E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation of SIRT7 and promotes cell death in response to hydrogen peroxide.

Parkinson's disease (PD) is a degenerative disorder of the central nervous system that affects 1% of the population over the age of 60. Although aging is one of the main risk factors for PD, the pathogenic mechanism of this disease remains unclear. Mutations in the F-box-only protein 7 (FBXO7) gene have been previously found to cause early onset autosomal recessive familial PD. FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates. Sirtuin 7 (SIRT7) is an NAD+-dependent histone deacetylase that regulates aging and stress responses. In this study, we identified FBXO7 as a novel E3 ligase for SIRT7 that negatively regulates intracellular SIRT7 levels through SCF-dependent Lys-48-linked polyubiquitination and proteasomal degradation. Consequently, we show that FBXO7 promoted the blockade of SIRT7 deacetylase activity, causing an increase in acetylated histone 3 levels at the Lys-18 and Lys-36 residues and the repression of downstream RPS20 gene transcription. Moreover, we demonstrate that treatment with hydrogen peroxide triggered the FBXO7-mediated degradation of SIRT7, leading to mammalian cell death. In particular, the PD-linked FBXO7-R498X mutant, which reduced SCF-dependent E3 ligase activity, did not affect the stability of SIRT7. Collectively, these findings suggest that FBXO7 negatively regulates SIRT7 stability and may suppress the cytoprotective effects of SIRT7 during hydrogen peroxide-induced mammalian cell death.

Exploring the Regulatory Landscape of Dementia: Insights from Non-Coding RNAs.

Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3' untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.

Exploring the Key Signaling Pathways and ncRNAs in Colorectal Cancer.

Colorectal cancer (CRC) is the third most prevalent cancer to be diagnosed, and it has a substantial mortality rate. Despite numerous studies being conducted on CRC, it remains a significant health concern. The disease-free survival rates notably decrease as CRC progresses, emphasizing the urgency for effective diagnostic and therapeutic approaches. CRC development is caused by environmental factors, which mostly lead to the disruption of signaling pathways. Among these pathways, the Wingless/Integrated (Wnt) signaling pathway, Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, Mitogen-Activated Protein Kinase (MAPK) signaling pathway, Transforming Growth Factor-ß (TGF-ß) signaling pathway, and p53 signaling pathway are considered to be important. These signaling pathways are also regulated by non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). They have emerged as crucial regulators of gene expression in CRC by changing their expression levels. The altered expression patterns of these ncRNAs have been implicated in CRC progression and development, suggesting their potential as diagnostic and therapeutic targets. This review provides an overview of the five key signaling pathways and regulation of ncRNAs involved in CRC pathogenesis that are studied to identify promising avenues for diagnosis and treatment strategies.

Global fitness landscapes of the Shine-Dalgarno sequence.

Shine-Dalgarno sequences (SD) in prokaryotic mRNA facilitate protein translation by pairing with rRNA in ribosomes. Although conventionally defined as AG-rich motifs, recent genomic surveys reveal great sequence diversity, questioning how SD functions. Here, we determined the molecular fitness (i.e., translation efficiency) of 49 synthetic 9-nt SD genotypes in three distinct mRNA contexts in Escherichia coli We uncovered generic principles governing the SD fitness landscapes: (1) Guanine contents, rather than canonical SD motifs, best predict the fitness of both synthetic and endogenous SD; (2) the genotype-fitness correlation of SD promotes its evolvability by steadily supplying beneficial mutations across fitness landscapes; and (3) the frequency and magnitude of deleterious mutations increase with background fitness, and adjacent nucleotides in SD show stronger epistasis. Epistasis results from disruption of the continuous base pairing between SD and rRNA. This "chain-breaking" epistasis creates sinkholes in SD fitness landscapes and may profoundly impact the evolution and function of prokaryotic translation initiation and other RNA-mediated processes. Collectively, our work yields functional insights into the SD sequence variation in prokaryotic genomes, identifies a simple design principle to guide bioengineering and bioinformatic analysis of SD, and illuminates the fundamentals of fitness landscapes and molecular evolution.

The Tumorigenic Role of Circular RNA-MicroRNA Axis in Cancer.

Circular RNAs (circRNAs) are a class of endogenous RNAs that control gene expression at the transcriptional and post-transcriptional levels. Recent studies have increasingly demonstrated that circRNAs act as novel diagnostic biomarkers and promising therapeutic targets for numerous cancer types by interacting with other non-coding RNAs such as microRNAs (miRNAs). The miRNAs are presented as crucial risk factors and regulatory elements in cancer by regulating the expression of their target genes. Some miRNAs are derived from transposable elements (MDTEs) that can transfer their location to another region of the genome. Genetic interactions between miRNAs and circular RNAs can form complex regulatory networks with various carcinogenic processes that play critical roles in tumorigenesis and cancer progression. This review focuses on the biological regulation of the correlative axis among circular RNAs, miRNAs, and their target genes in various cancer types and suggests the biological importance of MDTEs interacting with oncogenic or tumor-suppressive circRNAs in tumor progression.

FBXO7 triggers caspase 8-mediated proteolysis of the transcription factor FOXO4 and exacerbates neuronal cytotoxicity.

Parkinson's disease (PD) is characterized by the progressive loss of midbrain dopamine neurons in the substantia nigra. Mutations in the F-box only protein 7 gene (Fbxo7) have been reported to cause an autosomal recessive form of early-onset familial PD. FBXO7 is a part of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, which mediates ubiquitination of numerous substrates. FBXO7 also regulates mitophagy, cell growth, and proteasome activity. A member of the FOXO family, the transcription factor FOXO4, is also known to modulate several cellular responses, including cell cycle progression and apoptosis; however, the relationship between FBXO7 and FOXO4 has not been investigated. In this study, we determined that FBXO7 binds to FOXO4 and negatively regulates intracellular FOXO4 levels. Interestingly, we also found that FBXO7-mediated degradation of FOXO4 did not occur through either of two major proteolysis systems, the ubiquitin-proteasome system or the lysosome-autophagy pathway, although it was blocked by a caspase 8-specific inhibitor and caspase 8-knockdown. Moreover, intracellular FOXO4 levels were greatly reduced in dopaminergic MN9D cells following treatment with neurotoxic 6-hydroxydopamine (6-OHDA), which was produced upon FBXO7-mediated and caspase 8-mediated proteolysis. Taken together, these results suggest that FOXO4 is negatively regulated in FBXO7-linked PD through caspase 8 activation, suppressing the cytoprotective effect of FOXO4 during 6-OHDA-induced neuronal cell death.

Downregulated pol-miR-140-3p induces the expression of the kinesin family member 5A against Streptococcus parauberis infection in olive flounder.

MicroRNAs (miRNAs) are small non-coding RNAs that participate in various biological and cellular processes by regulating target gene expression. miRNAs are also known to play vital roles in the pathogenesis of various diseases, including infections, as well as the disease progression and defense responses. In this study, we examined the expression levels of pol-miR-140-3p and its target gene, kinesin family member 5A (KIF5A), in association with the Streptococcus parauberis (S. parauberis) infection, a major bacterial pathogen that causes streptococcosis in olive flounder (Paralichthys olivaceus). KIF5A is a heavy chain isoform of kinesin-1, which is known to be brain-specific, and this study is the first examination of KIF5A expression related to the regulation of miRNA in olive flounder (named PoKIF5A). There were significant differences in expression levels between infected and healthy olive flounder as the expression of pol-miR-140-3p in the infected fish was lower than that in the control, while the expression of PoKIF5A was higher in the infected fish than in the healthy controls. These contradictory results suggest that downregulated pol-miR-140-3p induces the expression of PoKIF5A against S. parauberis infection in olive flounder.

Genomic Analyses of Non-Coding RNAs Overlapping Transposable Elements and Its Implication to Human Diseases.

It is estimated that up to 80% of the human genome is transcribed into RNA molecules but less than 2% of the genome encodes the proteins, and the rest of the RNA transcripts that are not translated into protein are called non-coding RNAs (ncRNAs). Many studies have revealed that ncRNAs have biochemical activities as epigenetic regulators at the post-transcriptional level. Growing evidence has demonstrated that transposable elements (TEs) contribute to a large percentage of ncRNAs' transcription. The TEs inserted into certain parts of the genome can act as alternative promoters, enhancers, and insulators, and the accumulation of TEs increases genetic diversity in the human genome. The TEs can also generate microRNAs, so-called miRNA-derived from transposable elements (MDTEs), and are also implicated in disease progression, such as infectious diseases and cancer. Here, we analyzed the origin of ncRNAs and reviewed the published literature on MDTEs related to disease progression.

Integration of TE Induces Cancer Specific Alternative Splicing Events.

Alternative splicing of messenger RNA (mRNA) precursors contributes to genetic diversity by generating structurally and functionally distinct transcripts. In a disease state, alternative splicing promotes incidence and development of several cancer types through regulation of cancer-related biological processes. Transposable elements (TEs), having the genetic ability to jump to other regions of the genome, can bring about alternative splicing events in cancer. TEs can integrate into the genome, mostly in the intronic regions, and induce cancer-specific alternative splicing by adjusting various mechanisms, such as exonization, providing splicing donor/acceptor sites, alternative regulatory sequences or stop codons, and driving exon disruption or epigenetic regulation. Moreover, TEs can produce microRNAs (miRNAs) that control the proportion of transcripts by repressing translation or stimulating the degradation of transcripts at the post-transcriptional level. Notably, TE insertion creates a cancer-friendly environment by controlling the overall process of gene expression before and after transcription in cancer cells. This review emphasizes the correlative interaction between alternative splicing by TE integration and cancer-associated biological processes, suggesting a macroscopic mechanism controlling alternative splicing by TE insertion in cancer.

Targeted next-generation sequencing for comprehensive genetic analysis of external apical root resorption during orthodontic treatment with premolar extraction in the Korean population.

INTRODUCTION: External apical root resorption (EARR) is one of the most common unfavorable consequences of orthodontic treatment and causes loss of tooth structure. The present study aimed to investigate the genetics of EARR using next-generation sequencing comprehensively. METHODS: Targeted next-generation sequencing was performed for comprehensive genetic analysis of 118 Korean orthodontic patients. The patients were divided into 2 groups on the basis of their EARR value. The association of clinical and genetic parameters with EARR was assessed using the χ2 test or t test for matched pairs, followed by Bonferroni correction and linear regression analysis. In addition, haplotype analysis and in silico prediction were conducted to evaluate functional effects. RESULTS: No statistically significant difference was observed between clinical and treatment-related parameters and EARR. The single nucleotide polymorphisms SPP1 rs9138 (P = 0.001) and SFRP2 rs3810765 (P = 0.04) showed only nominal significance between EARR groups. However, these 2 SNPs were not significant after Bonferroni correction for multiple testing (cutoff P = 0.05/142 = 3.52 × 10-4). Variations in SPP1 rs9138 and SFRP2 rs3810765 may be related to EARR during orthodontic treatment. In summary, not only genes related to inflammatory reactions but also those related to Wnt signaling to affect the degree of EARR during orthodontic teeth movement.

Utilization of Inertial Measurement Units for Determining the Sequential Chain of Baseball Strike Posture.

The purpose of this study was to employ inertial measurement units (IMU) with an eye-tracking device to investigate different swing strategies between two levels of batters. The participants were 20 healthy males aged 20 to 30 years old, with ten professional and ten amateur batters. Eye gaze position, head, shoulder, trunk, and pelvis angular velocity, and ground reaction forces were recorded. The results showed that professional batters rotated segments more rhythmically and efficiently than the amateur group. Firstly, the professional group spent less time in the preparation stages. Secondly, the maximum angular velocity timing of each segment of the professional group was centralized in the swing cycle. Thirdly, the amateur group had significantly earlier gaze timing of the maximum angular velocity than the professional group. Moreover, the maximum angular velocity timing of the gaze was the earliest parameter among the five segments, and significantly earlier (at least 16.32% of cycle time) than the maximum angular velocity of the head, shoulder, trunk, and pelvis within the amateur group. The visual-motor coordination strategies were different between the two groups, which could successfully be determined by wearable instruments of IMU.

Control of vertical posture while standing on a sliding board and pushing an object.

Voluntary pushing or translation perturbation of the support surface each induces a body perturbation that affects postural control. The objective of the study was to investigate anticipatory (APA) and compensatory (CPA) postural adjustments when pushing an object (that induces self-initiated perturbation) and standing on a sliding board (that induces translational perturbation). Thirteen healthy young participants were instructed to push a handle with both hands while standing on a sliding board that was either free to move in the anterior-posterior direction or stationary. Electromyographic activity (EMG) of trunk and lower extremity muscles, center of pressure (COP) displacements, and the forces exerted by the hand were recorded and analyzed during the APA and CPA phases. When the sliding board was free to move during pushing (translation perturbation), onsets of activity of ventral leg muscles and COP displacement were delayed as compared to pushing when standing on a stationary board. Moreover, magnitudes of shank muscle activity and the COP displacement were decreased. When pushing heavier weight, magnitudes of muscle activity, COP displacement, and pushing force increased. The magnitude of activity of the shank muscles during the APA and CPA phases in conditions with translational perturbation varied with the magnitude of the pushing weight. The outcome of the study suggests that the central nervous system prioritizes the pushing task while attenuates the source of additional perturbation induced by translation perturbation. These results could be used in the development of balance re-training paradigms involving pushing weight while standing on a sliding surface.

Role of point of application of perturbation in control of vertical posture.

The role of point of application of perturbation in the anticipatory (APAs) and compensatory (CPAs) postural control was studied. Twelve healthy participants stood on a sliding board (that was either locked and as such motionless or unlocked and as such free to move in the anterior-posterior direction). The body perturbations were applied either to the shoulders (by a pendulum impact) or the feet (by the movement of the sliding board). Electromyographic activity (EMG) of the trunk and lower extremity muscles was recorded. Latencies, integrals of EMG and muscle co-contraction (C) and reciprocal (R) activation indices were calculated and analyzed within the intervals typical for the APAs and CPAs. Higher EMG integrals were seen in the APAs phase when perturbation was applied to the shoulders. Reciprocal activation of muscles was seen in the APAs phase in the shoulders perturbation condition, while co-contraction was seen in the feet perturbation condition. Co-contraction was observed within the CPA phase in both experimental conditions. Higher C values were found in the feet perturbation condition in the CPA phase. The results suggest that different motor control strategies are employed by the central nervous system when encounter perturbations of similar magnitude but applied to different parts of the body. The outcome highlights the importance of investigation of the role of the point of application of the perturbation.

Differential ubiquitin binding by the acidic loops of Ube2g1 and Ube2r1 enzymes distinguishes their Lys-48-ubiquitylation activities.

The ubiquitin E2 enzymes, Ube2g1 and Ube2r1, are able to synthesize Lys-48-linked polyubiquitins without an E3 ligase but how that is accomplished has been unclear. Although both E2s contain essential acidic loops, only Ube2r1 requires an additional C-terminal extension (184-196) for efficient Lys-48-ubiquitylation activity. The presence of Tyr-102 and Tyr-104 in the Ube2g1 acidic loop enhanced both ubiquitin binding and Lys-48-ubiquitylation and distinguished Ube2g1 from the otherwise similar truncated Ube2r1(1-183) (Ube2r1C). Replacement of Gln-105-Ser-106-Gly-107 in the acidic loop of Ube2r1C (Ube2r1C(YGY)) by the corresponding residues from Ube2g1 (Tyr-102-Gly-103-Tyr-104) increased Lys-48-ubiquitylation activity and ubiquitin binding. Two E2∼UB thioester mimics (oxyester and disulfide) were prepared to characterize the ubiquitin binding activity of the acidic loop. The oxyester but not the disulfide derivative was found to be a functional equivalent of the E2∼UB thioester. The ubiquitin moiety of the Ube2r1C(C93S)-[(15)N]UB(K48R) oxyester displayed two-state conformational exchange, whereas the Ube2r1C(C93S/YGY)-[(15)N]UB(K48R) oxyester showed predominantly one state. Together with NMR studies that compared UB(K48R) oxyesters of the wild-type and the acidic loop mutant (Y102G/Y104G) forms of Ube2g1, in vitro ubiquitylation assays with various mutation forms of the E2s revealed how the intramolecular interaction between the acidic loop and the attached donor ubiquitin regulates Lys-48-ubiquitylation activity.

Control of grip force and vertical posture while holding an object and being perturbed.

We investigated motor control perspectives of coordinating maintenance of posture and application of grip force when holding an object and being perturbed. Ten subjects stood on the force platform holding an instrumented object in their dominant hand and were exposed to an external perturbation applied to their shoulders. Task demands were manipulated by positioning a slippery cap on top of the instrumented object. Grip force applied to the object, the object acceleration and the center of pressure (COP) were recorded and analyzed during the time intervals typical for the anticipatory (APA) and compensatory (CPA) components of postural control. Onsets of grip force were seen before the onsets of the COP displacement and initiation of movements of the handheld object during the APA phase of postural control, while the onsets of maximum grip force preceded the maximum COP displacement during the CPA phase. When the task demands increased by holding a handheld object with the slippery cap, subjects tended to generate grip force earlier and of a smaller magnitude; also, the COP displacement in the APA phase was smaller as compared to holding a handheld object only. The outcome provides a foundation for future studies of maintenance of vertical posture in people with impairments of balance and grip force control when holding an object and being perturbed.

Effects of Contact-Induced Doping on the Behaviors of Organic Photovoltaic Devices.

Substrates can significantly affect the electronic properties of organic semiconductors. In this paper, we report the effects of contact-induced doping, arising from charge transfer between a high work function hole extraction layer (HEL) and the organic active layer, on organic photovoltaic device performance. Employing a high work function HEL is found to increase doping in the active layer and decrease photocurrent. Combined experimental and modeling investigations reveal that higher doping increases polaron-exciton quenching and carrier recombination within the field-free region. Consequently, there exists an optimal HEL work function that enables a large built-in field while keeping the active layer doping low. This value is found to be ~0.4 eV larger than the pinning level of the active layer material. These understandings establish a criterion for optimal design of the HEL when adapting a new active layer system and can shed light on optimizing performance in other organic electronic devices.

External root resorption during orthodontic treatment in root-filled teeth and contralateral teeth with vital pulp: A clinical study of contributing factors.

INTRODUCTION: There is a lack of research to support the belief that root canal treatment can be considered for stopping or decreasing external apical root resorption (EARR). There is conflicting evidence as to whether root-filled teeth are more or less likely to experience EARR after orthodontic treatment. The purpose of this study was to compare the degree of EARR of root-filled teeth with that of contralateral teeth with vital pulp after fixed orthodontic treatment. METHODS: The study sample consisted of 35 patients aged 25.23 ± 4.92 years who had at least 1 root-filled tooth before orthodontic treatment. Digital panoramic radiographs of each patient taken before and after orthodontic treatment were used to measure the EARR. The Student t test for matched pairs and the Pearson correlation analysis were applied. RESULTS: The mean EARR values were 0.22 (0.14, 0.35) for root-filled teeth and 0.87 (0.59, 1.31) for contralateral teeth with vital pulp, indicating significantly less EARR for root-filled teeth compared with the contralateral teeth with vital pulp after orthodontic treatment. EARR was influenced by the patient's age, treatment duration, treatment type, and periapical pathosis, but not by tooth type and sex. CONCLUSIONS: Root-filled teeth appear to be associated with significantly less EARR than are contralateral teeth with vital pulp. This study suggests that the possible complication of EARR in root-filled teeth may not be an important consideration in orthodontic treatment planning, and root canal treatment can be considered for stopping or decreasing EARR when severe EARR occurs during orthodontic treatment.

Enhancement of anticipatory postural adjustments in older adults as a result of a single session of ball throwing exercise.

The aim of the study was to investigate the role of short-term training in improvement of anticipatory postural adjustments (APAs) and its effect on subsequent control of posture in older adults. Nine healthy older adults were exposed to self-initiated and predictable external perturbations before and after a single training session consisting of throwing a medicine ball. EMG activity of eight trunk and leg muscles and ground reaction forces were recorded before and immediately after the training session. Muscle onsets and center of pressure displacements were analyzed during the anticipatory and compensatory phases of postural control. The training involving throwing of a medicine ball resulted in enhancement of the generation of APAs seen as significantly early onsets of leg and trunk muscle activity prior to the bilateral arm flexion task. Significantly early activation of postural muscles observed prior to the predictable external perturbation, the task that was not a part of training, indicates the transfer of the effect of the single training session. The observed training-related improvements of APAs suggest that APA-focused rehabilitation could be effective in improving postural control, functional balance, mobility, and quality of life in the elderly.

Anticipatory and compensatory postural adjustments in conditions of body asymmetry induced by holding an object.

The effect of body asymmetry on anticipatory and compensatory postural adjustments was studied. Ten healthy subjects stood on the force platform and held an object in one hand which induced body asymmetry. Subjects were exposed to external perturbations applied to their shoulders while standing with either normal or narrow base of support. Bilateral electromyographic activity (EMG) of dorsal and ventral trunk and leg muscles and center-of-pressure displacements were recorded. Data was analyzed within the intervals typical for anticipatory (APA) and compensatory postural adjustments. Integrals of EMG activity and co-contraction and reciprocal activation of muscles were calculated and analyzed. Reciprocal activation of muscles on the target side and co-contraction of muscles on the contralateral side were seen when standing in asymmetrical stance and being subjected to external perturbations. Decreased magnitudes of co-contraction and reciprocal activation of muscles were seen in the APA phase while standing asymmetrically with narrow base of support. The findings highlight the importance of investigating the role of body asymmetry in maintaining control of vertical posture. The outcome of the study provides a foundation for future studies focusing on improvement in postural control in individuals with body asymmetry due to unilateral weakness.

Anti-obesity and hypolipidaemic effects of Nelumbo nucifera seed ethanol extract in human pre-adipocytes and rats fed a high-fat diet.

BACKGROUND: We conducted this investigation in order to examine the anti-obesity and hypolipidaemic effects of Nelumbo nucifera seed ethanol extract (NSEE) in vitro and in vivo. METHODS: To study the anti-obesity effect of NSEE in vitro and in vivo, human pre-adipocytes were treated with NSEE, and male Sprague-Dawley rats were fed with a normal diet and a high-fat diet with or without NSEE, respectively. RESULTS: In vitro treatment with NSEE resulted in inhibition of lipid accumulation and decreased expression of peroxisome proliferator-activated receptor gamma (PPARγ), glucose transporter 4 (GLUT4), and leptin in cultured human adipocytes, indicating that it inhibited the differentiation of pre-adipocytes into adipocytes. Administration of NSEE resulted in significantly reduced body weight gain and adipose tissue weights in rats. Serum triglyceride and leptin level of the high-fat diet + NSEE group was significantly lower, compared to the high-fat group. CONCLUSION: These results demonstrate an inhibitory effect of NSEE on adipogenesis. In addition, NSEE had a beneficial effect, reducing adipose tissue weights, ameliorating blood lipid profile, and modulating serum leptin level in rats fed a high-fat diet. Therefore, we suggest that lotus seed has a potential to be developed as an effective agent against obesity-related diseases.