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Kinesin-3 is a family of microtubule-dependent motor proteins that transport various cargos within the cell. However, the mechanism underlying kinesin-3 activations remains largely elusive. In this study, we compared the biochemical properties of two Caenorhabditis elegans kinesin-3 family proteins, KLP-6 and UNC-104. Both KLP-6 and UNC-104 are predominantly monomeric in solution. As previously shown for UNC-104, non-processive KLP-6 monomer is converted to a processive motor when artificially dimerized. We present evidence that releasing the autoinhibition is sufficient to trigger dimerization of monomeric UNC-104 at nanomolar concentrations, which results in processive movement of UNC-104 on microtubules, although it has long been thought that enrichment in the phospholipid microdomain on cargo vesicles is required for the dimerization and processive movement of UNC-104. In contrast, KLP-6 remains to be a non-processive monomer even when its autoinhibition is unlocked, suggesting a requirement of other factors for full activation. By examining the differences between KLP-6 and UNC-104, we identified a coiled-coil domain called coiled-coil 2 (CC2) that is required for the efficient dimerization and processive movement of UNC-104. Our results suggest a common activation mechanism for kinesin-3 family members, while also highlighting their diversification.

Kinesin superfamily proteins are microtubule-based molecular motors driven by the energy of ATP hydrolysis. Among them, the kinesin-4 family is a unique motor that inhibits microtubule dynamics. Although mutations of kinesin-4 cause several diseases, its molecular mechanism is unclear because of the difficulty of visualizing the high-resolution structure of kinesin-4 working at the microtubule plus-end. Here, we report that KLP-12, a C. elegans kinesin-4 ortholog of KIF21A and KIF21B, is essential for proper length control of C. elegans axons, and its motor domain represses microtubule polymerization in vitro. The crystal structure of the KLP-12 motor domain complexed with tubulin, which represents the high-resolution structural snapshot of the inhibition state of microtubule-end dynamics, revealed the bending effect of KLP-12 for tubulin. Comparison with the KIF5B-tubulin and KIF2C-tubulin complexes, which represent the elongation and shrinking forms of microtubule ends, respectively, showed the curvature of tubulin introduced by KLP-12 is in between them. Taken together, KLP-12 controls the proper length of axons by modulating the curvature of the microtubule ends to inhibit the microtubule dynamics.

KIF1A is a kinesin superfamily motor protein that transports synaptic vesicle precursors in axons. Cargo binding stimulates the dimerization of KIF1A molecules to induce processive movement along microtubules. Mutations in human Kif1a lead to a group of neurodegenerative diseases called KIF1A-associated neuronal disorder (KAND). KAND mutations are mostly de novo and autosomal dominant; however, it is unknown if the function of wild-type KIF1A motors is inhibited by heterodimerization with mutated KIF1A. Here, we have established Caenorhabditis elegans models for KAND using CRISPR-Cas9 technology and analyzed the effects of human KIF1A mutation on axonal transport. In our C. elegans models, both heterozygotes and homozygotes exhibited reduced axonal transport. Suppressor screening using the disease model identified a mutation that recovers the motor activity of mutated human KIF1A. In addition, we developed in vitro assays to analyze the motility of heterodimeric motors composed of wild-type and mutant KIF1A. We find that mutant KIF1A significantly impaired the motility of heterodimeric motors. Our data provide insight into the molecular mechanism underlying the dominant nature of de novo KAND mutations. [ABSTRACT FROM AUTHOR]

An investigation is carried out through experiments and numerical calculations for the improvement of the resolution of measuring the pitch deviation of a diffraction scale grating with the diffracted beams. Since the changes in angles of diffraction of the diffracted beams detected by an optical head are utilized to evaluate the pitch deviation in the method, the sensitivity of the optical head directly affects the resolution for measurement of the pitch deviation. Meanwhile, in the previous studies, the resolution of a laser-autocollimation unit in the optical head for the detection of the change in the angle of diffraction of a diffracted beam has been limited to approximately 0.1 arc-second; this has been a bottleneck in increasing the resolution for measurement of the pitch deviation. In this paper, an investigation using a prototype optical head is first conducted in preliminary experiments to clarify the cause of the degradation of the resolution for measurement of the pitch deviation. Numerical calculations are also carried out to confirm the influence of the multiple longitudinal modes (MLM) of a laser beam, which is suggested as the main cause of the degradation of resolution in the results of preliminary experiments. Based on the results of experiments and numerical calculations, an attempt is made to employ a laser beam having a single longitudinal mode (SLM) in the optical head. The pitch deviation of a scale grating with a nominal pitch of 4 μm is measured by a prototype optical head with an SLM laser to verify the improvement of the resolution for measurement of the pitch deviation.

Abstract The automatic balancing mechanism introduced in 2004 aims to re-establish the financial equilibrium of the Japanese public pension systems. The non-linear functions for benefits embedded in the automatic balancing mechanism make it challenging to analyse the impact of market fluctuations on the adequacy of benefits and the sustainability of the pension system. Using a stochastic simulation model applied to the government’s public pension verification programmes, the risk of benefit levels and financial stability according to risk-taking in pension reserve funds for the Japanese public pension system is investigated. The Japanese public pension system is characterised by a pay-as-you-go system with substantial reserve funds. Benefit adequacy is measured by the replacement rate and financial sustainability by the reserve-to-expenditure ratio. The results show that for a high level of risk-taking in the reserve fund, the risk of benefits increases because the automatic balancing mechanism reduces benefits until the pension system recovers solvency. In addition, the risk of reserve funds increases because of the possibility of sizeable negative investment returns. In contrast, when risk-taking is low, the benefit level is locked in at a low level because investment returns are insufficient. Therefore, moderate risk-taking of reserve funds should be adequate.

This study explores the hypothetical elimination of Japan's retirement earnings test (ET) for public pensions, focusing on its implications for older workers' labor supply and pension-claiming behaviors. The ET currently reduces public pension benefits for individuals aged 65 and older if their earnings exceed specified thresholds, potentially discouraging employment in this demographic. Notably, the Japanese ET influences both immediate and future pension benefits, thus diminishing current payouts for working pensioners and foregoing beneficial actuarial adjustments-adjustments based on actuarial calculations that would otherwise increase future benefits to account for delayed pension claims. This dual impact may discourage the labor supply and influence pension-claiming behavior among older workers. Through a survey-based experiment with male workers aged 40-59 years expected to face the ET upon retirement, we assess three reform scenarios as the first study in the literature: (1) eliminating future benefit reductions through actuarial adjustments, thereby enhancing the value of deferred pension claims; (2) removing immediate benefit suspensions to increase current pension payments directly; and (3) a comprehensive reform combining both approaches. Our findings reveal that eliminating reductions through actuarial adjustments increases the intensive margin (labor hours and income) and encourages delayed pension claims. Conversely, removing immediate benefit suspensions influences both the extensive margin (decision to work) and the intensive margin but leads to earlier pension claims. By highlighting the importance of differentiating between immediate and future benefit components in designing ET reforms, this study demonstrates their significant impact on labor supply and pension-claiming decisions.

Abstract Background Eating alone has been significantly associated with psychological distress. However, there is no research that evaluates the effects or relation of eating together online to autonomic nervous system functions. Methods This is a randomized, open-label, controlled, pilot study conducted among healthy volunteers. Participants were randomized into either an eating together online group or an eating-alone group. The effect of eating together on autonomic nervous functions was evaluated and compared with that of the control (eating alone). The primary endpoint was the change in the standard deviation of the normal-to-normal interval (SDNN) scores among heart rate variabilities (HRV) before and after eating. Physiological synchrony was investigated based on changes in the SDNN scores. Results A total of 31 women and 25 men (mean age, 36.6 [SD = 9.9] years) were included in the study. In the comparison between the aforementioned groups, two-way analysis of variance revealed interactions between time and group on SDNN scores. SDNN scores in the eating together online group increased in the first and second halves of eating time (F[1,216], P

Abstract Deep inspiration breath-hold (DIBH) is widely used to reduce the cardiac dose in left-sided breast cancer radiotherapy. This study aimed to develop a deep learning chest X-ray model for cardiac dose prediction to select patients with a potentially high risk of cardiac irradiation and need for DIBH radiotherapy. We used 103 pairs of anteroposterior and lateral chest X-ray data of left-sided breast cancer patients (training cohort: n = 59, validation cohort: n = 19, test cohort: n = 25). All patients underwent breast-conserving surgery followed by DIBH radiotherapy: the treatment plan consisted of three-dimensional, two opposing tangential radiation fields. The prescription dose of the planning target volume was 42.56 Gy in 16 fractions. A convolutional neural network-based regression model was developed to predict the mean heart dose (∆MHD) reduction between free-breathing (MHDFB) and DIBH. The model performance is evaluated as a binary classifier by setting the cutoff value of ∆MHD > 1 Gy. The patient characteristics were as follows: the median (IQR) age was 52 (47–61) years, MHDFB was 1.75 (1.14–2.47) Gy, and ∆MHD was 1.00 (0.52–1.64) Gy. The classification performance of the developed model showed a sensitivity of 85.7%, specificity of 90.9%, a positive predictive value of 92.3%, a negative predictive value of 83.3%, and a diagnostic accuracy of 88.0%. The AUC value of the ROC curve was 0.864. The proposed model could predict ∆MHD in breast radiotherapy, suggesting the potential of a classifier in which patients are more desirable for DIBH.

We investigated the risk of secondary cancers in rectum and bladder for prostate cancer radiotherapy using a feasibility assessment tool. We calculated the risk of secondary cancer by generating a dose-volume histogram based on an ideal dose falloff function (f-value). This study found a smaller f-value was associated with a lower secondary cancer risk in the rectum but a higher risk in the bladder. The study suggests setting the f-value at 0-0.1 as the optimization goal for the rectum and 0.4 for the bladder is reasonable and feasible for reducing the risk of secondary cancer and other adverse events.

Abstract Background This study aimed to investigate preoperative spirometry and BMI as early predictors of the mean heart and lung dose (MHD, MLD) in deep inspiration breath-hold (DIBH) radiotherapy. Methods Left-sided breast cancer patients underwent breast-conserving surgery followed by DIBH radiotherapy enrolled. Patients who were not available for preoperative spirometry were excluded. One hundred eligible patients were performed free-breathing (FB-) CT and DIBH-CT for plan comparison. We completed the correlative and multivariate analysis to develop the linear regression models for dose prediction. The residuals were calculated to explore the unpreferable subgroups and compare the prediction accuracy. Results Among the parameters, vital capacity (VC) and BMI showed the strongest negative correlation with MHD (r = − 0.33) and MLD (r = − 0.34), respectively. They were also significant in multivariate analysis (P

Abstract This study aimed to develop a poly-ε-caprolactone (PCL) material that has a low melting point while maintaining the deformation ability. The new PCL (abbreviated as 4b45/2b20) was fabricated by mixing two types of PCL with different molecular weights, numbers of branches, and physical properties. To investigate the melting point, crystallization temperature, elastic modulus, and elongation at break for 4b45/2b20 and three commercially available masks, differential scanning calorimetry and tensile tests were performed. The melting point of 4b45/2b20 was 46.0 °C, and that of the commercially available masks was approximately 56.0 °C (55.7 °C–56.5 °C). The elastic modulus at 60 °C of 4b45/2b20 was significantly lower than the commercially available masks (1.1 ± 0.3 MPa and 46.3 ± 5.4 MPa, p = 0.0357). In addition, the elongation at break of 4b45/2b20 were significantly larger than the commercially available masks (275.2 ± 25.0% and 216.0 ± 15.2%, p = 0.0347). The crystallization temperature of 4b45/2b20 (22.1 °C) was clinically acceptable and no significant difference was found in the elastic modulus at 23 °C (253.7 ± 24.3 MPa and 282.0 ± 44.3 MPa, p = 0.4). As a shape memory-based thermoset material, 4b45/2b20 has a low melting point and large deformation ability. In addition, the crystallization temperature and strength are within the clinically acceptable standards. Because masks made using the new PCL material are formed with less pressure on the face than commercially available masks, it is a promising material for making a radiotherapy mask that can reduce the burden on patients.

Atlas-based auto-segmentation (ABS) procedure used in radiotherapy can be classified into two groups, one using one atlas per patient (sSM) and the other using multiple atlases (sMM). This study evaluated auto-contouring accuracy and contouring time in patients with prostate cancer using the two procedures. The Dice similarity coefficient of sMM was significantly better than that of sSM (prostate [median, 0.81 (range, 0.66–0.91) vs. 0.64 (0.27–0.71), p

The motor modules during human walking are identified using non-negative matrix factorization (NNMF) from surface electromyography (EMG) signals. The extraction of motor modules in healthy participants is affected by the change in pre-processing of EMG signals, such as low-pass filters (LPFs); however, the effect of different pre-processing methods, such as the number of necessary gait cycles (GCs) in post-stroke patients with varying steps, remains unknown. We aimed to specify that the number of GCs influenced the motor modules extracted in the consideration of LPFs in post-stroke patients. In total, 10 chronic post-stroke patients walked at a self-selected speed on an overground walkway, while EMG signals were recorded from the eight muscles of paretic lower limb. To verify the number of GCs, five GC conditions were set, namely, 25 (reference condition), 20, 15, 10, and 5 gate cycles with three LPFs (4, 10, and 15 Hz). First, the number of modules, variability accounted for (VAF), and muscle weightings extracted by the NNMF algorithm were compared between the conditions. Next, a modified NNMF algorithm, in which the activation timing profiles among different GCs were unified, was performed to compare the muscle weightings more robustly between GCs. The number of motor modules was not significantly different, regardless of the GCs. The difference in VAF and muscle weightings in the different GCs decreased with the LPF of 4 Hz. Muscle weightings in 15 GCs or less were significantly different from those in 25 GCs using the modified NNMF. Therefore, we concluded that the variability extracted motor modules by different GCs was suppressed with lower LPFs; however, 20 GCs were needed for more representative extraction of motor modules during walking in post-stroke patients.

Abstract Objective To develop and validate a preoperative nomogram to predict pathological locally advanced disease (pLAD) of clinically localized upper urinary tract urothelial carcinoma (UTUC) treated with extirpative surgery. Methods In total, 1101 patients with cN0M0 UTUC (development cohort, n = 604; validation cohort, n = 497) from 2 independent academic databases were retrospectively analyzed. pLAD was defined as pT3/4 and/or pN+. Multivariate logistic regression was used to develop a nomogram. The accuracy of the nomogram was evaluated with a receiver operating characteristic curve, calibration plot, and decision curve analysis. Results The development and validation cohorts comprised 204 (33.8%) and 178 (35.8%) patients with pLAD, respectively. The multivariate analyses showed that the neutrophil‐to‐lymphocyte ratio (hazard ratio [HR], 2.27; P

It is desirable that noninvasive differential diagnosis takes place without lymph node biopsy for histiocytic necrotizing lymphadenitis (HNL) or malignant lymphoma (ML). In this study, we propose a novel scoring model for the differential diagnosis of these diseases using clinical information and clinical findings. We retrospectively analyzed the data from 15 HNL and 13 ML pediatric patients. First, a univariate analysis identified 14 clinical factors with significant differences. Second, a subsequent analysis using receiver operating characteristic (ROC) curve analysis identified three factors among them with area under the ROC curve values of >0.95: body temperature (°C), maximum lymph node size (cm), and serum β2-microglobulin level (mg/L). Finally, the cut-off values of each of these three factors were determined and examined for the 28 cases. All 15 HNL cases were within 2–3 of the cut-off values among the three factors, no ML case was within two or more cut-off values. Thus, the diagnostic sensitivity and specificity of this novel scoring system were both 100%, indicating that clinical scoring with body temperature, maximum lymph node size, and β2-microglobulin are useful for distinguishing between HNL and ML.

Gold nanoparticles (AuNPs) can be used with megavolt (MV) X-rays to exert radiosensitization effects, as demonstrated in cell survival assays and mouse experiments. However, the detailed mechanisms are not clear; besides physical dose enhancement, several chemical and biological processes have been proposed. Reducing the AuNP concentration while achieving sufficient enhancement is necessary for the clinical application of AuNPs. Here, we used positively charged (+) AuNPs to determine the radiosensitization effects of AuNPs combined with MV X-rays on DNA damage in vitro. We examined the effect of low concentrations of AuNPs on DNA damage and reactive oxygen species (ROS) generation. DNA damage was promoted by 1.4 nm +AuNP with dose enhancement factors of 1.4 ± 0.2 for single-strand breaks and 1.2 ± 0.1 for double-strand breaks. +AuNPs combined with MV X-rays induced radiosensitization at the DNA level, indicating that the effects were physical and/or chemical. Although −AuNPs induced similar ROS levels, they did not cause considerable DNA damage. Thus, dose enhancement by low concentrations of +AuNPs may have occurred with the increase in the local +AuNP concentration around DNA or via DNA binding. +AuNPs showed stronger radiosensitization effects than −AuNPs. Combining +AuNPs with MV X-rays in radiation therapy may improve clinical outcomes.

Polyamines are involved in various biological functions, including cell proliferation, differentiation, gene regulation, etc. Recently, it was found that polyamines exhibit biphasic effects on gene expression: promotion and inhibition at low and high concentrations, respectively. Here, we compared the effects of three naturally occurring tetravalent polyamines, spermine (SPM), thermospermine (TSPM), and N4-aminopropylspermidine (BSPD). Based on the single DNA observation with fluorescence microscopy together with measurements by atomic force microscopy revealed that these polyamines induce shrinkage and then compaction of DNA molecules, at low and high concentrations, respectively. We also performed the observation to evaluate the effects of these polyamine isomers on the activity of gene expression by adapting a cell-free luciferase assay. Interestingly, the potency of their effects on the DNA conformation and also on the inhibition of gene expression activity indicates the highest for TSPM among spermine isomers. A numerical evaluation of the strength of the interaction of these polyamines with negatively charged double-strand DNA revealed that this ordering of the potency corresponds to the order of the strength of the attractive interaction between phosphate groups of DNA and positively charged amino groups of the polyamines.

Clinical arterial stiffness indexes such as PWV (pulse wave velocity) or PP (pulse pressure), which are obtained by analyzing blood pressure pulse waveforms in vivo, are used in the prognosis of cardiovascular diseases and thus analyses of pulse waveform are clinically important. The pulse wave in vivo, however, is complicated because of the complex viscoelastic property of the blood vessel wall. In addition, numerical flow simulations are useful for understanding pulse wave propagation in circulatory systems. Our proposed nonlinear one-dimensional numerical simulation model can accurately simulate the measurements of pressure waves in a silicone rubber tube and indicate that the viscoelasticity of the tube wall was significantly influenced by a single pulse waveform; however, the influence of viscoelasticity change on periodic pulsatile wave propagation has not yet been studied. The purpose of this study was therefore to investigate the effect of viscoelasticity change on the periodic pulsatile wave. For this purpose, we examined the effect of the viscoelasticity of a single silicone tube on periodic pulse wave propagation by comparing the calculated results using a one-dimensional model. As a result, the one-dimensional model could accurately express the experimental results with periodic pulsatile waves. In addition, both PWV and PP increase when the viscoelastic value of the dynamic modulus elasticity ratio increases, because increasing the elastic modulus is more effective than the energy dissipation effect by viscoelasticity change. Consequently, it is necessary to measure the viscoelastic property of the vessel wall accurately in order to estimate the arterial stiffness index (PWV and PP) accurately.

In order to analyze the pressure wave propagation in circulatory systems, we previously presented a one-dimensional numerical flow simulation model that describes wave propagation in silicone tubes well and shows that the viscoelasticity of the tube has an important role in the wave propagation. In the present study, by comparison with experimental results, we show that the one-dimensional numerical model describes well the propagation of small pressure waves in silicone tubes even when their deformation compliance and viscoelasticity change independently, provided that appropriate values of the viscoelastic parameter are used.