Unraveling the diagnostic odyssey: stimulator of interferon gene-associated vasculopathy with onset in infancy in a 30-year-old female.

Stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy (SAVI) is an extremely rare autoinflammatory disease. We present the case of a female Korean patient with early-onset interstitial lung disease who was initially suspected to have systemic lupus erythematosus (SLE) but was ultimately diagnosed with SAVI. The patient exhibited signs of interstitial lung disease and cutaneous manifestations before the age of 1 year and continued to have recurrent fever accompanied by pulmonary infiltrates. Based on positive findings for antibodies associated with SLE, such as antinuclear antibodies and anti-double-stranded DNA, the pulmonary involvement was considered a manifestation of SLE. Another significant symptom was recurrent skin ulceration, which led to partial spontaneous amputation of most of the toes due to inflammation. Given the early onset of interstitial lung disease, severe skin ulcers, and symptoms resembling SLE, autoinflammatory syndrome, especially SAVI was suspected. Following confirmation by genetic testing at age 29 years, the patient was started on tofacitinib, a Janus kinase inhibitor. Despite the prolonged use of multiple immunosuppressive therapies, the patient's lung condition continued to worsen, ultimately requiring lung transplantation. This observational report highlights the importance of considering SAVI as a potential diagnosis when manifestations of interstitial lung disease are observed during infancy. Early proactive treatment is crucial for lung involvement, as this can have long-term effects on patient's prognosis.

Broadening the scope of multigene panel analysis for adult epilepsy patients.

OBJECTIVE: Epilepsy is a suitable target for gene panel sequencing because a considerable portion of epilepsy is now explained by genetic components, especially in syndromic cases. However, previous gene panel studies on epilepsy have mostly focused on pediatric patients. METHODS: We enrolled adult epilepsy patients meeting any of the following criteria: family history of epilepsy, seizure onset age ≤ 19 years, neuronal migration disorder, and seizure freedom not achieved by dual anti-seizure medications. We sequenced the exonic regions of 211 epilepsy genes in these patients. To confirm the pathogenicity of a novel MTOR truncating variant, we electroporated vectors with different MTOR variants into developing mouse brains. RESULTS: A total of 92 probands and 4 affected relatives were tested, and the proportion of intellectual disability (ID) and/or developmental disability (DD) was 21.7%. As a result, twelve probands (13.0%) had pathogenic or likely pathogenic variants in the following genes or regions: DEPDC5, 15q12-q13 duplication (n = 2), SLC6A1, SYNGAP1, EEF1A2, LGI1, MTOR, KCNQ2, MEF2C, and TSC1 (n = 1). We confirmed the functional impact of a novel truncating mutation in the MTOR gene (c.7570C > T, p.Gln2524Ter) that disrupted neuronal migration in a mouse model. The diagnostic yield was higher in patients with ID/DD or childhood-onset seizures. We also identified additional candidate variants in 20 patients that could be reassessed by further studies. SIGNIFICANCE: Our findings underscore the clinical utility of gene panel sequencing in adult epilepsy patients suspected of having genetic etiology, especially those with ID/DD or early-onset seizures. Gene panel sequencing could not only lead to genetic diagnosis in a substantial portion of adult epilepsy patients but also inform more precise therapeutic decisions based on their genetic background. PLAIN LANGUAGE SUMMARY: This study demonstrated the effectiveness of gene panel sequencing in adults with epilepsy, revealing pathogenic or likely pathogenic variants in 13.0% of patients. Higher diagnostic yields were observed in those with neurodevelopmental disorders or childhood-onset seizures. Additionally, we have shown that expanding genetic studies into adult patients would uncover new types of pathogenic variants for epilepsy, contributing to the advancement of precision medicine for individuals with epilepsy. In conclusion, our results highlight the practical value of employing gene panel sequencing in adult epilepsy patients, particularly when genetic etiology is clinically suspected.

Prevalence and Characterization of NOTCH2NLC GGC Repeat Expansions in Koreans: From a Hospital Cohort Analysis to a Population-Wide Study.

Background and Objectives: GGC repeat expansions in the NOTCH2NLC gene are associated with a broad spectrum of progressive neurologic disorders, notably, neuronal intranuclear inclusion disease (NIID). We aimed to investigate the population-wide prevalence and clinical manifestations of NOTCH2NLC-related disorders in Koreans. Methods: We conducted a study using 2 different cohorts from the Korean population. Patients with available brain MRI scans from Seoul National University Hospital (SNUH) were thoroughly reviewed, and NIID-suspected patients presenting the zigzag edging signs underwent genetic evaluation for NOTCH2NLC repeats by Cas9-mediated nanopore sequencing. In addition, we analyzed whole-genome sequencing data from 3,887 individuals in the Korea Biobank cohort to estimate the distribution of the repeat counts in Koreans and to identify putative patients with expanded alleles and neurologic phenotypes. Results: In the SNUH cohort, among 90 adult-onset leukoencephalopathy patients with unknown etiologies, we found 20 patients with zigzag edging signs. Except for 2 diagnosed with fragile X-associated tremor/ataxia syndrome and 2 with unavailable samples, all 16 patients (17.8%) were diagnosed with NIID (repeat range: 87-217). By analyzing the Korea Biobank cohort, we estimated the distribution of repeat counts and threshold (>64) for Koreans, identifying 6 potential patients with NIID. Furthermore, long-read sequencing enabled the elucidation of transmission and epigenetic patterns of NOTCH2NLC repeats within a family affected by pediatric-onset NIID. Discussion: This study presents the population-wide distribution of NOTCH2NLC repeats and the estimated prevalence of NIID in Koreans, providing valuable insights into the association between repeat counts and disease manifestations in diverse neurologic disorders.

Presynaptic structural and functional plasticity are coupled by convergent Rap1 signaling.

Dynamic presynaptic actin remodeling drives structural and functional plasticity at synapses, but the underlying mechanisms remain largely unknown. Previous work has shown that actin regulation via Rac1 guanine exchange factor (GEF) Vav signaling restrains synaptic growth via bone morphogenetic protein (BMP)-induced receptor macropinocytosis and mediates synaptic potentiation via mobilization of reserve pool vesicles in presynaptic boutons. Here, we find that Gef26/PDZ-GEF and small GTPase Rap1 signaling couples the BMP-induced activation of Abelson kinase to this Vav-mediated macropinocytosis. Moreover, we find that adenylate cyclase Rutabaga (Rut) signaling via exchange protein activated by cAMP (Epac) drives the mobilization of reserve pool vesicles during post-tetanic potentiation (PTP). We discover that Rap1 couples activation of Rut-cAMP-Epac signaling to Vav-mediated synaptic potentiation. These findings indicate that Rap1 acts as an essential, convergent node for Abelson kinase and cAMP signaling to mediate BMP-induced structural plasticity and activity-induced functional plasticity via Vav-dependent regulation of the presynaptic actin cytoskeleton.

Brightening deep-blue perovskite light-emitting diodes: A path to Rec. 2020.

Deep-blue perovskite light-emitting diodes (PeLEDs) of high purity are highly sought after for next-generation displays complying with the Rec. 2020 standard. However, mixed-halide perovskite materials designed for deep-blue emitters are prone to halide vacancies, which readily occur because of the low formation energy of chloride vacancies. This degrades bandgap instability and performance. Here, we propose a chloride vacancy-targeting passivation strategy using sulfonate ligands with different chain lengths. The sulfonate groups have a strong affinity for lead(II) ions, effectively neutralizing vacancies. Our strategy successfully suppressed phase segregation, yielding color-stable deep-blue PeLEDs with an emission peak at 461 nanometers and a maximum luminance (Lmax) of 2707 candela per square meter with external quantum efficiency (EQE) of 3.05%, one of the highest for Rec. 2020 standard-compliant deep-blue PeLEDs. We also observed a notable increase in EQE up to 5.68% at Lmax of 1978 candela per square meter with an emission peak at 461 nanometers by changing the carbon chain length.

Effects of volatile organic compounds and new particle formation on real-time hygroscopicity of PM2.5 particles in Seosan, Republic of Korea.

The hygroscopicity of PM2.5 particles plays an important role in PM2.5 haze in Northeast Asian countries by influencing particle growth and chemical composition. New particle formation (NPF) and atmospheric volatile organic compounds (VOCs) are factors that influence particle hygroscopicity. However, the lack of real-time hygroscopicity measurements has deterred the understanding of their effects on particle hygroscopicity. In this study, two intensive monitoring campaigns were conducted during the summer of 2021 and spring of 2022 using real-time aerosol instruments, including a humidified tandem differential mobility analyzer (HTDMA), in Seosan, Republic of Korea. The hygroscopicity parameter κ was calculated from the real-time HTDMA measurement data (κGf). The diurnal variations in κGf exhibited strong inverse linear correlations with the total concentration of VOCs (CTVOC) during the two campaigns. The higher atmospheric CTVOC in summer increased the growth rate of the particle diameter from 10 to 40 nm (6 nm/h) compared with that in spring (2.7 nm/h), resulting in a faster change in κGf for 40-nm particles in summer than in spring because of the increase in organic matter in the chemical compositions of particles. In addition, NPF events introduced additional tiny fresh particles into the atmosphere, which reduced the κGf of 40-nm particles and increased the intensity of the less hygroscopic peaks (κGf < 0.1) of κ-probability density functions (κ-PDF) in NPF days. However, 100-nm particles exhibited fewer changes in κGf than 40-nm particles, resulting in additional dominant hygroscopic peaks (κ âˆ¼ 0.2) of κ-PDFs in both NPF and non-NPF days. When κGf values measured in Seosan were compared with those in other Northeast Asian countries in the literature, the κ values for 40-nm particles were lower than those (κ > 0.2) measured in Beijing and Guangzhou, but those for 100-nm particles were close to those measured in the two cities.

B-Cell-Mediated Immunity Predicts Survival of Patients With Estrogen Receptor-Positive Breast Cancer.

PURPOSE: The estrogen receptor-positive (ER+) breast cancer (BC), which constitutes the majority of BC cases, exhibits highly heterogeneous clinical behavior. To aid precision treatments, we aimed to find molecular subtypes of ER+ BC representing the tumor microenvironment and prognosis. METHODS: We analyzed RNA-seq data of 113 patients with BC and classified them according to the PAM50 intrinsic subtypes using gene expression profiles. Among them, we further focused on 44 patients with luminal-type (ER+) BC for subclassification. The Cancer Genome Atlas (TCGA) data of patients with BC were used as a validation data set to verify the new classification. We estimated the immune cell composition using CIBERSORT and further analyzed its association with clinical or molecular parameters. RESULTS: Principal component analysis clearly divided the patients into two subgroups separately from the luminal A and B classification. The top differentially expressed genes between the subgroups were distinctly characterized by immunoglobulin and B-cell-related genes. We could also cluster a separate cohort of patients with luminal-type BC from TCGA into two subgroups on the basis of the expression of a B-cell-specific gene set, and patients who were predicted to have high B-cell immune activity had better prognoses than other patients. CONCLUSION: Our transcriptomic approach emphasize a molecular phenotype of B-cell immunity in ER+ BC that may help to predict disease prognosis. Although further researches are required, B-cell immunity for patients with ER+ BC may be helpful for identifying patients who are good responders to chemotherapy or immunotherapy.

Diagnostic uplift through the implementation of short tandem repeat analysis using exome sequencing.

To date, approximately 50 short tandem repeat (STR) disorders have been identified; yet, clinical laboratories rarely conduct STR analysis on exomes. To assess its diagnostic value, we analyzed STRs in 6099 exomes from 2510 families with mostly suspected neurogenetic disorders. We employed ExpansionHunter and REViewer to detect pathogenic repeat expansions, confirming them using orthogonal methods. Genotype-phenotype correlations led to the diagnosis of thirteen individuals in seven previously undiagnosed families, identifying three autosomal dominant disorders: dentatorubral-pallidoluysian atrophy (n = 3), spinocerebellar ataxia type 7 (n = 2), and myotonic dystrophy type 1 (n = 2), resulting in a diagnostic gain of 0.28% (7/2510). Additionally, we found expanded ATXN1 alleles (≥39 repeats) with varying patterns of CAT interruptions in twelve individuals, accounting for approximately 0.19% in the Korean population. Our study underscores the importance of integrating STR analysis into exome sequencing pipeline, broadening the application of exome sequencing for STR assessments.

Synergistic effect of perovskites and nitrogen-doped carbon hybrid materials for improving oxygen reduction reaction.

A fundamental understanding of the electrochemical behavior of hybrid perovskite and nitrogen-doped (N-doped) carbon is essential for the development of perovskite-based electrocatalysts in various sustainable energy device applications. In particular, the selection and modification of suitable carbon support are important for enhancing the oxygen reduction reaction (ORR) of non-platinum group metal electrocatalysts in fuel cells. Herein, we address hybrid materials composed of three representative N-doped carbon supports (BP-2000, Vulcan XC-72 and P-CNF) with valid surface areas and different series of single, double and triple perovskites: Ba0.5Sr0.5Co0.8Fe0.2O3-δ, (Pr0.5Ba0.5)CoO3-δ, and Nd1.5Ba1.5CoFeMnO9-δ (NBCFM), respectively. The combination of NBCFM and N-doped BP-2000 produces a half-wave potential of 0.74 V and a current density of 5.42 mA cm-2 at 0.5 V versus reversible hydrogen electrode, comparable to those of the commercial Pt/C electrocatalyst (0.76 V, 5.21 mA cm-2). Based on physicochemical and electrochemical analyses, we have confirmed a significant improvement in the catalytic performance of low-conductivity perovskite catalyst in the ORR when nitrogen-doped carbon with enhanced electrical conductivity is introduced. Furthermore, it has been observed that nitrogen dopants play active sites, contributing to additional performance enhancement when hybridized with perovskite.

Heuristic Approach to Predict the Performance Degradation of a Solid Oxide Fuel Cell Cathode.

The present work aims to predict the degradation in the performance of a solid oxide fuel cell (SOFC) cathode owing to cation interdiffusion between the electrolyte and cathode and surface segregation. Cation migration in the (La0.60Sr0.40)0.95Co0.20Fe0.80O3-x (LSCF)-Gd0.10Ce0.90O1.95 (GDC) composite cathode is evaluated in relation to time up to 1000 h using scanning transmission electron microscopy (STEM)-energy-dispersive X-ray spectroscopy (EDXS). The resulting insulating phase formed within the GDC interlayer is quantified by means of the volume fraction using a two-dimensional (2D) image analysis technique. For the very first time, the amount of the insulating phase in the GDC interlayer is quantified, and the corresponding performance degradation of the LSCF cathode is predicted. Mathematical relationships are established for the estimation of degradation due to surface segregation of the cathode. The ohmic resistance between the cathode and the GDC interlayer/electrolyte interface and the polarization resistance of the cathode, characterized by electrochemical impedance spectroscopy (EIS), show an excellent match with the predicted results. The combined degradation analysis and modeling for the cathode lifetime prediction provide a systematic understanding of the time-dependent cation migration and segregation behavior.

Expansion of clinico-genetic spectrum of PRDX3 disease: a literature review with two additional cases.

Graphical Abstract.

Epilepsy phenotype and gene ontology analysis of the 129 genes in a large neurodevelopmental disorders cohort.

Objective: Although pediatric epilepsy is an independent disease entity, it is often observed in pediatric neurodevelopmental disorders (NDDs) as a major or minor clinical feature, which might provide diagnostic clues. This study aimed to identify the clinical and genetic characteristics of patients with epilepsy in an NDD cohort and demonstrate the importance of genetic testing. Methods: We retrospectively analyzed the detailed clinical differences of pediatric NDD patients with epilepsy according to their genetic etiology. Among 1,213 patients with NDDs, 477 were genetically diagnosed by exome sequencing, and 168 had epilepsy and causative variants in 129 genes. Causative genes were classified into two groups: (i) the "epilepsy-genes" group resulting in epilepsy as the main phenotype listed in OMIM, Epi25, and ClinGen (67 patients) and (ii) the "NDD-genes" group not included in the "epilepsy-genes" group (101 patients). Results: Patients in the "epilepsy-genes" group started having seizures, often characterized by epilepsy syndrome, at a younger age. However, overall clinical features, including treatment responses and all neurologic manifestations, showed no significant differences between the two groups. Gene ontology analysis revealed the close interactions of epilepsy genes associated with ion channels and neurotransmitters. Conclusion: We demonstrated a similar clinical presentation of different gene groups regarding biological/molecular processes in a large NDDs cohort with epilepsy. Phenotype-driven genetic analysis should cover a broad scope, and further studies are required to elucidate integrated pathomechanisms.

Spatial and PMF analysis of particle size distributions simultaneously measured at four locations at the roadside of highways.

In urban areas, particulate matter emitted from vehicles directly affects the health of citizens near roads. Thus, in this study, particle size distribution was measured by the horizontal and vertical distances along a highway road with heavy traffic to characterize the dispersion phenomena of particulate matter emitted from vehicles. In addition, the contribution of pollution sources was analyzed using a source-receptor model. A concentration gradient was observed in which the concentration decreased with the increase in the distance from the road when the wind blew from the road to the monitoring locations. The concentration was slightly higher within 50 m of the road when the wind blows parallel to the road, and similar concentrations were found at the other monitoring locations further away from the roads. In particular, the higher the turbulence intensity of the wind, the lower is the concentration gradient coefficient because of the more enhanced mixing and dispersion. A positive matrix factorization (PMF) model with the measured particle size distribution data in the range of 9-300 nm resulted in a contribution of about 70 % (number) and 20 % (mass) to particle concentrations because of six types of vehicles including LPG, two gasoline vehicles (GDI, MPI), and three diesel vehicles with 3rd, 4th, and 5th emission classes. It showed a decrease in the vehicular contribution as the distance from the road increased. Particle number concentrations decreased with increasing altitude up to 30 m above the ground. The results of this study can be useful in deriving generalized gradient equations of particle concentrations exposed by distance and wind direction at the roadside using traffic and meteorological conditions and for establishing environmental policies, such as roadside exposure assessment, in the future. A CAPSULE ABSTRACT: Dispersion of particles emitted from vehicles on a busy highway was characterized by roadside measurements of horizontal and vertical profiles of particle size distributions measured at four locations. The source profiles and contributions were estimated by major sources using a source-receptor model such as PMF.

Isolated Oculomotor Nerve Palsy After Temporoparietal Lobar Hemorrhage With a Mass Effect: A Case Report.

We report a case of a patient who presented with ipsilateral oculomotor nerve palsy after a spontaneous left temporoparietal lobar hemorrhage with mass effect. Primary symptomatology included ipsilateral ptosis, dilated fixed pupil, and a lack of superior and medial movement with limited inferior left eye movements. Brain imaging revealed compression of the left upper midbrain due to subtentorial herniation of the hemorrhage, and susceptibility-weighted images sequences showed cerebral microbleed in the left midbrain substantia nigra. Based on our observation from this case, physicians should consider temporoparietal lobar hemorrhage with mass effect as an attributable factor in the etiologic cause of ipsilateral oculomotor nerve palsy.

Temporal variations of volatile organic compounds inside the cabin of a new electric vehicle under different operation modes during winter using proton transfer reaction time-of-flight mass spectrometry.

Transportation is globally becoming more vehicle-dependent as public awareness towards the health risks caused by cabin-emitted volatile organic compounds (VOCs) increases. Therefore, the need for quantifying their concentration increases as well. This study measured the real-time VOCs in a new mini-truck-type electric vehicle cabin using a proton transfer reaction time-of-flight mass spectrometry under varying cabin heating conditions during winter. A total of 246 ions were detected between m/z 30 and 250, 82 of which were quantified. The total ion count in the cabin was double that of the ambient air. Morning-to-noon concentration of total VOCs increased 2.5 times in the cabin under solar exposure (164.47-405.92 µg·m-3). Additionally, 12 VOCs that either had higher indoor-to-outdoor ratios or globally regulated chosen to investigate the effects of cabin air conditions. Heater operation immediately increased concentrations of some VOCs by 54.62%. Furthermore, blocking solar exposure from windows reduced VOC emissions during heater off and on scenarios by 35.49% and 65.42%, respectively, indicating that window coverage also provided insulation against heat loss. Finally, the fresh air reduced cabin VOCs by 62.83% due to ambient air inflow. However, cabin concentrations remained higher than those of ambient air.

Prevalence and founder effect of DRC1 exon 1-4 deletion in Korean patients with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder affecting ciliary structure and function. PCD exhibiting dynein regulatory complex subunit 1 (DRC1) exon 1-4 deletion has been reported in several Japanese PCD patients; however, no large scale studies have been performed. Here, we aimed to determine the prevalence and founder effect of this variant in the Korean population. Using an in-house copy number variation tool, we screened for DRC1 exon 1-4 deletion in 20 patients with PCD and exome data of 1435 patients in the Seoul National University Hospital repository. In cases of suspected DRC1 deletion, confirmatory gap-PCR was performed. In a PCD cohort, three of 20 (15%) patients were positive for DRC1 exon 1-4 deletion (NM_145038.5(DRC1): c.1-3952_540 + 1331del27748-bp) while pathogenic variants were found in CCDC39 (N = 1), DNAAF6 (N = 1), DNAH9 (N = 1). In the 1,435-sample exome data, seven patients (0.49%) were confirmed to have DRC1 exon 1-4 deletion. A chimeric sequence including the junction was searched from the 1000 Genomes Project data repository. One Japanese patient (0.96%) was found to have the same DRC1 exon 1-4 deletion, which was absent in other populations. This study demonstrated that the DRC1 exon 1-4 deletion is a founder mutation based on haplotype analysis. In summary, the prevalence of PCD based on DRC1 exon 1-4 deletion is particularly high in Korean and Japanese populations, which is attributed to the founder effect. Genetic testing for DRC1 exon 1-4 deletion should be considered as an initial screening tool for Korean and Japanese patients with PCD.

A multicomponent equimolar proton-conducting quadruple hexagonal perovskite-related oxide system.

Since the high configurational entropy-driven structural stability of multicomponent oxide system was proposed Rost et al. in 2015, many experiments and simulations have been done to develop new multicomponent oxides. Although many notable findings have shown unique physical and chemical properties, high configurational entropy oxide systems that have more than 3 distinct cation sites are yet to be developed. By utilizing atomic-scale direct imaging with scanning transmission electron microscopy and AC-impedance spectroscopy analysis, we demonstrated for the first time that a multicomponent equimolar proton-conducting quadruple hexagonal perovskite-related Ba5RE2Al2ZrO13 (RE = rare earth elements) oxide system can be synthesized even when adding eight different rare earth elements. In particular, as the number of added elements was increased, i.e., as the configurational entropy was increased, we confirmed that the chemical stability toward CO2 was improved without a significant decrement of the proton conductivity. The findings in this work broaden the use of the crystal structure to which the multicomponent model can be applied, and a systematic study on the correlation between the configurational entropy and proton conductivity and/or chemical stability is noteworthy.