Intraflagellar transport (IFT) particles, a multi-protein apparatus composed of complex A and B, are known to be involved in homeostasis of flagella formation. IFT particles have recently become an interesting topic in Giardia lamblia, which has 4 pairs of flagella. In this experiment, we examined the function of giardial IFT components. When 7 components (IFT121, 140, 20, 46, 52, 81, and 88) of IFT were expressed in Giardia trophozoites as a tagged form with mNeonGreen, all of them were found in both flagella pores and cytoplasmic axonemes. In addition, motor proteins for IFT particles (kinesin-13 and kinesin-2b), were localized to a median body and cytoplasmic flagella, respectively. The CRISPRi-mediated knockdown of IFT88 significantly affected the lengths of all 4 flagella compared to the control cells, Giardia expressing dead Cas9 using control guide RNA. Decreased expression of kinesin-2b also resulted in shortening of flagella, excluding the ventral flagella. Live Giardia cells expressing IFT88-mNeonGreen clearly demonstrated fluorescence in flagella pores and cytoplasmic axonemes. These results on IFT88 and kinesin-2b indicate that IFT complex plays a role in maintenance of G. lamblia flagella.

Intraflagellar transport (IFT) particles, a multi-protein apparatus composed of complex A and B, are known to be involved in homeostasis of flagella formation. IFT particles have recently become an interesting topic in Giardia lamblia, which has 4 pairs of flagella. In this experiment, we examined the function of giardial IFT components. When 7 components (IFT121, 140, 20, 46, 52, 81, and 88) of IFT were expressed in Giardia trophozoites as a tagged form with mNeonGreen, all of them were found in both flagella pores and cytoplasmic axonemes. In addition, motor proteins for IFT particles (kinesin-13 and kinesin-2b), were localized to a median body and cytoplasmic flagella, respectively. The CRISPRi-mediated knockdown of IFT88 significantly affected the lengths of all 4 flagella compared to the control cells, Giardia expressing dead Cas9 using control guide RNA. Decreased expression of kinesin-2b also resulted in shortening of flagella, excluding the ventral flagella. Live Giardia cells expressing IFT88-mNeonGreen clearly demonstrated fluorescence in flagella pores and cytoplasmic axonemes. These results on IFT88 and kinesin-2b indicate that IFT complex plays a role in maintenance of G. lamblia flagella.

Intraflagellar transport (IFT) particles, a multi-protein apparatus composed of complex A and B, are known to be involved in homeostasis of flagella formation. IFT particles have recently become an interesting topic in Giardia lamblia, which has 4 pairs of flagella. In this experiment, we examined the function of giardial IFT components. When 7 components (IFT121, 140, 20, 46, 52, 81, and 88) of IFT were expressed in Giardia trophozoites as a tagged form with mNeonGreen, all of them were found in both flagella pores and cytoplasmic axonemes. In addition, motor proteins for IFT particles (kinesin-13 and kinesin-2b), were localized to a median body and cytoplasmic flagella, respectively. The CRISPRi-mediated knockdown of IFT88 significantly affected the lengths of all 4 flagella compared to the control cells, Giardia expressing dead Cas9 using control guide RNA. Decreased expression of kinesin-2b also resulted in shortening of flagella, excluding the ventral flagella. Live Giardia cells expressing IFT88-mNeonGreen clearly demonstrated fluorescence in flagella pores and cytoplasmic axonemes. These results on IFT88 and kinesin-2b indicate that IFT complex plays a role in maintenance of G. lamblia flagella.

Intraflagellar transport (IFT) particles, a multi-protein apparatus composed of complex A and B, are known to be involved in homeostasis of flagella formation. IFT particles have recently become an interesting topic in Giardia lamblia, which has 4 pairs of flagella. In this experiment, we examined the function of giardial IFT components. When 7 components (IFT121, 140, 20, 46, 52, 81, and 88) of IFT were expressed in Giardia trophozoites as a tagged form with mNeonGreen, all of them were found in both flagella pores and cytoplasmic axonemes. In addition, motor proteins for IFT particles (kinesin-13 and kinesin-2b), were localized to a median body and cytoplasmic flagella, respectively. The CRISPRi-mediated knockdown of IFT88 significantly affected the lengths of all 4 flagella compared to the control cells, Giardia expressing dead Cas9 using control guide RNA. Decreased expression of kinesin-2b also resulted in shortening of flagella, excluding the ventral flagella. Live Giardia cells expressing IFT88-mNeonGreen clearly demonstrated fluorescence in flagella pores and cytoplasmic axonemes. These results on IFT88 and kinesin-2b indicate that IFT complex plays a role in maintenance of G. lamblia flagella.

Intraflagellar transport (IFT) particles, a multi-protein apparatus composed of complex A and B, are known to be involved in homeostasis of flagella formation. IFT particles have recently become an interesting topic in Giardia lamblia, which has 4 pairs of flagella. In this experiment, we examined the function of giardial IFT components. When 7 components (IFT121, 140, 20, 46, 52, 81, and 88) of IFT were expressed in Giardia trophozoites as a tagged form with mNeonGreen, all of them were found in both flagella pores and cytoplasmic axonemes. In addition, motor proteins for IFT particles (kinesin-13 and kinesin-2b), were localized to a median body and cytoplasmic flagella, respectively. The CRISPRi-mediated knockdown of IFT88 significantly affected the lengths of all 4 flagella compared to the control cells, Giardia expressing dead Cas9 using control guide RNA. Decreased expression of kinesin-2b also resulted in shortening of flagella, excluding the ventral flagella. Live Giardia cells expressing IFT88-mNeonGreen clearly demonstrated fluorescence in flagella pores and cytoplasmic axonemes. These results on IFT88 and kinesin-2b indicate that IFT complex plays a role in maintenance of G. lamblia flagella.

Purpose: This study aimed to determine whether genetic factors affect the location of dilated perivascular spaces (dPVS) by comparing healthy young twins and non-twin (NT) siblings. Materials and Methods: A total of 700 healthy young adult twins and NT siblings [138 monozygotic (MZ) twin pairs, 79 dizygotic (DZ) twin pairs, and 133 NT sibling pairs] were collected from the Human Connectome Project dataset. dPVS was automatically segmented and normalized to standard space. Then, spatial similarity indices [mean squared error (MSE), structural similarity (SSIM), and dice similarity (DS)] were calculated for dPVS in the basal ganglia (BGdPVS) and white matter (WMdPVS) between paired subjects before and after propensity score matching of dPVS volumes between groups. Within-pair correlations for the regional volumes of dVPS were also assessed using the intraclass correlation coefficient. Results: The spatial similarity of dPVS was significantly higher in MZ twins [higher DS (median, 0.382 and 0.310) and SSIM (0.963 and 0.887) and lower MSE (0.005 and 0.005) for BGdPVS and WMdPVS, respectively] than in DZ twins [DS (0.121 and 0.119), SSIM (0.941 and 0.868), and MSE (0.010 and 0.011)] and NT siblings [DS (0.106 and 0.097), SSIM (0.924 and 0.848), and MSE (0.016 and 0.017)]. No significant difference was found between DZ twins and NT siblings. Similar results were found even after the subjects were matched according to dPVS volume. Regional dPVS volumes were also more correlated within pairs in MZ twins than in DZ twins and NT siblings. Conclusion Our results suggest that genetic factors affect the location of dPVS.

Purpose: This study aimed to determine whether genetic factors affect the location of dilated perivascular spaces (dPVS) by comparing healthy young twins and non-twin (NT) siblings. Materials and Methods: A total of 700 healthy young adult twins and NT siblings [138 monozygotic (MZ) twin pairs, 79 dizygotic (DZ) twin pairs, and 133 NT sibling pairs] were collected from the Human Connectome Project dataset. dPVS was automatically segmented and normalized to standard space. Then, spatial similarity indices [mean squared error (MSE), structural similarity (SSIM), and dice similarity (DS)] were calculated for dPVS in the basal ganglia (BGdPVS) and white matter (WMdPVS) between paired subjects before and after propensity score matching of dPVS volumes between groups. Within-pair correlations for the regional volumes of dVPS were also assessed using the intraclass correlation coefficient. Results: The spatial similarity of dPVS was significantly higher in MZ twins [higher DS (median, 0.382 and 0.310) and SSIM (0.963 and 0.887) and lower MSE (0.005 and 0.005) for BGdPVS and WMdPVS, respectively] than in DZ twins [DS (0.121 and 0.119), SSIM (0.941 and 0.868), and MSE (0.010 and 0.011)] and NT siblings [DS (0.106 and 0.097), SSIM (0.924 and 0.848), and MSE (0.016 and 0.017)]. No significant difference was found between DZ twins and NT siblings. Similar results were found even after the subjects were matched according to dPVS volume. Regional dPVS volumes were also more correlated within pairs in MZ twins than in DZ twins and NT siblings. Conclusion Our results suggest that genetic factors affect the location of dPVS.

Purpose: Vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been the standard of care for advanced and metastatic clear cell renal cell carcinoma (ccRCC). However, the therapeutic effect of TKI monotherapy remains unsatisfactory given the high rates of acquired resistance to TKI therapy despite favorable initial tumor response. Materials and Methods: To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through in vitro and in vivo studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. Results: Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. Conclusions These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.

Background: The efficacy and safety of direct oral anticoagulants (DOACs) versus warfarin in patients with antiphospholipid syndrome-associated venous thromboembolism (APS-VTE) remain uncertain. We aimed to evaluate efficacy and safety of DOACs in patients with APSVTE. Methods: Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified all APS-VTE cases. We examined the VTE recurrence, arterial thrombosis, death and bleeding in patients who received DOACs compared with warfarin for therapeutic anticoagulation. Results: Of all the VTE cases (n = 84,916) detected between 2014 and 2018, patients with APS-VTE (n = 410) accounted for 0.48%. Most patients with APS-VTE (73%) were aged < 60 years. The recurrent VTE occurred in 8 of 209 patients (3.8%) who received DOACs and in 7 of 201 (3.5%) who received warfarin (relative risk [RR], 1.099; 95% confidence interval [CI], 0.41–2.98; P = 1.000). The arterial thrombosis (ATE) occurred in 8 of 209 patients (3.8%) who received DOAC and in 20 of 201 (10%) who received warfarin (RR, 0.385; 95% CI, 0.17–0.85; P = 0.024). The composite outcomes of VTE recurrence, ATE, or mortality were significantly lower in patients (9.1%) on DOAC than in those (16.3%) on warfarin (RR, 0.537; 95% CI, 0.32–0.91; P = 0.028). The bleeding outcome occurred in 7 of 209 (3.4%) patients in the DOACs group and 7 of 201 (3.5%) patients in the warfarin group (RR, 0.96; 95% CI, 0.34–2.69; P = 0.840). Conclusion In patients with APS-VTE, DOACs group showed comparable rates of recurrent VTE, bleeding, and deaths, but a significantly lower incidence of ATE and composite outcomes compared with the warfarin group in Korea.

Purpose: This study aimed to determine whether genetic factors affect the location of dilated perivascular spaces (dPVS) by comparing healthy young twins and non-twin (NT) siblings. Materials and Methods: A total of 700 healthy young adult twins and NT siblings [138 monozygotic (MZ) twin pairs, 79 dizygotic (DZ) twin pairs, and 133 NT sibling pairs] were collected from the Human Connectome Project dataset. dPVS was automatically segmented and normalized to standard space. Then, spatial similarity indices [mean squared error (MSE), structural similarity (SSIM), and dice similarity (DS)] were calculated for dPVS in the basal ganglia (BGdPVS) and white matter (WMdPVS) between paired subjects before and after propensity score matching of dPVS volumes between groups. Within-pair correlations for the regional volumes of dVPS were also assessed using the intraclass correlation coefficient. Results: The spatial similarity of dPVS was significantly higher in MZ twins [higher DS (median, 0.382 and 0.310) and SSIM (0.963 and 0.887) and lower MSE (0.005 and 0.005) for BGdPVS and WMdPVS, respectively] than in DZ twins [DS (0.121 and 0.119), SSIM (0.941 and 0.868), and MSE (0.010 and 0.011)] and NT siblings [DS (0.106 and 0.097), SSIM (0.924 and 0.848), and MSE (0.016 and 0.017)]. No significant difference was found between DZ twins and NT siblings. Similar results were found even after the subjects were matched according to dPVS volume. Regional dPVS volumes were also more correlated within pairs in MZ twins than in DZ twins and NT siblings. Conclusion Our results suggest that genetic factors affect the location of dPVS.