic and Cyclooxygenase‐2 Inhibition for Lung Cancer and Spinal Metastasis
Authors: Wang Ben , Lu Zhen‐Ni , Song Meng‐Xiong , He Xiao‐Wen , Hu Zhi‐Chao , Liang Hai‐Feng , Lu Hong‐Wei , Chen Qing , Liang Bing , Yi Tao , Wei Peng , Jiang Li‐Bo , Dong Jian
Published: January 2024

Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single‐component dual‐functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)‐generated HOCl. A representative prodrug (DHU‐CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU‐CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU‐CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase‐2 (COX‐2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX‐2. Downstream prostaglandins E2 and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU‐CBA2 promotes infiltration and function of CD8+ T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single‐component dual‐functional prodrug activated by TME‐specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX‐2 inhibitor.
Effect of waterlogging on photosynthesis and growth of finger millet (Eleusine coracana)
Authors: Maai Eri
Published: January 2024

Finger millet (Eleusine coracana (L.) Gaertn.) is an important cereal crop grown in most parts of Asia and Africa owing to its ability to adapt to stressful environments. The objective of this study was to examine the effect of waterlogging on photosynthesis and growth of finger millet. Plants were subjected to waterlogging by keeping pots filled with water from June 16 (transplanting) until November 12 (harvesting) in 2021 in Tokyo. After being subject to 13 days of waterlogging, net photosynthetic rate (Pn) decreased by 10.1% due to reduced stomatal conductance (gs), transpiration rate, and relative chlorophyll content (SPAD). From July to September, long‐term waterlogging increased Pn in the range of 4.9%–26.3%. The alleviation of high temperature, increase in SPAD and gs, and other nonstomatal components were implicated as the cause of increased Pn in summer. These findings suggest that the effect of waterlogging on photosynthesis varies with the duration of waterlogging or the growing season. Plant height was significantly reduced by 27.9% during the first 13 days of waterlogging and remained lower throughout the waterlogging treatment than in irrigated conditions. Waterlogging also caused other morphological changes, such as a significant increase in the number of tillers (63.2%) and a 16.7% increase in the number of panicles. Grain yield decreased by 13.6%, but the reduction was not significant. Overall, finger millet has the potential to tolerate waterlogging and is a promising crop for both paddy and field farming.
Fast‐Moving and Highly Adaptable Hollow Piezoelectric Miniature Robot
Authors: Zhu Binbin , Wang Yan Qing
Published: January 2024

Fast motion and high adaptability are crucial for the practical applications of miniature robots. However, combining these capabilities into a single robot skillfully is challenging, particularly in the domain of miniature structural design. Inspired by the amphibious motion of crocodiles in nature, a hollow piezoelectric miniature robot (HPMR) is proposed. The key benefit of the HPMR is to concurrently output the oscillating motion of the driving foot (oscillating mode) and the rotating motion of the internal rotor (rotating mode). That is, the mode of single‐energy‐input‐multimotion output allows the robot to balance the requirements of speed and adaptability. In the oscillating mode, HPMR can run at speeds of up to 12.3 BL s−1 and realize a displacement resolution of 0.3 μm. Following the conical rotor assembly, the rotor can operate at a speed of 890 rpm, with a displacement resolution of 7.28 mrad. In the rotating mode, the robot demonstrates its multitasking ability in moving amphibiously, carrying loads, running on surfaces with varying roughness, crossing obstacles, and resisting shocks. The results show that the HPMR is capable of fast, high‐resolution moving combined with high adaptability, opening up the possibility of using it for mobile detection tasks in real‐world settings.
Mapping nut‐cracking in a new population of wild capuchin monkeys (Sapajus libidinosus) at Ubajara National Park, Brazil
Authors: Falótico Tiago , Valença Tatiane , Verderane Michele P. , Santana Beatriz C. , Sirianni Giulia
Published: January 2024

Populations of bearded capuchin monkeys (Sapajus libidinosus) vary in their tool use behaviors, with some of this divergence regarded as culturally determined. The use of stone tools, primarily to crack open encased foods, is widespread among bearded capuchins living in dry habitats (Caatinga and Cerrado). Significant diversity in targets, processed foods, material, and size of tools is observed across populations. However, so far, only a few sites have been systematically studied, and we are still distant from a representative picture of the range of variation in capuchins’ culture. In this study, we did a systematic assessment of stone tool use sites in the Ubajara National Park (UNP), in the Caatinga region of Ceará, Brazil, recording and measuring stone tools, processed foods, and available lithic resources as part of an extensive comparative research, the CapCult project. We found indirect and direct evidence that capuchin monkeys at UNP customarily use hammerstones and anvils to process at least two species of palm nuts, macauba (Acrocomia aculeata) and the harder babaçu (Attalea speciosa). Most of the anvils were rock surfaces and had leftovers of only one palm nut species. The hammerstones used to process both palm nuts were not significantly different in weight, although the ones used for Ac. aculeata were longer. We found a higher frequency of nut‐cracking sites in the drier lowland area of the park, reflecting differences in the density of the most common palm species, Ac. aculeata, and availability of raw stone material. The stone tool use observed in UNP is within the scope of previously reported in savannah capuchin populations. Our study widens the knowledge of stone tool‐use diversity in wild capuchin monkeys, which could contribute to shaping conservation policy, including cultural traits.
Regulating Crystallinity Mismatch Between Donor and Acceptor to Improve Exciton/Charge Transport in Efficient Organic Solar Cells
Authors: Liao Xunfan , Liu Mingtao , Pei Hongqiao , Zhu Peipei , Xia Xinxin , Chen Zeng , Zhang Yihan , Wu Zhongyuan , Cui Yongjie , Xu Guodong , Gao Mengyuan , Ye Long , Ma Ruijie , Liu Tao , Lu Xinhui , Zhu Haiming , Chen Yiwang
Published: January 2024

Achieving a more balanced charge transport by morphological control is crucial in reducing bimolecular and trap‐assisted recombination and enhancing the critical parameters for efficient organic solar cells (OSCs). Hence, a facile strategy is proposed to reduce the crystallinity difference between donor and acceptor by incorporating a novel multifunctional liquid crystal small molecule (LCSM) BDTPF4‐C6 into the binary blend. BDTPF4‐C6 is the first LCSM based on a tetrafluorobenzene unit and features a low liquid crystal phase transition temperature and strong self‐assembly ability, conducive to regulating the active layer morphology. When BDTPF4‐C6 is introduced as a guest molecule into the PM6 : Y6 binary, it exhibits better compatibility with the donor PM6 and primarily resides within the PM6 phase because of the similarity‐intermiscibility principle. Moreover, systematic studies revealed that BDTPF4‐C6 could be used as a seeding agent for PM6 to enhance its crystallinity, thereby forming a more balanced and favourable charge transport with suppressed charge recombination. Intriguingly, dual Förster resonance energy transfer was observed between the guest molecule and the host donor and acceptor, resulting in an improved current density. This study demonstrates a facile approach to balance the charge mobilities and offers new insights into boosting the efficiency of single‐junction OSCs beyond 20 %.
Epigenetic Regulatory Axis MIR22‐TET3‐MTRNR2L2 Represses Fibroblast‐Like Synoviocyte–Mediated Inflammation in Rheumatoid Arthritis
Authors: Fang Yilong , Huang Wei , Zhu Xiangling , Wang Xinming , Wu Xuming , Wang Huihui , Hong Wenming , Yan Shangxue , Zhang Lingling , Deng Yujie , Wei Wei , Tu Jiajie , Zhu Chen
Published: January 2024

Objective

The specific role of fibroblast‐like synoviocytes (FLSs) in the pathogenesis of rheumatoid arthritis (RA) is still not fully elucidated. This study aimed to explore the molecular mechanisms of epigenetic pathways, including three epigenetic factors, microRNA (miRNA)‐22 (MIR22), ten‐eleven translocation methylcytosine dioxygenase 3 (TET3), and MT‐RNR2 like 2 (MTRNR2L2), in RA‐FLSs.

Methods

The expression of MIR22, TET3, and MTRNR2L2 in the synovium of patients with RA and arthritic mice were determined by fluorescence in situ hybridization, quantitative polymerase chain reaction (qPCR), immunohistochemistry, and Western blot. Mir22−/− and Tet3+/− mice were used to establish a collagen antibody–induced arthritis (CAIA) model. Mir22 angomir and Tet3 small interfering RNA (siRNA) were used to illustrate the therapeutic effects on arthritis using a collagen‐induced (CIA) model. Bioinformatics, luciferase reporter assay, 5‐hydroxymethylcytosine (5hmC) dot blotting, chromatin immunoprecipitation–qPCR, and hydroxymethylated DNA immunoprecipitation were conducted to show the direct repression of MIR22 on the TET3 and transcriptional activation of TET3 on MTRNR2L2.

Results

The Mir22−/− CAIA model and RA‐FLS–related in vitro experiments demonstrated the inhibitory effect of MIR22 on inflammation. MIR22 can directly inhibit the translation of TET3 in RA‐FLSs by binding to its 3′ untranslated region in TET3. The Tet3+/− mice–established CAIA model showed less severe symptoms of arthritis in vivo. In vitro experiments further confirmed the proinflammatory effect of TET3 in RA. In addition, the CIA model was used to validate the therapeutic effects of Mir22 angomir and Tet3 siRNA. Finally, TET3 exerts its proinflammatory effect by promoting 5hmC production in the promoter of its target MTRNR2L2 in RA‐FLSs.

Conclusion

The key role of the MIR22‐TET3‐MTRNR2L2 pathway in RA‐FLSs provided an experimental basis for further studies into the pathogenesis and related targets of RA from the perspective of FLSs.
Sustainability isomorphism in buyer–supplier relationships: The impact of supply chain leadership
Authors: Ahmadi‐Gh Zahra , Bello‐Pintado Alejandro
Published: January 2024

Within the framework of institutional theory, this study explores how the proactiveness of focal (or buying) manufacturing firms, demonstrated through the adoption of various sustainability practices, influences the sustainability performance of suppliers. Additionally, it examines how the leadership capability of buying firms, particularly in terms of supply chain leadership, can play a crucial role in this link. Through empirical analysis of a sample taken from the fourth round of the High‐Performance Management (HPM) project, our study reveals compelling evidence indicating that buying firms, by adopting diverse sustainability practices, such as internal initiatives, monitoring efforts and collaborative approaches with suppliers, are able to create distinct institutional pressures. These pressures serve as a conduit for the diffusion of a shared set of sustainability goals, values and norms among suppliers, ultimately contributing to the development of sustainability competences and improving their overall sustainability performance. Furthermore, our findings suggest that when buying firms undertake a leading position, they can effectively translate isomorphism pressures into sustainability improvements on the supplier side. Overall, this study sheds light on important and understudied aspects of sustainability practices in buyer–supplier relationships and underscores the critical role that supply chain leadership can play in promoting sustainable practices across the entire supply chain.