Early Invasive Strategy for Octogenarians and Nonagenarians With Acute Myocardial Infarction.

Background: Older adults with acute myocardial infarction (AMI) are currently a rapidly growing population. However, their clinical presentation and outcomes remain unresolved. Methods and Results: A total of 268 consecutive AMI patients were analyzed for clinical characteristics and outcomes with major adverse cardiovascular events (MACE) and all-cause mortality within 1 year. Patients aged ≥80 years (Over-80; n=100) were compared with those aged ≤79 years (Under-79; n=168). (1) Primary percutaneous coronary intervention (PCI) was frequently and similarly performed in both the Over-80 group and the Under-79 group (86% vs. 89%; P=0.52). (2) Killip class III-IV (P<0.01), in-hospital mortality (P<0.01), MACE (P=0.03) and all-cause mortality (P<0.01) were more prevalent in the Over-80 group than in the Under-79 group. (3) In the Over-80 group, frail patients showed a significantly worse clinical outcome compared with non-frail patients. (4) Multivariate analysis revealed Killip class III-IV was associated with MACE (odds ratio [OR]=3.51; P=0.02) and all-cause mortality (OR=9.49; P<0.01) in the Over-80 group. PCI was inversely associated with all-cause mortality (OR=0.13; P=0.02) in the Over-80 group. Conclusions: The rate of primary PCI did not decline with age. Although octogenarians/nonagenarians showed more severe clinical presentation and worse short-term outcomes compared with younger patients, particularly in those with frailty, the prognosis may be improved by early invasive strategy even in these very old patients.

Takotsubo Syndrome in Older Men　- Clinical Characteristics Differ by Sex and Age.

Background: Takotsubo syndrome (TTS) in male patients is under-studied, particularly in the older population. Methods and Results: From 226 patients with TTS, 44 older male patients (prevalence rate: 19.5%, age: median 77 years) were compared with 182 older female patients (prevalence rate: 80.5%, age: median 80 years). Emotional triggers of TTS were less frequent (2% vs. 19%; P=0.007), whereas physical triggers were more frequent (75% vs. 58%; P=0.040) in older men than in women. Among physical triggers, serious respiratory infection was more common in older men than in women. As initial clues to the diagnosis, ECG T-wave inversion was more frequent (48% vs. 29%; P=0.018) and chest pain and/or dyspnea were less common (23% vs. 38%; P=0.050) in older men than in women. In total, 14 patients (6%) had cardiogenic shock and 41 (18%) had severe heart failure as complications, although there were no significant differences in the frequency of these complications between older men and women. Although cardiac death occurred in 3 female patients (1%) and noncardiac death in 3 male and 5 female patients (4%), there were no significant differences in death rate between older men and women. Conclusions: Emotional triggers of TTS were extremely infrequent whereas physical triggers were common in older men. Although severe heart failure was common, there were no significant differences in the frequency of complications and in-hospital deaths between older men and women.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants for Japanese Patients With Venous Thromboembolism　- The Primary Results From the KUROSIO Study.

BACKGROUND: Direct oral anticoagulants (DOACs) are recommended as the first-choice anticoagulation therapy in the acute phase of venous thromboembolism (VTE). However, there is limited real-world data for Japanese VTE patients.Methods and Results: The KUROSIO study (UMIN000023747) was a prospective long-term observational study comprising 1,017 patients with concurrent acute symptomatic pulmonary thromboembolism and proximal deep vein thrombosis (DVT) or isolated calf DVT initially treated with DOACs. After excluding 24 patients, 993 (mean age, 66.3±15.1 years; 58.6% females) were analyzed. The incidences of recurrent symptomatic VTE and major bleeding for up to 52 weeks after diagnosis were 3.2% and 2.2%, respectively. Multivariate analyses revealed chemotherapy and anemia as significant risk factors associated with recurrent symptomatic VTE and major bleeding, respectively. CONCLUSIONS: The efficacy and safety of DOACs in Japanese patients with VTE were determined in this real-world observational study.

The Japanese version of the reduced morningness-eveningness questionnaire.

Circadian typology, or "morningness" and "eveningness," is generally assessed using the Morningness-Eveningness Questionnaire (MEQ), a 19-item scale that could be burdensome in large-scale surveys. To overcome this, a 5-item version known as the reduced morningness-eveningness questionnaire (rMEQ), which is sensitive to the assessment of circadian typology, was developed; however, a validated Japanese version of the rMEQ is yet to be established. This study aimed to develop and validate the Japanese version of the rMEQ. Five essential items for the rMEQ were selected from existing Japanese MEQ data (N = 2,213), and the rMEQ was compiled. We conducted a confirmatory factor analysis for the psychometric properties of the rMEQ and confirmed its robust one-factor structure for evaluating morningness-eveningness (GFI = 0.984, AGFI = 0.951, CFI = 0.935, and RMSEA = 0.091). Reliability was evaluated via internal consistency of rMEQ items using Cronbach's α and McDonald's ω, and the values were 0.618 and 0.654, respectively. The rMEQ scores strongly correlated with MEQ (ρ = 0.883, p < 0.001), and classification agreement (Morning, Neither, and Evening types) between rMEQ and MEQ was 77.6% (Cramer's V = 0.643, Weighted Cohen's κ = 0.72), confirming the validity. The Japanese rMEQ may be a valuable tool for the efficient assessment of circadian typologies.

Frequent nonhomologous replacement of replicative helicase loaders by viruses in Vibrionaceae.

Several microbial genomes lack textbook-defined essential genes. If an essential gene is absent from a genome, then an evolutionarily independent gene of unknown function complements its function. Here, we identified frequent nonhomologous replacement of an essential component of DNA replication initiation, a replicative helicase loader gene, in Vibrionaceae. Our analysis of Vibrionaceae genomes revealed two genes with unknown function, named vdhL1 and vdhL2, that were substantially enriched in genomes without the known helicase-loader genes. These genes showed no sequence similarities to genes with known function but encoded proteins structurally similar with a viral helicase loader. Analyses of genomic syntenies and coevolution with helicase genes suggested that vdhL1/2 encodes a helicase loader. The in vitro assay showed that Vibrio harveyi VdhL1 and Vibrio ezurae VdhL2 promote the helicase activity of DnaB. Furthermore, molecular phylogenetics suggested that vdhL1/2 were derived from phages and replaced an intrinsic helicase loader gene of Vibrionaceae over 20 times. This high replacement frequency implies the host's advantage in acquiring a viral helicase loader gene.

Validation of compositional MRI from a histological standpoint: Advantages of three-dimensional T1ρ mapping for quantitative evaluation of articular cartilage.

PURPOSE: We aimed to investigate the relationship between quantitative evaluation by compositional MRI, including T1ρ, and histological and macroscopic assessments, to verify the validity of compositional MRI, and examine the relationship between compositional MRI evaluation reconstructed in three dimensions (3D) and histological and visual assessments. METHOD: Twenty-seven patients with knee osteoarthritis underwent T1ρ and T2 magnetic resonance imaging (MRI). Histological and gross tissue evaluations were performed on the excised bone sections of total knee arthroplasty. Semi-quantitative histological evaluation of tissue changes were assessed by measuring the optical density of digitally captured safranin O-stained and Collagen type II antibody-stained paraffin sections. Macroscopic cartilage severity was determined on a 5-grade scale (G0-G5). T1ρ and T2 values (3D and 2D), and their correlation with each of these parameters were investigated. RESULTS: 3D T1 ρ is negatively correlated with histological evaluations and positively correlated with visual assessments. Only 3D T1ρ values correlated with histological quantitative evaluation (Safranin-O staining; r = -0.53, P = 0.014, Collagen type II antibody staining; r = -0.60, P = 0.019). 2D T1ρ and 3D, 2D T2 values did not correlate with histological evaluation results. Macroscopic cartilage severity grade correlated with all T1ρ and T2 values (3D T1ρ; r = 0.61, P < 0.001, 2D T1ρ; r = 0.52, P < 0.001, 3D T2; r = 0.33, P = 0.045, 2D T2; r = 0.41, P = 0.01). CONCLUSIONS: 3D T1ρ mapping reflects the changes in the molecular structure of the cartilage matrix that occur in arthropathic changes and may be an effective tool for detecting cartilage degeneration.

Cell surface architecture of the cultivated DPANN archaeon Nanobdella aerobiophila.

The DPANN archaeal clade includes obligately ectosymbiotic species. Their cell surfaces potentially play an important role in the symbiotic interaction between the ectosymbionts and their hosts. However, little is known about the mechanism of ectosymbiosis. Here, we show cell surface structures of the cultivated DPANN archaeon Nanobdella aerobiophila strain MJ1T and its host Metallosphaera sedula strain MJ1HA, using a variety of electron microscopy techniques, i.e., negative-staining transmission electron microscopy, quick-freeze deep-etch TEM, and 3D electron tomography. The thickness, unit size, and lattice symmetry of the S-layer of strain MJ1T were different from those of the host archaeon strain MJ1HA. Genomic and transcriptomic analyses highlighted the most highly expressed MJ1T gene for a putative S-layer protein with multiple glycosylation sites and immunoglobulin-like folds, which has no sequence homology to known S-layer proteins. In addition, genes for putative pectin lyase- or lectin-like extracellular proteins, which are potentially involved in symbiotic interaction, were found in the MJ1T genome based on in silico 3D protein structure prediction. Live cell imaging at the optimum growth temperature of 65°C indicated that cell complexes of strains MJ1T and MJ1HA were motile, but sole MJ1T cells were not. Taken together, we propose a model of the symbiotic interaction and cell cycle of Nanobdella aerobiophila.IMPORTANCEDPANN archaea are widely distributed in a variety of natural and artificial environments and may play a considerable role in the microbial ecosystem. All of the cultivated DPANN archaea so far need host organisms for their growth, i.e., obligately ectosymbiotic. However, the mechanism of the ectosymbiosis by DPANN archaea is largely unknown. To this end, we performed a comprehensive analysis of the cultivated DPANN archaeon, Nanobdella aerobiophila, using electron microscopy, live cell imaging, transcriptomics, and genomics, including 3D protein structure prediction. Based on the results, we propose a reasonable model of the symbiotic interaction and cell cycle of Nanobdella aerobiophila, which will enhance our understanding of the enigmatic physiology and ecological significance of DPANN archaea.

Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Homozygous gene disruption in diploid yeast through a single transformation.

As industrial shochu yeast is a diploid strain, obtaining a strain with mutations in both allelic genes was considered difficult. We investigated a method for disrupting two copies of a homozygous gene with a single transformation. We designed a disruption cassette containing an intact LYS5 flanked by nonfunctional ura3 gene fragments divided into the 5'- and 3'-regions. These fragments had overlapping sequences that enabled LYS5 removal as well as URA3 regeneration through loop-out. Furthermore, both ends of the disruption cassette had an additional repeat sequence that allowed the cassette to be removed from the chromosome through loop-out. First, 45 bases of 5'- and 3'-regions of target gene sequences were added on both ends of this cassette using polymerase chain reaction; the resultant disruption cassette was introduced into a shochu yeast strain (ura3/ura3 lys5/lys5); then, single allele disrupted strains were selected on Lys drop-out plates; and after cultivation in YPD medium, double-disrupted strains, in which replacement of another allelic gene with disruption cassette by loss of heterozygosity and regeneration of URA3 in one of the cassettes by loop-out, were obtained by selection on Ura and Lys drop-out plates. The disruption cassettes were removed from the double-disrupted strain via loop-out between repeat sequences in the disruption cassette. The strains that lost either URA3 or LYS5 were counter-selected on 5-fluoroorotic acid or α-amino adipic acid plates, respectively. Using this method, we obtained leu2/leu2 and leu2/leu2 his3/his3 strains in shochu yeast, demonstrating the effectiveness and repeatability of this gene disruption technique in diploid yeast Saccharomyces cerevisiae.

Epithelial-to-mesenchymal transition, inflammation, subsequent collagen production, and reduced proteinase expression cooperatively contribute to cyclosporin-A-induced gingival overgrowth development.

Drug-induced gingival overgrowth (DIGO), induced by certain immunosuppressive drugs, antihypertensive agents, and antiepileptic drugs, may contribute to the formation of deeper periodontal pockets and intractableness in periodontitis. To date, multiple factors such as enhanced matrix production, inflammation, and reduced matrix degradation might be involved in the pathogenesis of DIGO. We have previously reported that SPOCK-1, a heparan sulfate proteoglycan, could affect gingival thickening by promoting epithelial-to-mesenchymal transition (EMT) in gingival keratinocytes. However, few studies have investigated whether a combination of these factors enhances the DIGO phenotype in animal models. Therefore, we investigated whether SPOCK-1, periodontal inflammation, and cyclosporin-A (CsA) could cooperatively promote gingival overgrowth. We first confirmed that Spock-1 overexpressing (Spock1-Tg) mice showed significantly thicker gingiva and greater alveolar bone loss than WT mice in response to ligature-induced experimental periodontitis. DIGO was induced by the combination of CsA administration and experimental periodontitis was significantly enhanced in Spock1-Tg mice compared to that in WT mice. Ligature-induced alveolar bone loss in CsA-treated Spock1-Tg mice was also significantly greater than that in CsA-treated WT mice, while being accompanied by an increase in Rankl and Col1a1 levels and a reduction in matrix metalloprotease expression. Lastly, SPOCK-1 promoted RANKL-induced osteoclast differentiation in both human peripheral blood mononuclear cells and murine macrophages, while peritoneal macrophages from Spock1-Tg mice showed less TNFα and IL-1ß secretion than WT mice in response to Escherichia coli lipopolysaccharide. These results suggest that EMT, periodontal inflammation, and subsequent enhanced collagen production and reduced proteinase production contribute to CsA-induced DIGO pathogenesis.

The impact of the COVID-19 pandemic on hepatocellular carcinoma diagnosis and treatment in Japan: A multicenter collaborative observational study.

AIM: Coronavirus disease 2019 emerged in December 2019 and spread worldwide. This study aimed to clarify the impact of the coronavirus disease 2019 pandemic on the diagnosis and treatment of hepatocellular carcinoma (HCC) in Japan. METHODS: First, we collected the monthly numbers of HCC-related general medical practices from January 2019 to December 2021 at liver disease-specific medical institutions in Japan. Next, we collected individual clinical information from patients with newly diagnosed HCC during this period. RESULTS: There was a decrease in the number of HCC-related medical practices, including referrals, enhanced abdominal ultrasonography and radiofrequency ablation, in Japan's first state of emergency (SOE; April-May 2020) compared with 2019. Fewer patients were diagnosed with new HCC during the first SOE than before or after it. There was no difference in tumor diameter, number of tumors or Barcelona Clinic Liver Cancer stage between patients diagnosed before the first SOE and those diagnosed during or after the first SOE. The median waiting times for treatment of patients diagnosed during and after the first SOE were 31 and 37 days, which were significantly shorter and not longer than that of patients diagnosed before the first SOE (36 days), respectively. CONCLUSION: The number of HCC-related general medical practices decreased during the first SOE. However, the coronavirus disease 2019 pandemic did not lead to HCC progression by diagnostic delays or cause HCC treatment delays in Japan.

Effects of work-related electronic communication during non-working hours after work from home and office on fatigue, psychomotor vigilance performance and actigraphic sleep: observational study on information technology workers.

OBJECTIVES: This study examined the effects of work-related electronic communication (WREC) during non-working hours in the work from home or office setting on health. METHODS: The study recruited 98 information technology workers in a 9-day observational study. They recorded work-life events (eg, work style (working mostly from home or the office) and duration of WREC during non-working hours) and subjective ratings (eg, current fatigue, sleepiness and depression) and wore a sleep actigraph to measure objective sleep variables before bedtime every day. They completed the Brief Psychomotor Vigilance Test (PVT-B) before bedtime for 4 days. RESULTS: The frequency of WREC was significantly higher when working mostly from home than in the office (p<0.01). In addition, the duration of WREC was longer when working mostly from home than in the office (p<0.001). Linear or generalised linear mixed model analysis for fatigue, depression and PVT lapse revealed significant interaction effects between work style and WREC (all p<0.05). Post hoc analysis showed that the longer the WREC, the worse the fatigue and depression and the lower the lapse on working mostly from the office (all p<0.05). CONCLUSIONS: Longer WREC is associated with worse fatigue and depression and lower lapse of PVT (higher alertness) before bedtime for working mostly from the office. Workers, especially those working from the office, should minimise WREC during non-working hours to maintain good health. Therefore, companies, managers and other relevant stakeholders should refrain from contacting workers during non-working hours.

WeMo: A Prototype of a Wearable Mobility Device Adapting to User's Natural Posture Changes.

Mobility is fundamental for human beings. In the current society, many personal mobility solutions have been invented to enable more time-efficient mobility, such as self-balancing vehicles, electric unicycles, and electric scooters. Personal mobility devices can provide flexibility to transportation. However, most personal mobility devices need to be carried by their users in the case that they climb stairs and steps. Therefore, many researchers have focused on developing stair-climbing vehicles, but due to the complicated mechanism, these devices are usually huge and heavy. To realize a new type of personal mobility device with more flexibility, we proposed a novel concept of a personal mobility device design that combines the agile mobility of a wheel type mechanism but does not limit a human's natural stair climbing ability. In this study, we introduced a compact personal mobility device, namely WeMo, under the concept of "wearing mobility", which extends humans' mobility in daily life. The developed hardware realizes "walking mode" and "driving mode". Users can move with the motorized driven wheels of the device during driving mode, and users can walk on their feet without any interference from the device during walking mode. In this manuscript, the detailed design of the hardware and control strategy were explained first.Then, we conducted fundamental user tests and discussed the ability of the developed device from test results. Finally, the conclusions and future work were provided.

Risk factors for mortality after hip fracture surgery in Japan using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

We investigated the risk factors for mortality of hip fracture in the elderly using the National Database of Health Insurance Claims in Japan, and survival was significantly related to sex, age, fracture type, surgical procedure, delayed operative date, comorbidities, blood transfusions, and pulmonary embolism. PURPOSE: Hip fracture is the most common fracture in the elderly and is known to have a high mortality rate. In Japan, to the best of our knowledge, no studies have reported on mortality risk factors for hip fracture using nationwide registry databases. This study aimed to determine the number of occurrences of hip fracture and factors that increase mortality using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. METHODS: This study included extracted data from patients who were hospitalized and underwent surgical treatment for hip fracture between 2013 and 2021, using a nationwide health insurance claims database in Japan. Patient characteristics, such as sex, age, fracture type, surgical procedure, delayed operative date, comorbidities, blood transfusions, and pulmonary embolism, were tabulated to obtain 1-year and in-hospital mortality rates. RESULTS: Both 1-year and in-patient survival were significantly lower in men, older patients, patients who underwent surgery after 3 days of admission, and patients with trochanteric and subtrochanteric fractures, internal fixation, more preoperative comorbidities, blood transfusions, and pulmonary embolism. CONCLUSIONS: Survival was significantly related to sex, age, fracture type, surgical procedure, delayed operative date, comorbidities, blood transfusions, and pulmonary embolism. As the number of male patients with hip fracture will increase with the aging of society, medical staff must provide sufficient information before surgery to avoid postoperative mortality.

Pulmonary hypertension secondary to interstitial fibrosis with pulmonary venous lesions masquerading pulmonary veno-occlusive disease.

We present a 41-year-old man with idiopathic interstitial pneumonia and pulmonary hypertension (PH) in the setting of a non-autoimmune background whose clinical presentation masqueraded pulmonary veno-occlusive disease (PVOD). Because of no histological evidence of venous occlusion in his previous lung biopsy, phosphodiesterase type-5 inhibitor was given, resulting in sudden onset of pulmonary edema. At autopsy, there were histological features of interstitial fibrosis with occlusion of the lobular septal veins and venules. Clinical presentations of PH due to interstitial fibrosis with pulmonary venous lesions may simulate those of PVOD and careful diagnostic and therapeutic approaches are required.

Intracardiac Thrombosis and Systemic Embolism in a Patient with Cardiac Amyloidosis in Sinus Rhythm.

Intracardiac thrombosis formation in patients in sinus rhythm is a rare phenomenon. An 84-year-old woman was admitted because of worsening dyspnea on exertion. An electrocardiogram showed sinus rhythm, left atrial overload, marked left axis deviation, low voltage, and poor r-wave progression in leads V1-4. An echocardiogram showed relatively preserved left ventricular ejection fraction with minimal wall thickening. Her serum level of B-type natriuretic peptide (931 pg/mL) was markedly elevated and a diagnosis of worsening heart failure was made. During the course of treatment for heart failure, she was complicated by acute abdominal aortic thromboembolism together with left atrial thrombus. An emergency abdominal aortic thrombectomy was followed by the removal of a left atrial thrombus 2 days later. Left ventricular biopsy performed during the surgery revealed amyloid deposits in the myocardial interstitium. Immunohistochemical study confirmed the diagnosis of transthyretin cardiac amyloidosis. It is postulated that the risk of intracardiac thrombosis and systemic embolism is increased even in sinus rhythm in patients with cardiac amyloidosis.

Refractory electrical storm in a patient with hypertrophic cardiomyopathy and an implantable cardioverter-defibrillator.

A 63-year-old man with hypertrophic cardiomyopathy (HCM), mid-ventricular obstruction, and an apical aneurysm had an episode of cardiac arrest due to sustained ventricular tachycardia (VT). He was resuscitated and an implantable cardioverter-defibrillator (ICD) was implanted. In the following years, several episodes of VT and ventricular fibrillation were successfully terminated by antitachycardia pacing or ICD shocks. Three years after ICD implantation, he was re-admitted because of refractory electrical storm (ES). Since aggressive pharmacological treatments, direct current cardioversions, and deep sedation were not effective, he underwent epicardial catheter ablation which was successful to terminate ES. However, because of the recurrence of refractory ES after one year, he proceeded to surgical left ventricular myectomy with apical aneurysmectomy which provided him a relatively stable clinical course for six years. Although epicardial catheter ablation may be an acceptable option, surgical resection of apical aneurysm seems to be most efficacious for ES in patients with HCM and an apical aneurysm. Learning objectives: In patients with hypertrophic cardiomyopathy (HCM), implantable cardioverter-defibrillators (ICDs) are the gold standard of therapy for prophylaxis against sudden death. Electrical storm (ES) caused by recurrent episodes of ventricular tachycardia can cause sudden death even in patients with ICDs. Although epicardial catheter ablation may be an acceptable option, surgical resection of apical aneurysm is most efficacious for ES in patients with HCM, mid-ventricular obstruction, and an apical aneurysm.

Pathogenic LRRK2 compromises the subcellular distribution of lysosomes in a Rab12-RILPL1-dependent manner.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). Recent studies have shown that LRRK2 physiologically phosphorylates several Rab family proteins including Rab12 and that this phosphorylation is accelerated by the pathogenic mutations in LRRK2, although the significance in the PD pathogenesis remains unknown. Here we examined the effect of the overexpression of LRRK2 on the distribution of organelles in cultured cells and found that lysosomes become clustered in a perinuclear region upon the overexpression of pathogenic mutant LRRK2 in a manner dependent on its kinase activity. The perinuclear clustering of lysosomes was abolished by knocking out RAB12 as well as its effector protein RILPL1. Re-expression of Rab12 in RAB12 knockout cells suggested that the phosphorylation at Ser106 of Rab12 is required for the perinuclear clustering of lysosomes. Moreover, phosphorylated Rab12 was also accumulated on the clustered lysosomes, and the phosphorylation of Rab12 increased its interaction with RILPL1, leading us to conclude that the increase in the phosphorylation of Rab12 by pathogenic LRRK2 compromised intracellular lysosomal transport via the enhanced interaction of Rab12 with RILPL1. These data suggest the involvement of abnormal regulation of lysosomal transport in the LRRK2-mediated pathogenesis of PD.