Brain hypothyroidism silences the immune response of microglia in Alzheimer's disease animal model.

Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimer's disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-ß. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5'-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-ß, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

The effect of complex posttraumatic stress and poverty on quality of life among adult survivors of childhood institutional maltreatment: evidence from survivors of the 'Hyeongje Welfare Institution' in South Korea.

Background: Childhood institutional maltreatment (IM) is associated with both complex posttraumatic stress disorder (CTPSD) and poverty in adulthood life, each of which may impact an individual's quality of life (QoL). To find implications for clinical practice and policy making for adult survivors with childhood IM experiences, it is necessary to conduct research examining their current QoL and identifying related factors.Objective: By applying the model of the conservation of resources theory, we focused on how adulthood QoL can be indicated by childhood IM as well as the life outcomes of IM such as additional lifetime trauma, CPTSD, and poverty.Methods: In a cross-sectional study, self-report data were collected from 127 adults who were survivors of the 'Hyeongje' childhood IM in South Korea. We conducted regression analyses of childhood IM experiences, trauma experiences after escape from the institution, current CPTSD symptoms, and current poverty experiences on current QoL.Results: The duration of placement at the 'Hyeongje' (ß = .24, p = .009) was associated with trauma experiences after escape from the institution. Trauma experiences after escape from the institution (ß = .25, p = .007) were associated with CPTSD symptoms. CPTSD symptoms (ß = .26, p = .005) were associated with poverty, and both CPTSD symptoms (ß = -.52, p < .001) and poverty (ß = -.26, p = .003) were negatively associated with current QoL.Conclusions: Prolonged childhood IM brings about loss spirals by increasing an individual's exposure to experiences of further cumulative trauma, CPTSD, and poverty. There is a need for due diligence-based policy making and public support from the government to help create upward spirals for QoL. This may include the imminent detection and rescue of children as well as providing a safe environment, offering multidisciplinary interventions including evidence-based treatment for CPTSD, and considering economic support including collective reparations.

Duration of placement at the 'Hyeongje' institution was associated with additional trauma experience after escaping the institution.Cumulative trauma after escape was associated with CPTSD symptoms; CPTSD symptoms were associated with poverty; and both CPTSD symptoms and poverty were associated with poor current QoL.Multidisciplinary interventions including evidence-based treatment for CPTSD and considering economic resources for childhood IM survivors would be crucial in increasing QoL.

Effects of Social Acknowledgment and Interpersonal Shame on Complex Posttraumatic Stress Disorder Symptoms of Sexual Violence Survivors in South Korea.

Sexual violence (SV) survivors face negative social reactions, which can affect their recovery. Based on the socio-interpersonal model of trauma, understanding how societal circumstances impact SV survivors' mental health is important. This study examined conditional indirect effects of interpersonal shame and social acknowledgment on the relationship between perceived SV event severity and complex post-traumatic stress disorder (CPTSD) symptoms. Cross-sectional data from 157 community-based adults who had previously experienced SV were collected from an online panel. Exploratory factor analysis of the Social Acknowledgment Questionnaire was conducted, followed by conditional indirect analyses using Models 1, 4, and 7 of PROCESS macro. First, results showed that a two-factor model of social acknowledgment consisting of "social disapproval" and "social recognition" was more suitable for this study than a three-factor model predominantly used by Western societies. Second, interpersonal shame partially mediated the relationship between perceived SV event severity and CPTSD symptoms. Third, the conditional indirect effect of social disapproval on the mediating effect of interpersonal shame was significant when the social disapproval level was high. This indicates that the indirect effect of interpersonal shame on CPTSD increases when the social disapproval level is high. This study supported the socio-interpersonal perspective of trauma and suggested that increasing social acknowledgment beyond personal-level intervention would be a critical step for recovery of SV survivors to decrease their interpersonal shame and CPTSD.

ICD-11 complex posttraumatic stress disorder and subclasses of borderline personality disorder in a South Korean adult population with childhood abuse experiences: a latent class analysis.

BACKGROUND: Complex posttraumatic stress disorder (CPTSD) and borderline personality disorder (BPD), which are distinctive diagnoses, share the common risk factor of childhood abuse experiences. However, additional evidence is needed to determine which factors contribute to the manifestation of different symptoms. METHOD: Participants were 499 South Korean early and midlife adults with primarily college level education who reported experiences of childhood abuse. They were enrolled from an online panel using a stratified sampling considering gender, age, and residence information. A latent class analysis (LCA) was conducted to identify the patterns of CPTSD and BPD symptoms. We adopted a three-step LCA to compare types of childhood abuse, invalidating environments, attachment styles, and pathological personality traits among different classes. RESULTS: The LCA revealed four classes. Class 1 showed the highest scores in all symptoms and risk factors. Class 2 was distinguished from Class 3 by the externalizing versus internalizing associated pathological personality traits. Class 3 experienced high emotional neglect in addition to other types of abuse and it also showed an additional avoidant attachment style. Class 4 showed low symptomatology. CONCLUSION: Class 1 was named as a CPTSD and BPD "comorbid" class, Class 2 as an "externalizing BPD" class, Class 3 as an "avoidant BPD" class, and Class 4 as a "low symptom" class. Childhood abuse may heighten the risk for high comorbidity of CPTSD and BPD as well as externalizing-internalizing subgroups of BPD. Beyond the identification of CPTSD and BPD, assessing attachment styles and pathological personality traits based on dimensional approaches would benefit the tailoring of effective treatment.

Functional effects of gut microbiota-derived metabolites in Alzheimer's disease.

The precise causation of Alzheimer's disease (AD) is unknown, and the factors that contribute to its etiology are highly complicated. Numerous research has been conducted to investigate the potential impact of various factors to the risk of AD development or prevention against it. A growing body of evidence suggests to the importance of the gut microbiota-brain axis in the modulation of AD, which is characterized by altered gut microbiota composition. These changes can alter the production of microbial-derived metabolites, which may play a detrimental role in disease progression by being involved in cognitive decline, neurodegeneration, neuroinflammation, and accumulation of Aß and tau. The focus of this review is on the relationship between the key metabolic products of the gut microbiota and AD pathogenesis in the brain. Understanding the action of microbial metabolites can open up new avenues for the development of AD treatment targets.

Whole-Genome Sequence Analysis of Candida glabrata Isolates from a Patient with Persistent Fungemia and Determination of the Molecular Mechanisms of Multidrug Resistance.

Whole-genome sequencing (WGS) was used to determine the molecular mechanisms of multidrug resistance for 10 serial Candida glabrata bloodstream isolates obtained from a neutropenic patient during 82 days of amphotericin B (AMB) or echinocandin therapy. For WGS, a library was prepared and sequenced using a Nextera DNA Flex Kit (Illumina) and the MiseqDx (Illumina) instrument. All isolates harbored the same Msh2p substitution, V239L, associated with multilocus sequence type 7 and a Pdr1p substitution, L825P, that caused azole resistance. Of six isolates with increased AMB MICs (≥2 mg/L), three harboring the Erg6p A158fs mutation had AMB MICs ≥ 8 mg/L, and three harboring the Erg6p R314K, Erg3p G236D, or Erg3p F226fs mutation had AMB MICs of 2-3 mg/L. Four isolates harboring the Erg6p A158fs or R314K mutation had fluconazole MICs of 4-8 mg/L while the remaining six had fluconazole MICs ≥ 256 mg/L. Two isolates with micafungin MICs > 8 mg/L harbored Fks2p (I661_L662insF) and Fks1p (C499fs) mutations, while six isolates with micafungin MICs of 0.25-2 mg/L harbored an Fks2p K1357E substitution. Using WGS, we detected novel mechanisms of AMB and echinocandin resistance; we explored mechanisms that may explain the complex relationship between AMB and azole resistance.

Evaluation of the Accuracy of Cr and BUN Using the ABL90 FLEX PLUS Blood Gas Analyzer and the Equivalence of Candidate Specimens for Assessment of Renal Function.

BACKGROUND: The ABL90 FLEX PLUS (Radiometer) is a blood gas analyzer that also provides creatinine (Cr) and blood urea nitrogen (BUN) results. We assessed the accuracy of the ABL90 FLEX PLUS to measure Cr and BUN and find suitable candidate specimens against primary specimens (heparinized whole-blood (H-WB)). METHODS: Paired H-WB, serum, and sodium-citrated whole-blood (C-WB) samples (105) were collected. The Cr and BUN levels in the H-WB using the ABL90 FLEX PLUS were compared with those of the serum using four automated chemistry analyzers. The suitability of the candidate specimens was assessed at each medical decision level according to the CLSI guideline EP35-ED1. RESULTS: The respective mean differences of the ABL90 FLEX PLUS for the Cr and BUN were below -0.10 and -3.51 mg/dL compared to the other analyzers. The systematic differences between the serum and the H-WB at the low, medium, and high medical decision levels were all 0% for Cr, but those of the C-WB were -12.96%, -11.81%, and -11.30%, respectively. Regarding imprecision, the SDserum/SDH-WB ratios at each level were 0.14, 1.41, and 0.68, whereas the SDC-WB/SDH-WB ratios were 0.35, 2.00, and 0.73, respectively. CONCLUSIONS: The ABL90 FLEX PLUS provided Cr and BUN results comparable with the four widely used analyzers. Among the candidates, the serum was suitable for Cr testing using the ABL90 FLEX PLUS, while the C-WB did not satisfy the acceptance criteria.

Validation and application of new NGS-based HLA genotyping to clinical diagnostic practice.

Next-generation sequencing (NGS) has revolutionized clinical genotyping, providing high-resolution HLA genotyping with a low ambiguity rate. This study aimed to develop new NGS-based HLA genotyping (HLAaccuTest, NGeneBio, Seoul, KOREA) on the Illumina MiSeq platform and validate the clinical performance. The analytical performance of HLAaccuTest was validated for 11 loci comprising HLA-A, -B, -C, -DRB1/3/4/5, -DQA1, -DQB1, -DPA1, and -DPB1 using 157 reference samples. Among the 345 clinical samples, 180 were tested for performance evaluation and protocol optimization, and 165 were used in clinical trials in the validation phase for five loci, including HLA-A, -B, -C, -DRB1, and -DQB1. In addition, the improvement in the resolution of ambiguous alleles was also evaluated and compared with other NGS-based HLA genotyping for 18 reference samples, including five overlapping samples in analytical performance validation. All reference materials produced 100% concordant results for 11 HLA loci, 96.9% (2092 of 2160 HLA alleles) of the clinical samples were matched with the SBT results in the pre-validation phase. After the optimization phase, the clinical trials in the validation phase showed 99.7% (1645/1650 alleles) concordance with the complete resolution for 34 ambiguity results. The retesting of five discordant cases resolved all issues and yielded 100% concordant results with the SBT method. Additionally, for ambiguity using 18 reference materials with ambiguous alleles, about 30% of ambiguous alleles were more resolved than Trusight HLA v2. HLAaccuTest was successfully validated using a large volume of clinical samples and is fully applicable to the clinical laboratory.

Factor Structure and Clinical Correlates of The Dissociative Symptoms Scale (DSS) Korean Version Among Community Sample With Adverse Childhood Experiences.

This study examined the factor structure and psychometric properties of the Dissociative Symptoms Scale (DSS) among the Korean community adult population with adverse childhood experiences (ACE). Data were drawn from community sample data sets collected from an online panel investigating the impact of ACE and ultimately consisted of data from a total of 1304 participants. A confirmatory factor analysis revealed a bi-factor model with a general factor and four sub-factors such as depersonalization/derealization, gaps in awareness and memory, sensory misperceptions, and cognitive behavioral reexperiencing, which are the four factors that correspond to the original DSS. The DSS showed good internal consistency as well as convergent validity with clinical correlates such as posttraumatic stress disorder, somatoform dissociation, and emotion dysregulation. The high-risk group with more ACE was associated with increased DSS. These findings support the multidimensionality of dissociation and the validity of Korean DSS scores in a general population sample.

Melasolv™: a potential preventive and depigmenting agent for the senescence of melanocytes.

Introduction: Senescent melanocytes are major contributors to age-related changes in the skin, highlighting the contribution to skin aging. Moreover, prolonged photodamage, such as that caused by UV exposure, can result in melanin accumulation and accelerated melanocyte senescence, thereby exacerbating aging. Melasolv™ is a substance that induces potent depigmentation effects and exhibits low toxicity. The present study aimed to investigate the potential effect of Melasolv™ on senescent melanocytes. Methods: We profiled the transcriptomics of Melasolv™-treated melanocytes and identified the possible mechanism of action (MOA) and targets using connectivity mapping analysis. We identified differentially expressed genes in response to treatment with Melasolv™ and validated the data using quantitative real-time PCR. Moreover, we performed an in vitro ß-gal assay in senescent melanocytes for further validation. Results: Melasolv™ reduced ß-gal and melanin levels in senescent melanocytes. Moreover, the identified MOAs are associated with anti-aging and anti-senescence effects. Discussion: Our findings clearly indicate that Melasolv™ not only exhibits anti-senescent properties but can also potentially alleviate melanin accumulation in senescent cells. These findings could have far-reaching implications in the treatment of age-related photodamaged skin conditions, such as senile lentigo and melasma.

Determination of the Long-Term Thermal Performance of Foam Insulation Materials through Heat and Slicing Acceleration.

Foam insulation materials are widely used in the construction industry due to their low thermal conductivity attributable to their microstructures and their low-conductivity blowing agents and affordability. In this study, we evaluate how the thermal performance of foam insulation materials used for the exterior walls of buildings, viz., extruded polystyrene (XPS), polyisocyanurate (PIR), and phenolic foam (PF), age over the life cycle of a building. To compare the aging of thermal performance during the life cycle of a building, each material was tested at 70 and 110 °C and with slicing acceleration according to EN and ISO standards. The thermal conductivity of each foam insulation material was measured using a heat flow meter at an operating temperature of 23 °C and converted into thermal resistance values. Different foam insulation materials have different aging procedures according to material-specific EN standards, while ISO 11561 applies the same procedure to all material classifications. Upon comparing the aged values according to ISO and EN standards to the initial values, the analysis showed a change rate of 23 to 26% in PIR and 18 to 20% in PF. In XPS, a rate of change of 10 to 23.8% was calculated. Our results indicated that the slicing acceleration induced a thermal resistance reduction rate about three times faster than aging at 70 °C. However, the long-term changed thermal resistance values of the foam insulation material applied via the calculating procedure specified in the ISO and EN standards were similar.

Transcriptome Analysis of Particulate Matter 2.5-Induced Abnormal Effects on Human Sebocytes.

Particulate matter 2.5 (PM2.5), an atmospheric pollutant with an aerodynamic diameter of <2.5 µm, can cause serious human health problems, including skin damage. Since sebocytes are involved in the regulation of skin homeostasis, it is necessary to study the effects of PM2.5 on sebocytes. We examined the role of PM2.5 via the identification of differentially expressed genes, functional enrichment and canonical pathway analysis, upstream regulator analysis, and disease and biological function analysis through mRNA sequencing. Xenobiotic and lipid metabolism, inflammation, oxidative stress, and cell barrier damage-related pathways were enriched; additionally, PM2.5 altered steroid hormone biosynthesis and retinol metabolism-related pathways. Consequently, PM2.5 increased lipid synthesis, lipid peroxidation, inflammatory cytokine expression, and oxidative stress and altered the lipid composition and expression of factors that affect cell barriers. Furthermore, PM2.5 altered the activity of sterol regulatory element binding proteins, mitogen-activated protein kinases, transforming growth factor beta-SMAD, and forkhead box O3-mediated pathways. We also suggest that the alterations in retinol and estrogen metabolism by PM2.5 are related to the damage. These results were validated using the HairSkin® model. Thus, our results provide evidence of the harmful effects of PM2.5 on sebocytes as well as new targets for alleviating the skin damage it causes.

Neutrophil Recruitment in Arterial Thrombus and Characteristics of Stroke Patients with Neutrophil-Rich Thrombus.

PURPOSE: Neutrophils contribute to thrombosis. However, there is limited information on the temporal course of neutrophil recruitment in thrombosis, the contribution of neutrophils to thrombus growth, and the characteristics of stroke patients with neutrophil-rich thrombi. MATERIALS AND METHODS: After inducing carotid artery thrombosis in Institute of Cancer Research mice using ferric chloride, aged thrombi were produced by ligating the distal portion of the carotid artery in mice for 0.5, 1, 2, 3, 6, or 24 h. For thrombus analysis in stroke patients, we used registry data and thrombi that were obtained during intra-arterial thrombectomy. Immunohistochemistry was performed to determine thrombus composition. RESULTS: In the thrombi of 70 mice, Ly6G positive cell counts (neutrophils) and histone H3-positive cell counts increased in a time-dependent manner (both p<0.001). Ly6G-positive cell count was strongly correlated with histone H3-positive cell counts (r=0.910, p<0.001), but not with thrombus size (p=0.320). In 75 stroke patients, atrial fibrillation and cardioembolism were more frequent in the higher neutrophil group (32/37, 86.5%) than in the lower neutrophil group (19/38, 50%) (p=0.002). The median erythrocyte fraction was higher [52.0 (interquartile range 39.9-57.8)] in the higher neutrophil group than in the lower neutrophil group [40.3 (interquartile range 23.5-53.2)]. The fraction of neutrophils was positively correlated with that of erythrocytes (R=0.35, p=0.002). CONCLUSION: Neutrophils were recruited and increased in arterial thrombosis in a time-dependent manner; however, they were not associated with the growth of formed thrombi. Neutrophil fractions in the thrombi of stroke patients appeared to be associated with atrial fibrillation and erythrocyte fraction.

Integrative analysis to explore the biological association between environmental skin diseases and ambient particulate matter.

Although numerous experimental studies have suggested a significant association between ambient particulate matter (PM) and respiratory damage, the etiological relationship between ambient PM and environmental skin diseases is not clearly understood. Here, we aimed to explore the association between PM and skin diseases through biological big data analysis. Differential gene expression profiles associated with PM and environmental skin diseases were retrieved from public genome databases. The co-expression among them was analyzed using a text-mining-based network analysis software. Activation/inhibition patterns from RNA-sequencing data performed with PM2.5-treated normal human epidermal keratinocytes (NHEK) were overlapped to select key regulators of the analyzed pathways. We explored the adverse effects of PM on the skin and attempted to elucidate their relationships using public genome data. We found that changes in upstream regulators and inflammatory signaling networks mediated by MMP-1, MMP-9, PLAU, S100A9, IL-6, and S100A8 were predicted as the key pathways underlying PM-induced skin diseases. Our integrative approach using a literature-based co-expression analysis and experimental validation not only improves the reliability of prediction but also provides assistance to clarify underlying mechanisms of ambient PM-induced dermal toxicity that can be applied to screen the relationship between other chemicals and adverse effects.

Effects of Interleukin-17A on the Early Stages of Arterial Thrombosis in Mice.

PURPOSE: Interleukin (IL)-17A has been suggested to play a role in the growth and organization of thrombi. We examined whether IL-17A plays a role in the early stages of thrombosis and whether there are sex differences in the effects of IL-17A. MATERIALS AND METHODS: We performed a blinded, randomized, placebo-controlled study to compare time to thrombotic occlusion and sex differences therein between mice treated with IL-17A and those treated with saline using a ferric chloride-induced model. We also assessed thrombus histology, blood coagulation, and plasma levels of coagulation factors. RESULTS: Time to occlusion values did not differ between the IL-17A group and the control group (94.6±86.9 sec vs. 121.0±84.4 sec, p=0.238). However, it was significantly shorter in the IL-17A group of female mice (74.6±57.2 sec vs. 130.0±76.2 sec, p=0.032). In rotational thromboelastometry, the IL-17A group exhibited increased maximum clot firmness (71.3±4.5 mm vs. 66.7±4.7 mm, p=0.038) and greater amplitude at 30 min (69.7±5.2 mm vs. 64.5±5.3 mm, p=0.040) than the control group. In Western blotting, the IL-17A group showed higher levels of coagulation factor XIII (2.2±1.5 vs. 1.0±0.9, p=0.008), monocyte chemoattractant protein-1 (1.6±0.6 vs. 1.0±0.4, p=0.023), and tissue factor (1.5±0.6 vs. 1.0±0.5, p=0.003). CONCLUSION: IL-17A plays a role in the initial st ages of arterial thrombosis in mice. Coagulation factors and monocyte chemoattractant protein-1 may be associated with IL-17A-mediated thrombosis.

Split T7 promoter-based isothermal transcription amplification for one-step fluorescence detection of SARS-CoV-2 and emerging variants.

The negative global impact of the coronavirus disease pandemic has highlighted the crucial need for a rapid and convenient method of viral RNA detection. In this study, we report a novel method, termed as the split T7 promoter-based isothermal transcription amplification with light-up RNA aptamer (STAR), for one-pot detection of viral RNA. STAR uses a split T7 promoter that is applied to a three-way junction to mediate the selective transcription by the T7 RNA polymerase in the presence of target RNA. In addition, a light-up RNA aptamer is used for signal amplification. STAR can detect viral RNA in less than 30 min with high specificity and sensitivity. By testing of 60 nasopharyngeal SARS-CoV-2 samples, the STAR assay demonstrates an excellent sensitivity and specificity of 96.7% and 100%, respectively. Moreover, we provide experimental evidence of the broad applicability of this assay through the multiplex detection of SARS-CoV-2 variants (D614G mutation) and direct detection of bacterial 16S rRNA.

3,4,5-Trimethoxycinnamate thymol ester inhibits melanogenesis in normal human melanocytes and 3D human epidermal equivalents via the PGC-1α-independent PPARγ partial agonism.

BACKGROUND: 3,4,5-Trimethoxycinnamate thymol ester (TCTE), an anti-melanogenic cosmetic agent prescribed currently, promotes adiponectin synthesis during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Adiponectin inhibits melanin biosynthesis and its biosynthesis is directly regulated by peroxisome proliferator-activated receptor (PPAR) γ. In this regard, TCTE may potentially affect PPARγ activity. However, contradicting effects of PPARγ agonists with different chemical structures on human melanogenesis have been reported. OBJECTIVE: A molecular target of TCTE was investigated to elucidate the association of both adiponectin and PPARγ with anti-melanogenic activity. METHODS: The adiponectin secretion-promoting activity of TCTE was tested in an adipogenesis model of hBM-MSCs. A molecular target of TCTE for adiponectin secretion was evaluated via time-resolved fluorescence resonance energy transfer-based receptor binding and transactivation of PPARs. RESULTS: TCTE significantly promoted adiponectin secretion (EC50, 27.9 µM) during adipogenesis in hBM-MSCs and directly bound to PPARγ (Ki, 13.2 µM). The TCTE-bound PPARγ increased the recruitment of SRC-1, SRC-3, and TRAP220/DRIP-1 coactivator peptides without affecting PGC-1α coactivation. In the docking analysis, the optimal ligand binding mode of TCTE exhibited typical ligand-receptor interactions of PPARγ partial agonists. The PPARγ partial agonism of TCTE was established experimentally and the anti-melanogenic activity of TCTE was decreased by treatment with a PPARγ antagonist in cultured normal human melanocytes and a 3D model of human epidermis. CONCLUSION: The anti-melanogenic activity of TCTE was associated with a PGC-1α-independent PPARγ partial agonism.

Identification of the novel HLA-C*04:440 allele using next-generation sequencing.

The HLA-C*04:440 allele differs from HLA-C*04:82:01 by a single non-synonymous change, c.14C > A.