This study aimed to analyze the relationship between the hardness and the mineral contents of cementum. From previous research results, fifty extracted premolars were classified as soft, moderate, ...and hard according to the Vickers hardness test. In this study, six specimens selected randomly in each group were used for the experiments, and three representative premolars in each group of cementum hardness were analyzed.The hard specimens had more calcium (Ca) content than did softer specimens, according to scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM-EDS). In the element mapping image, magnesium (Mg) was densely distributed in the surface layer of the root apex in the softer specimens. X-ray μCT analysis revealed that the hard specimens had higher tissue mineral density (TMD) than did the other specimens (P<0.01).The difference in density of Ca and Mg contained in cementum may be related to the variation of Vickers hardness, and may influence the susceptibility to orthodontic root resorption.
In the literature on inter-limb coordination, the coordination among ''focal'' body parts (i.e., the two limbs) directly engaged in a pendulum swinging task has been studied by immobilizing other ...body parts to reduce "noise," while putting aside questions of how one maintains posture while performing the task. However, in practical performance of musical instruments, for example, performers must coordinate different body parts in sync with the music while maintaining the whole body's balance. This study demonstrates the effectiveness and necessity of understanding inter-limb coordination in whole-body coordination. Participants were asked to move two pendulums either in sync or alternatively with metronome beeps under two conditions: immobile (fixed forearms) and mobile (forearms not fixed). The explorative analyses focused on whether and how coordinative structures emerged and whether the degree of task achievement differed according to the phase mode, frequency, and mobility conditions. The motion similarity and phase difference between different parts and the pendulums showed that task-specific coordinative structures emerged in both immobile and mobile conditions. In the in-phase mobile condition, the emergent coordinative structure may have improved task achievement, shown by the phase difference between the left and right pendulums. These findings suggest that the global coordinative structure is involved in achieving the local pendulum swinging task.
The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with ...pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1 (c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland. A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency.
Abstract
Aims
The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation ...of SCN5A variations improves prognostic predictability.
Methods and results
Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves.
Conclusion
In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.
Graphical Abstract
Among currently recognized genetic and non-genetic risk factors for Brugada syndrome, functionally validated loss-of-function SCN5A mutations are associated with worse prognosis with earlier manifestation of lethal arrhythmic events (7.9%/year) than in silico algorithm-predicted SCN5A rare variations (5.1%/year) or Brugada-type ECG (2.5%/year).
Orthodontic root resorption (ORR) is an unintended side effect of orthodontic treatment, and severe ORR can affect treatment outcome. Receptor activator of nuclear factor kappa-B ligand (RANKL) has ...been detected in the resorbed cementum and periodontal (PDL) tissues exposed to excessive orthodontic forces. Recent studies have demonstrated that PDL cells and cementoblasts express RANKL that may play a role in ORR during orthodontic tooth movement. It is known that the hardness of cementum in human maxillary premolars differs among individuals. Furthermore, this difference has been reported to be attributed to differences in the calcium (Ca)/phosphorus (P) ratio. A correlation was observed between the Vickers hardness and Ca/P ratio of the cementum in the apical region. These findings suggest that cementum hardness and the Ca/P ratio may be indirectly involved in ORR caused by orthodontic forces. In this review, it aims to identify the role of RANKL and involvement of cementum in ORR.
Nakajo-Nishimura syndrome (NNS) is a disorder that segregates in an autosomal recessive fashion. Symptoms include periodic fever, skin rash, partial lipomuscular atrophy, and joint contracture. Here, ...we report a mutation in the human proteasome subunit beta type 8 gene (PSMB8) that encodes the immunoproteasome subunit β5i in patients with NNS. This G201V mutation disrupts the β-sheet structure, protrudes from the loop that interfaces with the β4 subunit, and is in close proximity to the catalytic threonine residue. The β5i mutant is not efficiently incorporated during immunoproteasome biogenesis, resulting in reduced proteasome activity and accumulation of ubiquitinated and oxidized proteins within cells expressing immunoproteasomes. As a result, the level of interleukin (IL)-6 and IFN-γ inducible protein (IP)-10 in patient sera is markedly increased. Nuclear phosphorylated p38 and the secretion of IL-6 are increased in patient cells both in vitro and in vivo, which may account for the inflammatory response and periodic fever observed in these patients. These results show that a mutation within a proteasome subunit is the direct cause of a human disease and suggest that decreased proteasome activity can cause inflammation.
Most studies on aperture passability focus on aperture passing involving non-human physical objects. In this study, we examined experimentally how participants pass between two box-shaped frames and ...between the same frames, each with a human confederate in it, facing various directions. Seven configuration conditions were set up, six of which differed in terms of the human confederates' sets of directions in the two frames: face-to-face, back-to-back, facing toward or away from the participants, facing leftward or rightward from the participants' perspective, and the empty frames condition without human confederates. There were seven aperture-width conditions-50, 55, 60, 65, 70, 75, and 80 cm-and participants walked at their normal speed through the apertures. We found that the participants' shoulder rotation angle in the face-to-face condition was significantly greater than that in the empty frames condition. Further, the participants preferred to rotate their shoulders counterclockwise when our confederates in the aperture faced leftward, and clockwise, when they faced rightward. These results suggest that people change their passing-through methods by considering the social nature of the aperture as well as its width.
Collection of CD3+ lymphocytes via lymphapheresis is essential for manufacturing autologous chimeric antigen receptor (CAR) T cells. Optimization of timing and procedures for lymphapheresis for each ...patient is critical because patients often have progressive diseases and receive medications that could reduce T cell counts. We conducted a retrospective study of clinical data from 28 patients who underwent lymphapheresis for CD19-directed CAR-T therapy with tisagenlecleucel to identify factors that could affect CD3+ lymphocyte yields. The numbers of CD3+ cells in peripheral blood were significantly correlated with CD3+ cell yields (correlation coefficient
r
= 0.84), which enabled us to estimate the volume of blood to process before apheresis. We also found that small cell ratio (SCR) at the apheresis site precisely reflected the proportion of lymphocytes, especially in patients without circulating blasts (coefficient of determination:
r
2
= 0.9). We were able to predict the CD3+ cell yield and prevent excessive apheresis by measuring pre-apheresis circulating CD3+ cell counts and monitoring SCR. Collectively, these results will help us to establish a strategy for optimization of lymphapheresis procedures for CAR-T cell production on a patient-by-patient basis.
Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis ...technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.
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