Search Results (1,335)

Maturity-onset diabetes of the young (MODY; OMIM # 606391) comprises a cluster of inherited disorders within non-autoimmune diabetes mellitus (DM), typically emerging during adolescence or young adulthood. We report a novel in-frame deletion of HNF1B in a family with renal cysts and MODY, furthering our understanding of HNF1B-related phenotypes. We conducted sequential genetic testing to investigate the glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas observed in the proband. A comprehensive clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Considering the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous HNF1B variant, c.36_38delCCT/p.(Leu13del) (reference transcript ID: NM_000458.4), as the most likely cause of MODY in the proband. The patient’s clinical presentation was consistent with MODY caused by the HNF1B variant, showing signs of glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas. Sanger sequencing confirmed the same HNF1B variant and established the paternally inherited autosomal dominant status of the heterozygous variant in the patient, as well as in his father and sister. The presence of early-onset diabetes, renal cysts, a family history of the condition, and nephropathy appearing before or after the diagnosis of diabetes mellitus (DM) suggests a diagnosis of HNF1B-MODY5. Early diagnosis is crucial for preventing complications of DM, enabling family screening, providing pre-conceptional genetic counseling, and monitoring kidney function decline. Full article

Miniaturized energy storage devices, such as electrostatic nanocapacitors and electrochemical micro-supercapacitors (MSCs), are important components in on-chip energy supply systems, facilitating the development of autonomous microelectronic devices with enhanced performance and efficiency. The performance of the on-chip energy storage devices heavily relies on the electrode materials, necessitating continuous advancements in material design and synthesis. This review provides an overview of recent developments in electrode materials for on-chip MSCs and electrostatic (micro-/nano-) capacitors, focusing on enhancing energy density, power density, and device stability. The review begins by discussing the fundamental requirements for electrode materials in MSCs, including high specific surface area, good conductivity, and excellent electrochemical stability. Subsequently, various categories of electrode materials are evaluated in terms of their charge storage mechanisms, electrochemical performance, and compatibility with on-chip fabrication processes. Furthermore, recent strategies to enhance the performance of electrode materials are discussed, including nanostructuring, doping, heteroatom incorporation, hybridization with other capacitive materials, and electrode configurations. Full article

In this manuscript, a novel presenilin-2 (PSEN2) mutation, Val226Ala, was found in a 59-year-old Korean patient who exhibited rapid progressive memory dysfunction and hallucinations six months prior to her first visit to the hospital. Her Magnetic Resonance Imaging (MRI) showed brain atrophy, and both amyloid positron emission tomography (PET) and multimer detection system-oligomeric amyloid-beta (Aβ) results were positive. The patient was diagnosed with early onset Alzheimer’s disease. The whole-exome analysis revealed a new PSEN2 Val226Ala mutation with heterozygosity in the 5th transmembrane domain of the PSEN2 protein near the lumen region. Analyses of the structural prediction suggested structural changes in the helix, specifically a loss of a hydrogen bond between Val226 and Gln229, which may lead to elevated helix motion. Multiple PSEN2 mutations were reported in PSEN2 transmembrane-5 (TM5), such as Tyr231Cys, Ile235Phe, Ala237Val, Leu238Phe, Leu238Pro, and Met239Thr, highlighting the dynamic importance of the 5th transmembrane domain of PSEN2. Mutations in TM5 may alter the access tunnel of the Aβ substrate in the membrane to the gamma-secretase active site, indicating a possible influence on enzyme function that increases Aβ production. Interestingly, the current patient with the Val226Ala mutation presented with a combination of hallucinations and memory dysfunction. Although the causal mechanisms of hallucinations in AD remain unclear, it is possible that PSEN2 interacts with other disease risk factors, including Notch Receptor 3 (NOTCH3) or Glucosylceramidase Beta-1 (GBA) variants, enhancing the occurrence of hallucinations. In conclusion, the direct or indirect role of PSEN2 Val226Ala in AD onset cannot be ruled out. Full article

The AKT1 oncogene is related to various cancers due to its critical role in the PIC3CA/AKT1 pathway; however, most of the studies screened the hotspot mutation AKT1 (E17K) with various incidences. Low frequency or lack of AKT1 (E17K) mutation was reported in prostate cancer (PC) patients. This study aims to explore genetic alterations in the AKT1 PH domain by extending the sequencing to include AKT1 gene exons 3 and 4. Genomic DNA was extracted from 84 Formalin-Fixed Paraffin-Embedded samples of PC patients in Jordan, and then subjected to PCR and sequencing for the targeted exons. This study revealed the presence of two novel mutations (N53Y and Q59K) and a high frequency of mutations in exon 4, with a lack of mutations in the E17K hotspot. Nine missense and two synonymous mutations were detected in exon 4 (Phe27Tyr, Phe27Leu, Ala58Thr, Ser56Phe, Arg41Trp, Phe35Leu, Asp32Glu, Phe35Tyr, and Gln43Lys) and (Ser56 and Glu40), respectively. Two synonymous mutations were detected in exon 3 (Leu12 and Ser2). It is concluded that there is a high frequency of AKT1 mutation in PC patients in Jordan with two novel missense mutations in the Pleckstrin homology (PH) domain. E17K hotspot mutation was not detected in any tested samples, which underlined the significant role of mutations in other AKT1 exons in PC development. Full article

Hereditary tyrosinemia type I (HT1), or hepatorenal tyrosinemia, is an amino acid disorder which may cause hepatic failure as well as renal and neurologic comorbidities. Early detection of this disorder is possible with newborn screening (NBS). The objective of this study is to describe the clinical, biochemical, and molecular characteristics of Filipino patients diagnosed with HT1 through the expansion of the Philippine NBS program in 2014. There were a total of 16 patients with confirmed HT1 from then until September 2022. Clinical and biochemical data during confirmation and initial evaluation, as well as molecular data, were obtained from the patients’ medical records. The cohort included children between the ages of 18 and 54 months at the time of data collection. The mean age at treatment initiation was 26.8 days. The mean succinylacetone level from dried blood spot sampling using tandem mass spectrometry (MS) was 11.1 µmol/L. Biochemical confirmatory tests via plasma amino acid analysis showed mean levels of tyrosine, phenylalanine, and methionine of 506.1 µmol/L, 111.5 µmol/L, and 125.4 µmol/L, respectively. Upon urine organic acid (UOA) analysis, succinylacetone was detected in all except for one patient, who was managed prior to UOA analysis. The most common clinical characteristics were abnormal clotting times (62.5%), elevated alpha fetoprotein (37.5%), anemia (31.3%), and metabolic acidosis (31.3%). The most common genotype was homozygous c.122T>C p.Leu41Pro in 64.3% of patients. The allelic frequency of this pathogenic variant is 71.4%. The inclusion of HT1 in the Philippine NBS program allowed early diagnosis and management of HT1 patients. Full article

This case report concerns a 48-year-old man with a history of ischemic stroke at the age of 41 who reported cardiac hypertrophy, registered in his twenties when explained by increased physical activity. Family history was positive for a mother with permanent atrial fibrillation from her mid-thirties. At the age of 44, he had a first episode of persistent atrial fibrillation, accompanied by left atrial thrombosis while on a direct oral anticoagulant. He presented at our clinic at the age of 45 with another episode of persistent atrial fibrillation and decompensated heart failure. Echocardiography revealed a dilated left atrium, reduced left ventricular ejection fraction, and an asymmetric left ventricular hypertrophy. Cardiac magnetic resonance was positive for a cardiomyopathy with diffuse fibrosis, while slow-flow phenomenon was present on coronary angiography. Genetic testing by whole-exome sequencing revealed three variants in the patient, c.309C > A, p.His103Gln in the ACTC1 gene, c.116T > G, p.Leu39Ter in the PLN gene, and c.5827C > T, p.His1943Tyr in the SCN5A gene, the first two associated with hypertrophic cardiomyopathy and the latter possibly with familial atrial fibrillation. This case illustrates the need for advanced diagnostics in unexplained left ventricular hypertrophy, as hypertrophic cardiomyopathy is often overlooked, leading to potentially debilitating health consequences. Full article

A miniature nuclear reactor is desirable for deployment as a localized nuclear power station in support of a carbon-free power supply. Coupling aspects of proliferation-resistant fuel with natural burnable absorber loading are evaluated for once-through operation cycle performance to minimize the need for refueling and fuel shuffling operations. The incorporation of 0.075 wt.% ²³⁷Np provides favorable plutonium isotopic vectors throughout an operational lifetime of 5.5 years. providing 35 MWe. Core performance was assessed using a verification-by-comparison approach for core designs with or without ²³⁷Np and/or gadolinia burnable absorber. Burnup Monte Carlo calculations were performed via MCOS coupling of MCNP and ORIGEN to an achievable burnup of ~62.5 GWd/t. The results demonstrate a minimal penalty to reactor performance due to the addition of these materials as compared against the reference design. Coupling of a proliferation-resistant fuel concept with a uniform loading of natural gadolinia burnable absorber for LEU+ fuel (7.5 wt.% ²³⁵U/U UO₂) provides favorable excess reactivity considerations with minimized concerns for additional residual waste and more uniform distribution of un-depleted ²³⁵U in discharged fuel assemblies. Full article

In order to explore the response mechanism of Lilium pumilum (L. pumilum) to saline–alkali stress, we successfully cloned LpGDSL (GDSL lipase, Gly-Asp-Ser-Leu) from L. pumilum. The qRT-PCR results indicated that the LpGDSL expression was higher in the leaves of L. pumilum, and the expression of the LpGDSL reached the highest level at 12 h in leaves under 11 mM H₂O₂, 200 mM NaCl, 25 mM Na₂CO₃, and 20 mM NaHCO₃. The bacteriophage overexpressing LpGDSL was more tolerant than the control under different NaHCO₃ contents. Overexpressed and wild-type plants were analyzed for phenotype, chlorophyll content, O₂⁻ content, H₂O₂ content, lignin content, and so on. Overexpressed plants had significantly higher resistance than the wild type and were less susceptible to saline–alkali stress. The yeast two-hybrid and BiFC assays demonstrated the existence of an interaction between LpGDSL and LpBCP. The yeast one-hybrid assay and transcriptional activation assay confirmed that B3 transcription factors could act on LpGDSL promoters. Under saline–alkali stress, L. pumilum will promote the expression of LpGDSL, which will then promotes the accumulation of lignin and the scavenging of reactive oxygen species (ROS) to reduce its damage, thus improving the saline–alkali resistance of the plant. Full article

Goat milk protein can release a variety of bioactive peptides after digestion, while most of them are digested into free amino acids or dipeptides via the GI tract. We investigated the peptide profiles of goat milk protein following in vitro gastrointestinal digestion using LC-MS/MS and identified 683 bioactive peptides, including 105 DPP-IV inhibitory peptides. Among these peptides, ILDKVGINY (IL), derived from β-lactoglobulin, was found to be high in content and resistance to digestion. Herein, we explore the effect of amino acid residue substitution at the second N-terminus on its DPP-IV inhibitory activity. Three 9 polypeptide fragments (peptide IL, IP, and II) were synthesized and subjected to molecular docking and activity analysis. The peptide IL demonstrated the highest affinity for DPP-IV with a binding energy of −8.4 kcal/mol and a moderate IC50 value of 1.431 mg/mL determined based on the Caco-2 cell model. The replacement of specific amino acid residues by Pro and Leu led to an increase in the hydrophobic force interaction between the inhibitor peptide and DPP-IV. The inhibition rates of the three peptides were significantly different (p < 0.05). Peptide II containing an Ile residue instead of Leu resulted in a significant enhancement of DPP-IV inhibitory activity, with an IC50 value of 0.577 mg/mL. The GRAVY changes in the three peptides were consistent with the trend of the inhibitory rates. Therefore, the GRAVY of peptides and branch-chain amino acids should be considered in its activity improvement. The present study revealed the presence and activity of DPP-IV inhibitory peptides in goat milk, providing important insights for further investigation of their potential food functionality and health benefits. Full article

Over the last decades, the increased incidence of metabolic disorders, such as type two diabetes and obesity, has motivated researchers to investigate new enzyme inhibitors. Inhibition of the α-amylase enzyme is one therapeutic approach in lowering glucose levels in the blood to manage diabetes mellitus. The objective of this study was to synthesize short α-/β-mixed peptides in the solution phase. The Boc-protected α-L-leucine was converted to β-analogue by using Arndt–Eistert synthesis with the advantage of no racemization and retention of configuration. Three novel short peptides were successfully synthesized: N(Boc)-Gly-β-Leu–OCH₃(14), N(Boc)-O(Bz)α-Ser-β-Leu–OCH₃(16), and N(Boc)-O(Bz)-α-Tyr-α-Gly-β-Leu–OCH₃(17), characterized by FTIR and ¹H NMR analysis. The synthesized peptide 16 showed highest inhibitory activity (45.22%) followed by peptide 14 (18.51%) and peptide 17 (17.05%), respectively. Intriguingly, peptide 16 showed higher inhibition on α-amylase compared with other α-/β-mixed peptides. Full article

Amino acid (AA)-related inherited metabolic disorders (IMDs) and urea cycle disorders (UCDs) require strict dietary management including foods low in protein such as fruits, vegetables and starchy roots. Despite this recommendation, there are limited data on the AA content of many of these foods. The aim of this study is to describe an analysis of the protein and AA content of a range of fruits, vegetables and starchy roots, specifically focusing on amino acids (AAs) relevant to AA-related IMDs such as phenylalanine (Phe), methionine (Met), leucine (Leu), lysine (Lys) and tyrosine (Tyr). AA analysis was performed using high-performance liquid chromatography (HPLC) on 165 food samples. Protein analysis was also carried out using the Dumas method. Foods were classified as either ‘Fruits’, ‘Dried fruits’, ‘Cruciferous vegetables’, ‘Legumes’, ‘Other vegetables’ or ‘Starchy roots’. ‘Dried fruits’ and ‘Legumes’ had the highest median values of protein, while ‘Fruits’ and ‘Cruciferous vegetables’ contained the lowest median results. ‘Legumes’ contained the highest and ‘Fruits’ had the lowest median values for all five AAs. Variations were seen in AA content for individual foods. The results presented in this study provide useful data on the protein and AA content of fruits, vegetables and starchy roots which can be used in clinical practice. This further expansion of the current literature will help to improve diet quality and metabolic control among individuals with AA-related IMDs and UCDs. Full article

The proper functioning of neural circuits that integrate sensory signals is essential for individual adaptation to an ever-changing environment. Many molecules can modulate neuronal activity, including neurotransmitters, receptors, and even amino acids. Here, we ask whether amino acid transporters expressed by neurons can influence neuronal activity. We found that minidiscs (mnd), which encodes a light chain of a heterodimeric amino acid transporter, is expressed in different cell types of the adult Drosophila brain: in mushroom body neurons (MBs) and in glial cells. Using live calcium imaging, we found that MND expressed in α/β MB neurons is essential for sensitivity to the L-amino acids: Leu, Ile, Asp, Glu, Lys, Thr, and Arg. We found that the Target Of Rapamycin (TOR) pathway but not the Glutamate Dehydrogenase (GDH) pathway is involved in the Leucine-dependent response of α/β MB neurons. This study strongly supports the key role of MND in regulating MB activity in response to amino acids. Full article

The three 31 nucleotide minihelix tRNA evolution theorem describes the evolution of type I and type II tRNAs to the last nucleotide. In databases, type I and type II tRNA V loops (V for variable) were improperly aligned, but alignment based on the theorem is accurate. Type II tRNA V arms were a 3′-acceptor stem (initially CCGCCGC) ligated to a 5′-acceptor stem (initially GCGGCGG). The type II V arm evolved to form a stem–loop–stem. In Archaea, tRNA^Leu and tRNA^Ser are type II. In Bacteria, tRNA^Leu, tRNA^Ser, and tRNA^Tyr are type II. The trajectory of the type II V arm is determined by the number of unpaired bases just 5′ of the Levitt base (V_max). For Archaea, tRNA^Leu has two unpaired bases, and tRNA^Ser has one unpaired base. For Bacteria, tRNA^Tyr has two unpaired bases, tRNA^Leu has one unpaired base, and tRNA^Ser has zero unpaired bases. Thus, the number of synonymous type II tRNA sets is limited by the possible trajectory set points of the arm. From the analysis of aminoacyl-tRNA synthetase structures, contacts to type II V arms appear to adjust allosteric tension communicated primarily via tRNA to aminoacylating and editing active sites. To enhance allostery, it appears that type II V arm end loop contacts may tend to evolve to V arm stem contacts. Full article

Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP—Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients. Full article

Maize (Zea mays L.) is one of the most demanded grain crops in the world. Currently, production has exceeded one billion tons and is increasing by 3–5% annually. Such growth is due to the genetic potential of the crop and the use of heterosis F1 hybrids in production. However, the need to produce first-generation seed annually poses significant challenges and is an economically costly technology. A solution to this problem may be the transfer of the asexual (apomictic) mode of reproduction to maize from its wild relative, eastern gamagrass (Tripsacum dactyloides L.). In this work, we report the production of 56-chromosome apomictic hybrids of maize (Zea mays L.) with eastern gamagrass (T. dactyloides L.) with restored anther fertility. The mode of reproduction of the plant was confirmed by counting chromosomes and sequencing the nuclear gene (Pox3) and chloroplast tRNA-Leu (trnL) gene. These apomictic hybrids had karyotypes of 2n = 56 = [(10Zm(573MB) + 36Td) + 10Zm(611CB)] and 2n = 56 = [(10Zm(611CB) + 36Td) + 10Zm(611CB)]. The resulting hybrids can be widely used as a fodder crop. Full article