Temperamental Shyness, Peer Competence, and Loneliness in Middle Childhood: The Role of Positive Emotion.

Guided by the conceptual frameworks of social withdrawal (Rubin, K. H., & Chronis-Tuscano, A. (2021). Perspectives on social withdrawal in childhood: Past, present, and prospects. Child Development Perspectives, 15(3), 160-167.) and emotion socialization (Eisenberg, N., Cumberland, A., & Spinrad, T. L. (1998). Parental socialization of emotion. Psychological Inquiry, 9, 241-273.; Morris, (A) S., Criss, M. M., Silk, J. S., & Houltberg, (B) J. (2017). The impact of parenting on emotion regulation during childhood and adolescence. Child Development Perspectives, 11(4), 233-238.), the current study examined multifaceted relations among temperamental shyness, peer competence, and loneliness and focused on the role of socializing and expressing positive emotion in middle childhood. Participants included 1,364 families, among whom mothers reported children's temperament when children were 4.5 years old. Mothers and alternative caregivers (usually fathers) independently rated family expressiveness when children were 8-9 years old. Mothers rated their children's peer competence, and children's positive affect with peers were observed when children were ages 8-9 and 10-11. Children self-rated their loneliness levels at ages 10-11. A path model revealed a moderated mediation effect, such that family positive expressiveness moderated the sequential mediation pathway from child temperamental shyness through child peer competence at ages 8-9 and positive affect with peers at ages 10-11 to loneliness at ages 10-11. This sequential mediation was significant only under low but not high levels of family positive expressiveness. Findings support the importance of socializing positive emotion in the context of temperamental shyness and have implications for family-based intervention strategies aimed at children exhibiting high temperamental shyness.

Recurrent fever of unknown origin and unexplained bacteremia in a patient with a novel 4.5 Mb microdeletion in Xp11.23-p11.22.

Fever of unknown origin (FUO) remains a formidable diagnostic challenge in the field of medicine. Numerous studies suggest an association between FUO and genetic factors, including chromosomal abnormalities. Here, we report a female patient with a 4.5 Mb Xp microdeletion, who presented with recurrent FUO, bacteremia, colitis, and hematochezia. To elucidate the underlying pathogenic mechanism, we employed a comprehensive approach involving single cell RNA sequencing, T cell receptor sequencing, and flow cytometry to evaluate CD4 T cells. Analysis of peripheral blood mononuclear cells revealed augmented Th1, Th2, and Th17 cell populations, and elevated levels of proinflammatory cytokines in serum. Notably, the patient exhibited impaired Treg cell function, possibly related to deletion of genes encoding FOPX3 and WAS. Single cell analysis revealed specific expansion of cytotoxic CD4 T lymphocytes, characterized by upregulation of various signature genes associated with cytotoxicity. Moreover, interferon-stimulated genes were upregulated in the CD4 T effector memory cluster. Further genetic analysis confirmed maternal inheritance of the Xp microdeletion. The patient and her mother exhibited X chromosome-skewed inactivation, a potential protective mechanism against extensive X chromosome deletions; however, the mother exhibited complete skewing and the patient exhibited incomplete skewing (85:15), which may have contributed to emergence of immunological symptoms. In summary, this case report describes an exceptional instance of FUO stemming from an incompletely inactivated X chromosome microdeletion, thereby increasing our understanding of the genetics underpinning FUO.

A family systems investigation on couple emotional intimacy, parent-child relationships, and child social skills in middle childhood.

This study investigated familial attachment-based processes in middle childhood, using 788 families (50.6% boys; 84.4% White), assessed six times from 4.5 years old to Grade 6. An adapted Random Intercept Cross-Lagged Panel Model revealed between-family associations among couple emotional intimacy, relationships with both parents, and child social skills (ß = .18-.66). Within-family increases in child assertion and self-control prospectively predicted relationships with parents (ßs = .13), and parent-child relationships predicted various child social skills (ßs = .13-.17). Couple emotional intimacy predicted child cooperation, assertion, and responsibility (ßs = .12-.24) and father-child relationships in Grade 6 (ßs = .20-22) at the within-family level. Findings underscore a systemic consideration of attachment-based processes in the family.

Effects of Microplastic Exposure against White Spot Syndrome Virus Infection in Pacific White Shrimp (Penaeus vannamei).

Plastic waste has emerged as a major environmental concern in recent years. As plastic waste discharged into the marine environment, it undergoes a breakdown process, eventually accumulating in aquatic organisms in the form of microplastics (MPs). To date, reduced food intake, nutritional absorption, and impaired immune system are known adverse effects of MPs-exposed aquatic organisms. This study aims to investigate whether MP exposure accelerated white spot syndrome virus (WSSV) infection in Pacific white shrimp (Penaeus vannamei) via laboratory tests. Briefly, experimental shrimp were divided into four groups; WSSV (group 1); MP (group 2); WSSV + MP (group 3); and Control (group 4). No mortality was observed in group 2, group 4, and even in group 1. However, group 3 showed a cumulative mortality of 50% during the experimental period. The PCR assay results showed no WSSV in the other three groups (groups 1, 2, and 4), but the dead and alive shrimp collected from group 3 were confirmed to be infected with the virus. Histopathological examination revealed normal structures in the hepatopancreas, gill, and muscle tissues of group 4, whereas numerous abnormally shaped nuclei were detected in the gill tissue of group 2. Moreover, group 1 showed minor WSSV-related lesions with few basophilic inclusion bodies in the gills, interestingly, group 3 exhibited severe lesions with numerous basophilic inclusion bodies in the gills. In conclusion, this study confirmed the correlation between the viral disease of shrimp and MPs, which can cause significant economic losses to the shrimp aquaculture industry.

Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma.

TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC.

The Use of the Internal Transcribed Spacer Region for Phylogenetic Analysis of the Microsporidian Parasite Enterocytozoon hepatopenaei Infecting Whiteleg Shrimp (Penaeus vannamei) and for the Development of a Nested PCR as Its Diagnostic Tool.

The increasing economic losses associated with growth retardation caused by Enterocytozoon hepatopenaei (EHP), a microsporidian parasite infecting penaeid shrimp, require effective monitoring. The internal transcribed spacer (ITS)-1 region, the non-coding region of ribosomal clusters between 18S and 5.8S rRNA genes, is widely used in phylogenetic studies due to its high variability. In this study, the ITS-1 region sequence (~600-bp) of EHP was first identified, and primers for a polymerase chain reaction (PCR) assay targeting that sequence were designed. A newly developed nested-PCR method successfully detected the EHP in various shrimp (Penaeus vannamei and P. monodon) and related samples, including water and feces collected from Indonesia, Thailand, South Korea, India, and Malaysia. The primers did not cross-react with other hosts and pathogens, and this PCR assay is more sensitive than existing PCR detection methods targeting the small subunit ribosomal RNA (SSU rRNA) and spore wall protein (SWP) genes. Phylogenetic analysis based on the ITS-1 sequences indicated that the Indonesian strain was distinct (86.2% nucleotide sequence identity) from other strains collected from Thailand and South Korea, and also showed the internal diversity among Thailand (N = 7, divided into four branches) and South Korean (N = 5, divided into two branches) samples. The results revealed the ability of the ITS-1 region to determine the genetic diversity of EHP from different geographical origins.

Efficacy of Allograft Versus Bioactive Glass-Ceramic Cage in Anterior Cervical Discectomy and Fusion: A Randomized Controlled Study.

STUDY DESIGN: A randomized controlled trial. OBJECTIVE: The aim of this study is to compare the efficacy of allografts and bioactive glass-ceramic (BG) cages for anterior cervical discectomy and fusion (ACDF) in treating cervical degenerative disc disease. METHODS: We conducted a single-center, randomized controlled trial between August 2017 and August 2022. Participants were randomized into two groups, and consecutive patients requiring ACDF were randomly assigned to receive either the allograft cage or the BG cage. The surgical outcomes measured included pain levels, neck disability, surgical details, and radiological assessments. RESULTS: Of the 45 assessed, 40 participants were included, with 18 in the allograft cage group and 22 in the BG cage group. By the 12-month follow-up, both groups exhibited significant improvements in pain levels and disability scores, with no notable intergroup differences. Over 85% of patients in both groups were satisfied with their outcomes. Radiological assessments revealed stability in the cervical spine with both cage types post intervention. Although both materials showed a trend toward increased subsidence over time, the difference between them was not statistically significant. Fusion rates were comparable between the groups at 12 months, with BG cage showing a slightly higher early fusion rate at 6 months. No significant differences were observed between the two groups in terms of complications. CONCLUSIONS: Both allograft and BG cages are effective in ACDF surgeries for cervical degenerative disc disease, with both contributing to substantial postoperative improvements. Differences in disc height, interspinous motion, and subsidence were not significant in the last follow-up, indicating both materials' suitability for clinical use. Future research with a larger cohort and longer follow-up is needed to confirm these preliminary findings.

Mycoplasma fermentans infection induces human necrotic neuronal cell death via IFITM3-mediated amyloid-ß (1-42) deposition.

Mycoplasma fermentans is a proposed risk factor of several neurological diseases that has been detected in necrotic brain lesions of acquired immunodeficiency syndrome patients, implying brain invasiveness. However, the pathogenic roles of M. fermentans in neuronal cells have not been investigated. In this study, we found that M. fermentans can infect and replicate in human neuronal cells, inducing necrotic cell death. Necrotic neuronal cell death was accompanied by intracellular amyloid-ß (1-42) deposition, and targeted depletion of amyloid precursor protein by a short hairpin RNA (shRNA) abolished necrotic neuronal cell death. Differential gene expression analysis by RNA sequencing (RNA-seq) showed that interferon-induced transmembrane protein 3 (IFITM3) was dramatically upregulated by M. fermentans infection, and knockdown of IFITM3 abolished both amyloid-ß (1-42) deposition and necrotic cell death. A toll-like receptor 4 antagonist inhibited M. fermentans infection-mediated IFITM3 upregulation. M. fermentans infection also induced necrotic neuronal cell death in the brain organoid. Thus, neuronal cell infection by M. fermentans directly induces necrotic cell death through IFITM3-mediated amyloid-ß deposition. Our results suggest that M. fermentans is involved in neurological disease development and progression through necrotic neuronal cell death.

Is navigation beneficial for transforaminal endoscopic lumbar foraminotomy? A preliminary comparison study with fluoroscopic guidance.

PURPOSE: The primary purpose of this study was to determine radiation exposure of the surgeon during transforaminal endoscopic lumbar foraminotomy (TELF). Secondary purpose of this study was to compare clinical and radiologic outcomes between TELF under C-arm fluoroscopic guidance (C-TELF) and O-arm navigation-guided TELF (O-TELF). METHODS: The author reviewed patients' medical records who underwent TELF at our institute from June 2015 to November 2022. A total of 40 patients were included (18 patients with C-TELF and 22 with O-TELF). Basic demographic data were collected. Preoperative/postoperative visual analog scale (VAS) and Oswestry Disability Index (ODI) were recorded at the outpatient clinic. Radiologic features were compared on X-rays at each follow-up. The degree of foraminal expansion was measured/compared through MRI. In the C-TELF group, the amount of exposure was calculated with a dosimeter. RESULTS: Average surgeon's effective dose in the C-TELF group was 0.036 mSv. In the case of the O-TELF group, there was no radiation exposure during operation. However, the operation time in the O-TELF group was about 37 min longer than that in the C-TELF group. There were significant improvements in VAS/ODI after operation in both groups. Complications were identified in three patients. CONCLUSION: O-TELF showed similarly favorable clinical and radiologic outcomes to C-TELF in lumbar foraminal stenosis, including complication rate. Compared to C-TELF, O-TELF has an advantage of not wearing a lead apron since the operator is not exposed to radiation. However, the operation time was longer with O-TELF due to O-arm setting time. Because there are pros and cons, the choice of surgical method depends on the surgeon's preference.

Systematic analysis of inheritance pattern determination in genes that cause rare neurodevelopmental diseases.

Despite recent advancements in our understanding of genetic etiology and its molecular and physiological consequences, it is not yet clear what genetic features determine the inheritance pattern of a disease. To address this issue, we conducted whole exome sequencing analysis to characterize genetic variants in 1,180 Korean patients with neurological symptoms. The diagnostic yield for definitive pathogenic variant findings was 50.8%, after including 33 cases (5.9%) additionally diagnosed by reanalysis. Of diagnosed patients, 33.4% carried inherited variants. At the genetic level, autosomal recessive-inherited genes were characterized by enrichments in metabolic process, muscle organization and metal ion homeostasis pathways. Transcriptome and interactome profiling analyses revealed less brain-centered expression and fewer protein-protein interactions for recessive genes. The majority of autosomal recessive genes were more tolerant of variation, and functional prediction scores of recessively-inherited variants tended to be lower than those of dominantly-inherited variants. Additionally, we were able to predict the rates of carriers for recessive variants. Our results showed that genes responsible for neurodevelopmental disorders harbor different molecular mechanisms and expression patterns according to their inheritance patterns. Also, calculated frequency rates for recessive variants could be utilized to pre-screen rare neurodevelopmental disorder carriers.

Overexpression of Replication-Dependent Histone Signifies a Subset of Dedifferentiated Liposarcoma with Increased Aggressiveness.

Liposarcoma (LPS) is an adult soft tissue malignancy that arises from fat tissue, where well-differentiated (WD) and dedifferentiated (DD) forms are the most common. DDLPS represents the progression of WDLPS into a more aggressive high-grade and metastatic form. Although a few DNA copy-number amplifications are known to be specifically found in WD- or DDLPS, systematic genetic differences that signify subtype determination between WDLPS and DDLPS remain unclear. Here, we profiled the genome and transcriptome of 38 LPS tumors to uncover the genetic signatures of subtype differences. Replication-dependent histone (RD-HIST) mRNAs were highly elevated and their regulation was disrupted in a subset of DDLPS, increasing cellular histone molecule levels, as measured using RNA-seq (the averaged fold change of 53 RD-HIST genes between the DD and WD samples was 10.9) and immunohistochemistry. The change was not observed in normal tissues. Integrated whole-exome sequencing, RNA-seq, and methylation analyses revealed that the overexpressed HMGA2 (the fold change between DD and WD samples was 7.3) was responsible for the increased RD-HIST level, leading to aberrant cell proliferation. Therefore, HMGA2-mediated elevation of RD-HISTs were crucial events in determining the aggressiveness of DDLPS, which may serve as a biomarker for prognosis prediction for liposarcoma patients.

Biallelic mutations in ABCB1 display recurrent reversible encephalopathy.

The clinical phenotype linked with mutations in ABCB1, encoding P-glycoprotein, has never been reported. Here, we describe twin sisters with biallelic mutations in ABCB1 who showed recurrent reversible encephalopathy accompanied by acute febrile or afebrile illness. Whole-exome sequencing was performed on one of the twin and her healthy parents, and revealed compound heterozygous loss-of-function variants in ABCB1. The patient brains displayed substantial loss of xenobiotic clearance ability, as demonstrated by [11 C]verapamil positron emission tomography (PET) study, linking this phenotype with ABCB1 function. The endogenous cytokine clearance from the brain was also decreased in LPS-treated ABCB1 knockout mice compared to controls. The results provide insights into the physiological requirement of ABCB1 in maintaining homeostasis of various compounds for normal brain function.

Kidney residency of VISTA-positive macrophages accelerates repair from ischemic injury.

Tissue-resident macrophages have unique tissue-specific functions in maintaining homeostasis and resolving inflammation. However, the repair role and relevant molecules of kidney-resident macrophages after ischemic injury remain unresolved. To this end, mice without kidney-resident R1 macrophages but containing infiltrating monocyte-derived R2 macrophages were generated using differential cellular kinetics following clodronate liposome treatment. When ischemia-reperfusion injury was induced in these mice, late phase repair was reduced. Transcriptomic and flow cytometric analyses identified that V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint molecule, was constitutively expressed in kidney-resident R1 macrophages, but not in other tissue-resident macrophages. Here, VISTA functioned as a scavenger of apoptotic cells and served as a checkpoint to control kidney-infiltrating T cells upon T cell receptor-mediated stimulation. Together these functions improved the repair process after ischemia-reperfusion injury. CD14+ CD33+ mononuclear phagocytes of human kidney also expressed VISTA, which has similar functions to the mouse counterpart. Thus, VISTA is upregulated in kidney macrophages in a tissue-dependent manner and plays a repair role during ischemic injury.

Characterization of Multiple Cytokine Combinations and TGF-ß on Differentiation and Functions of Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) regulate T cell immunity, and this population is a new therapeutic target for immune regulation. A previous study showed that transforming growth factor-ß (TGF-ß) is involved in controlling MDSC differentiation and immunoregulatory function in vivo. However, the direct effect of TGF-ß on MDSCs with various cytokines has not previously been tested. Thus, we examined the effect of various cytokine combinations with TGF-ß on MDSCs derived from bone marrow cells. The data show that different cytokine combinations affect the differentiation and immunosuppressive functions of MDSCs in different ways. In the presence of TGF-ß, interleukin-6 (IL-6) was the most potent enhancer of MDSC function, whereas granulocyte colony-stimulating factors (G-CSF) was the most potent in the absence of TGF-ß. In addition, IL-4 maintained MDSCs in an immature state with an increased expression of arginase 1 (Arg1). However, regardless of the cytokine combinations, TGF-ß increased expansion of the monocytic MDSC (Mo-MDSC) population, expression of immunosuppressive molecules by MDSCs, and the ability of MDSCs to suppress CD4⁺ T cell proliferation. Thus, although different cytokine combinations affected the MDSCs in different ways, TGF-ß directly affects monocytic-MDSCs (Mo-MDSCs) expansion and MDSCs functions.

Myeloid-Derived Suppressor Cells Are Controlled by Regulatory T Cells via TGF-ß during Murine Colitis.

Myeloid-derived suppressor cells (MDSCs) are well known regulators of regulatory T cells (Treg cells); however, the direct regulation of MDSCs by Treg cells has not been well characterized. We find that colitis caused by functional deficiency of Treg cells leads to altered expansion and reduced function of MDSCs. During differentiation of MDSCs in vitro from bone marrow cells, Treg cells enhanced MDSC function and controlled their differentiation through a mechanism involving transforming growth factor-ß (TGF-ß). TGF-ß-deficient Treg cells were not able to regulate MDSC function in an experimentally induced model of colitis. Finally, we evaluated the therapeutic effect of TGF-ß-mediated in-vitro-differentiated MDSCs on colitis. Adoptive transfer of MDSCs that differentiated with TGF-ß led to better colitis prevention than the transfer of MDSCs that differentiated without TGF-ß. Our results demonstrate an interaction between Treg cells and MDSCs that contributes to the regulation of MDSC proliferation and the acquisition of immunosuppressive functions.

Epigenetic regulation of Kcna3-encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4+ T-cell activation.

The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4(+) T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Consequently, in the absence of CRBN, the expression of Kv1.3 is derepressed, resulting in increased Kv1.3 expression, potassium flux, and CD4(+) T-cell hyperactivation. In addition, experimental autoimmune encephalomyelitis in T-cell-specific Crbn-deficient mice was exacerbated by increased T-cell activation via Kv1.3. Thus, CRBN limits CD4(+) T-cell activation via epigenetic regulation of Kv1.3 expression.

Secretion of IL-1ß from imatinib-resistant chronic myeloid leukemia cells contributes to BCR-ABL mutation-independent imatinib resistance.

Some cases of chronic myelogenous leukemia are resistant to tyrosine kinase inhibitors (TKIs) independently of mutation in BCR-ABL, but the detailed mechanism underlying this resistance has not yet been elucidated. In this study, we generated a TKI-resistant CML cell line, K562R, that lacks a mutation in BCR-ABL. Interleukin-1ß (IL-1ß) was more highly expressed in K562R than in the parental cell line K562S, and higher levels of IL-1ß contributed to the imatinib resistance of K562R. In addition, IL-1ß secreted from K562R cells affected stromal cell production of CXCL11, which in turn promoted migration of K562R cells into the stroma. Thus, elevated IL-1ß production from TKI-resistant K562R cells may contribute to TKI resistance by increasing cell viability and promoting cell migration.