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Medicine Jun 2024Fahr syndrome is a rare, degenerative neurological condition characterized by bilateral idiopathic calcification of the periventricular region, especially the basal...
RATIONALE
Fahr syndrome is a rare, degenerative neurological condition characterized by bilateral idiopathic calcification of the periventricular region, especially the basal ganglia. This condition is often misdiagnosed as other neurological or psychiatric disorders due to its rarity and overlapping symptoms.
PATIENT CONCERNS
A 34-year-old man had been experiencing seizures and cognitive dysfunction for few years, which were further compounded by slurred speech and motor difficulties as acute conditions.
DIAGNOSIS
After investigations, severe hypocalcemia, and hypoparathyroidism were detected and his brain computed tomography showed extensive bilateral calcifications in basal ganglia, thalamus, dentate nuclei, and some parts of subcortical white matter, suggestive of Fahr syndrome. Although, the patient was initially misdiagnosed due to a lack of information and the rarity of this disease.
INTERVENTION
The patient was treated with intravenous calcium gluconate, vitamin D3, l-ornithine l-aspartate syrup, and levetiracetam, replacing carbamazepine.
OUTCOME
His symptoms, including slurred speech, muscle pain, and stiffness improved, serum calcium normalized, and he was discharged with medications for memory deficit and depression.
LESSONS
This case underscores the importance of raising awareness among physicians, especially in areas with limited medical resources, about the significance of prompt diagnosis and appropriate symptomatic treatment in enhancing patient prognosis and quality of life.
Topics: Humans; Male; Adult; Seizures; Cognitive Dysfunction; Calcinosis; Afghanistan; Basal Ganglia Diseases; Hypoparathyroidism; Hypocalcemia; Tomography, X-Ray Computed; Neurodegenerative Diseases
PubMed: 38905413
DOI: 10.1097/MD.0000000000038542 -
Applied and Environmental Microbiology Jun 2024uses allantoin as the sole nitrogen source during anaerobic growth. In the final step of allantoin degradation, oxamic transcarbamylase (OXTCase) converts oxalurate to...
uses allantoin as the sole nitrogen source during anaerobic growth. In the final step of allantoin degradation, oxamic transcarbamylase (OXTCase) converts oxalurate to carbamoyl phosphate (CP) and oxamate. The activity of this enzyme was first measured in in the 1960s, but no OXTCase enzyme or the encoding gene(s) have been found in any strain. This study discovered that (, , and ) are the genes that encode the global orphan enzyme OXTCase. The three genes form an operon together with (), encoding catabolic carbamate kinase. The operon is located directly downstream of the operon that encodes enzymes for the preceding steps of OXTCase. The OXTCase kinetic parameters were analyzed using the purified protein composed of AllF-AllG-AllH (FdrA-YlbE-YlbF); for the substrate CP, and were 1.3 mM and 15.4 U/mg OXTCase, respectively, and for the substrate oxamate, they were 36.9 mM and 27.0 U/mg OXTCase. In addition, the OXTCase encoded by the three genes is a novel transcarbamylase that shows no similarity with known enzymes of the transcarbamylase family such as aspartate transcarbamylase, ornithine transcarbamylase, and YgeW transcarbamylase. The present study elucidated the anaerobic allantoin degradation pathway of . Therefore, we suggest that the genes , , and are renamed , , and , respectively.IMPORTANCEThe anaerobic allantoin degradation pathway of includes a global orphan enzyme, oxamic transcarbamylase (OXTCase), which converts oxalurate to carbamoyl phosphate and oxamate. This study found that the (, , and ) genes encode OXTCase. The OXTCase activity and kinetics were successfully determined with purified recombinant AllF-AllG-AllH (FdrA-YlbE-YlbF). This OXTCase is a novel transcarbamylase that shows no similarity with known enzymes of the transcarbamylase family such as aspartate transcarbamylase (ATCase), ornithine transcarbamylase (OTCase), and YgeW transcarbamylase (YTCase). In addition, OXTCase activity requires three genes, whereas ATCase is encoded by two genes, and OTCase and YTCase are encoded by a single gene. The current study discovered OXTCase, the last unknown step in allantoin degradation, and this enzyme is a new member of the transcarbamylase group that was previously unknown.
PubMed: 38888336
DOI: 10.1128/aem.00957-24 -
L-arginine loading porous PEEK promotes percutaneous tissue repair through macrophage orchestration.Bioactive Materials Oct 2024Infection and poor tissue repair are the key causes of percutaneous implantation failure. However, there is a lack of effective strategies to cope with due to its high...
Infection and poor tissue repair are the key causes of percutaneous implantation failure. However, there is a lack of effective strategies to cope with due to its high requirements of sterilization, soft tissue healing, and osseointegration. In this work, l-arginine (L-Arg) was loaded onto a sulfonated polyetheretherketone (PEEK) surface to solve this issue. Under the infection condition, nitric oxide (NO) and reactive oxygen species (ROS) are produced through catalyzing L-Arg by inducible nitric oxide synthase (iNOS) and thus play a role in bacteria sterilization. Under the tissue repair condition, L-Arg is catalyzed to ornithine by Arginase-1 (Arg-1), which promotes the proliferation and collagen secretion of L929 and rBMSCs. Notably, L-Arg loading samples could polarize macrophages to M1 and M2 in infection and tissue repair conditions, respectively. The results show that the L-Arg loading samples could enhance infected soft tissue sealing and bone regeneration. In summary, L-Arg loading sulfonated PEEK could polarize macrophage through metabolic reprogramming, providing multi-functions of antibacterial abilities, soft tissue repair, and bone regeneration, which gives a new idea to design percutaneous implantation materials.
PubMed: 38882001
DOI: 10.1016/j.bioactmat.2024.05.025 -
The Journal of Biological Chemistry Jun 2024Glucoselysine (GL) is a unique advanced glycation end-product derived from fructose. The main source of fructose in vivo is the polyol pathway, and an increase in its...
Glucoselysine (GL) is a unique advanced glycation end-product derived from fructose. The main source of fructose in vivo is the polyol pathway, and an increase in its activity leads to diabetic complications. Here, we aimed to demonstrate that GL can serve as an indicator of the polyol pathway activity. Additionally, we propose a novel approach for detecting GL in peripheral blood samples using LC-MS/MS and evaluate its clinical usefulness. We successfully circumvent interference from fructoselysine, which shares the same molecular weight as GL, by performing ultrafiltration and hydrolysis without reduction, successfully generating adequate peaks for quantification in serum. Furthermore, using immortalized aldose reductase knockout mouse Schwann cells, we demonstrate that GL reflects the downstream activity of the polyol pathway and that GL produced intracellularly is released into the extracellular space. Clinical studies reveal that GL levels in patients with type 2 diabetes are significantly higher than those in healthy participants, while N-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1) levels are significantly lower. Both GL and MG-H1 show higher values among patients with vascular complications; however, GL varies more markedly than MG-H1 as well as hemoglobin A1c, fasting plasma glucose, and estimated glomerular filtration rate. Furthermore, GL remains consistently stable under various existing drug treatments for type 2 diabetes, whereas MG-H1 is impacted. To the best of our knowledge, we provide important insights in predicting diabetic complications caused by enhanced polyol pathway activity via assessment of GL levels in peripheral blood samples from patients.
PubMed: 38879006
DOI: 10.1016/j.jbc.2024.107479 -
Gut Microbes 2024Metformin is widely used for treating type 2 diabetes mellitus (T2D). However, the efficacy of metformin monotherapy is highly variable within the human population....
Metformin is widely used for treating type 2 diabetes mellitus (T2D). However, the efficacy of metformin monotherapy is highly variable within the human population. Understanding the potential indirect or synergistic effects of metformin on gut microbiota composition and encoded functions could potentially offer new insights into predicting treatment efficacy and designing more personalized treatments in the future. We combined targeted metabolomics and metagenomic profiling of gut microbiomes in newly diagnosed T2D patients before and after metformin therapy to identify potential pre-treatment biomarkers and functional signatures for metformin efficacy and induced changes in metformin therapy responders. Our sequencing data were largely corroborated by our metabolic profiling and identified that pre-treatment enrichment of gut microbial functions encoding purine degradation and glutamate biosynthesis was associated with good therapy response. Furthermore, we identified changes in glutamine-associated amino acid (arginine, ornithine, putrescine) metabolism that characterize differences in metformin efficacy before and after the therapy. Moreover, metformin Responders' microbiota displayed a shifted balance between bacterial lipidA synthesis and degradation as well as alterations in glutamate-dependent metabolism of N-acetyl-galactosamine and its derivatives (e.g. CMP-pseudaminate) which suggest potential modulation of bacterial cell walls and human gut barrier, thus mediating changes in microbiome composition. Together, our data suggest that glutamine and associated amino acid metabolism as well as purine degradation products may potentially condition metformin activity via its multiple effects on microbiome functional composition and therefore serve as important biomarkers for predicting metformin efficacy.
Topics: Humans; Metformin; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Amino Acids; Male; Middle Aged; Female; Purines; Bacteria; Biomarkers; Hypoglycemic Agents; Aged; Adult; Treatment Outcome; Metabolomics
PubMed: 38868903
DOI: 10.1080/19490976.2024.2361491 -
Frontiers in Genetics 2024Inborn errors of metabolism (IEMs) are uncommon. Although some studies have explored the distribution and characteristics of IEMs in newborns, the impact of these...
Inborn errors of metabolism (IEMs) are uncommon. Although some studies have explored the distribution and characteristics of IEMs in newborns, the impact of these disorders on hospitalized newborns remains unclear. In this study, we gathered data from 21,840 newborn patients admitted for various medical conditions at the Children's Hospital of Chongqing Medical University from January 2017 and December 2022. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography-mass spectrometry (GC-MS/MS), and genetic analysis were used to elucidate the disease spectrum, incidence rate, and genetic characteristics of IEMs in hospitalized newborns. The results revealed that the incidence of IEMs in hospitalized newborns was 1/377 (58/21,840), with a higher incidence in full-term infants (1/428) than in premature infants (1/3,120). Among the diagnosed genetic metabolic diseases, organic acid metabolism disorders (1/662), amino acid metabolism disorders (1/950), and fatty acid oxidation disorders (1/10,920) were the most prevalent. Methylmalonic acidemia (MMA), especially the isolated form, emerged as the most common IEM, while neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and ornithine transcarbamylase deficiency (OTCD) were prevalent in premature infants. Of the 58 confirmed cases of IEMs, 72 variants were identified, of which 31.94% (23/72) had not been reported previously. This study contributes to understanding the incidence and clinical features of IEMs in hospitalized newborns, offering more efficient strategies for screening and diagnosing these disorders.
PubMed: 38863445
DOI: 10.3389/fgene.2024.1395988 -
BioRxiv : the Preprint Server For... Jun 2024Tau protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia (FTD) and progressive supranuclear...
Tau protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP), spurring development of tau-lowering therapeutic strategies. Here, we report fully human bifunctional anti-tau-PEST intrabodies that bind the mid-domain of tau to block aggregation and degrade tau via the proteasome using the ornithine decarboxylase (ODC) PEST degron. They effectively reduced tau protein in human iPSC-derived cortical neurons in 2D cultures and 3D organoids, including those with the disease-associated tau mutations R5L, N279K, R406W, and V337M. Anti-tau-hPEST intrabodies facilitated efficient ubiquitin-independent proteolysis, in contrast to tau-lowering approaches that rely on the cell's ubiquitination system. Importantly, they counteracted the proteasome impairment observed in V337M patient-derived cortical neurons and significantly improved neuronal survival. By serial mutagenesis, we created variants of the PEST degron that achieved graded levels of tau reduction. Moderate reduction was as effective as high reduction against tau V337M-induced neural cell death.
PubMed: 38854137
DOI: 10.1101/2024.05.28.596248 -
BioRxiv : the Preprint Server For... May 2024Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic...
Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate the metabolic consequences of uniporter loss- and gain-of-function, and identify a key transcriptional regulator that mediates these effects. Using gene expression profiling and proteomic, we find that loss of uniporter function increases the expression of proteins in the branched-chain amino acid (BCAA) catabolism pathway. Activity is further augmented through phosphorylation of the enzyme that catalyzes this pathway's committed step. Conversely, in the liver cancer fibrolamellar carcinoma (FLC)-which we demonstrate to have high mitochondrial calcium levels- expression of BCAA catabolism enzymes is suppressed. We also observe uniporter-dependent suppression of the transcription factor KLF15, a master regulator of liver metabolic gene expression, including those involved in BCAA catabolism. Notably, loss of uniporter activity upregulates KLF15, along with its transcriptional target ornithine transcarbamylase (OTC), a component of the urea cycle, suggesting that uniporter hyperactivation may contribute to the hyperammonemia observed in FLC patients. Collectively, we establish that FLC has increased mitochondrial calcium levels, and identify an important role for mitochondrial calcium signaling in metabolic adaptation through the transcriptional regulation of metabolism.
PubMed: 38853984
DOI: 10.1101/2024.05.27.596106 -
BioRxiv : the Preprint Server For... May 2024is a commensal bacterium in the gastrointestinal tract (GIT) of humans and other organisms. also causes infections in root canals, wounds, the urinary tract, and on...
is a commensal bacterium in the gastrointestinal tract (GIT) of humans and other organisms. also causes infections in root canals, wounds, the urinary tract, and on heart valves. metabolizes arginine through the arginine deiminase (ADI) pathway, which converts arginine to ornithine and releases ATP, ammonia, and CO. arginine metabolism also affects virulence of other pathogens during co-culture. may encounter elevated levels of arginine in the GIT or the oral cavity, where arginine is used as a dental therapeutic. Little is known about how responds to growth in arginine in the absence of other bacteria. To address this, we used RNAseq and additional assays to measure growth, gene expression, and biofilm formation in OG1RF grown in arginine. We demonstrate that arginine decreases biofilm production and causes widespread differential expression of genes related to metabolism, quorum sensing, and polysaccharide synthesis. Growth in arginine also increases aggregation of and promotes decreased susceptibility to the antibiotics ampicillin and ceftriaxone. This work provides a platform for understanding of how the presence of arginine in biological niches affects physiology and virulence of surrounding microbes.
PubMed: 38853917
DOI: 10.1101/2024.05.30.596650 -
Food Chemistry May 2024White tea stored for various times have different flavors. However, the mechanism of flavor conversion remains elusive. Flavonoids and amino acids are two typical flavor...
White tea stored for various times have different flavors. However, the mechanism of flavor conversion remains elusive. Flavonoids and amino acids are two typical flavor components in tea. Herein, the contents of 46 flavonoids and 40 amino acids were measured in white tea (Shoumei) stored for 1, 3, 5 and 7 years, respectively. L-tryptophan, L-ornithine and L-theanine contribute to the refreshing taste of Shoumei 1 and 3. Quercetin, rutin and hesperidin contribute to aging charm and grain aroma of Shoumei 5 and 7. 306 bacterial OTUs and 268 fungal OTUs core microbiota existed in all samples. Interestingly, white teas contained higher richness of fungi than bacteria. The correlation analysis showed that the cooperation with bacteria and fungi may result in the flavonoids and amino acids composition changes in white teas during storage. Overall, this study provides new insights into flavor conversion of white tea during storage.
PubMed: 38843719
DOI: 10.1016/j.foodchem.2024.139932