Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System.

Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating "bad sectors" in the mitochondrial network, serving as a mitochondrial quality surveillance system.

Regulatory networks in plant responses to drought and cold stress.

Drought and cold represent distinct types of abiotic stress, each initiating unique primary signaling pathways in response to dehydration and temperature changes, respectively. However, a convergence at the gene regulatory level is observed where a common set of stress-responsive genes is activated to mitigate the impacts of both stresses. In this review, we explore these intricate regulatory networks, illustrating how plants coordinate distinct stress signals into a collective transcriptional strategy. We delve into the molecular mechanisms of stress perception, stress signaling, and the activation of gene regulatory pathways, with a focus on insights gained from model species. By elucidating both the shared and distinct aspects of plant responses to drought and cold, we provide insight into the adaptive strategies of plants, paving the way for the engineering of stress-resilient crop varieties that can withstand a changing climate.

Arabidopsis TBP-ASSOCIATED FACTOR 12 ortholog NOBIRO6 controls root elongation with unfolded protein response cofactor activity.

Plant root growth is indeterminate but continuously responds to environmental changes. We previously reported on the severe root growth defect of a double mutant in bZIP17 and bZIP28 (bz1728) modulating the unfolded protein response (UPR). To elucidate the mechanism by which bz1728 seedlings develop a short root, we obtained a series of bz1728 suppressor mutants, called nobiro, for rescued root growth. We focused here on nobiro6, which is defective in the general transcription factor component TBP-ASSOCIATED FACTOR 12b (TAF12b). The expression of hundreds of genes, including the bZIP60-UPR regulon, was induced in the bz1728 mutant, but these inductions were markedly attenuated in the bz1728nobiro6 mutant. In view of this, we assigned transcriptional cofactor activity via physical interaction with bZIP60 to NOBIRO6/TAF12b. The single nobiro6/taf12b mutant also showed an altered sensitivity to endoplasmic reticulum stress for both UPR and root growth responses, demonstrating that NOBIRO6/TAF12b contributes to environment-responsive root growth control through UPR.

Visual Mental Imagery and Neural Dynamics of Sensory Substitution in the Blindfolded Subjects.

Although one can recognize the environment by soundscape substituting vision to auditory signal, whether subjects could perceive the soundscape as visual or visual-like sensation has been questioned. In this study, we investigated hierarchical process to elucidate the recruitment mechanism of visual areas by soundscape stimuli in blindfolded subjects. Twenty-two healthy subjects were repeatedly trained to recognize soundscape stimuli converted by visual shape information of letters. An effective connectivity method called dynamic causal modeling (DCM) was employed to reveal how the brain was hierarchically organized to recognize soundscape stimuli. The visual mental imagery model generated cortical source signals of five regions of interest better than auditory bottom-up, cross-modal perception, and mixed models. Spectral couplings between brain areas in the visual mental imagery model were analyzed. While within-frequency coupling is apparent in bottom-up processing where sensory information is transmitted, cross-frequency coupling is prominent in top-down processing, corresponding to the expectation and interpretation of information. Sensory substitution in the brain of blindfolded subjects derived visual mental imagery by combining bottom-up and top-down processing.

Interfacial Triboelectricity Lights Up Phosphor-Polymer Elastic Composites: Unraveling the Mechanism of Mechanoluminescence in Zinc Sulfide Microparticle-Embedded Polydimethylsiloxane Films.

Composites comprising copper-doped zinc sulfide phosphor microparticles embedded in polydimethylsiloxane (ZnS:Cu-PDMS) have received significant attention over the past decade because of their bright and durable mechanoluminescence (ML); however, the underlying mechanism of this unique ML remains unclear. This study reports empirical and theoretical findings that confirm this ML is an electroluminescence (EL) of the ZnS:Cu phosphor induced by the triboelectricity generated at the ZnS:Cu microparticle-PDMS matrix interface. ZnS:Cu microparticles that exhibit bright ML are coated with alumina, an oxide with strong positive triboelectric properties; the contact separation between this oxide coating and PDMS, a polymer with strong negative triboelectric properties, produces sufficient interfacial triboelectricity to induce EL in ZnS:Cu microparticles. The ML of ZnS:Cu-PDMS composites varies on changing the coating material, exhibiting an intensity that is proportional to the amount of interfacial triboelectricity generated in the system. Finally, based on these findings, a mechanism that explains the ML of phosphor-polymer elastic composites (interfacial triboelectric field-driven alternating-current EL model) is proposed in this study. It is believed that understanding this mechanism will enable the development of new materials (beyond ZnS:Cu-PDMS systems) with bright and durable ML.

Deep learning-assisted inverse design of nanoparticle-embedded radiative coolers.

Radiative cooling is an energy-efficient technology without consuming power. Depending on their use, radiative coolers (RCs) can be designed to be either solar-transparent or solar-opaque, which requires complex spectral characteristics. Our research introduces a novel deep learning-based inverse design methodology for creating thin-film type RCs. Our deep learning algorithm determines the optimal optical constants, material volume ratios, and particle size distributions for oxide/nitride nanoparticle-embedded polyethylene films. It achieves the desired optical properties for both types of RCs through Mie Scattering and effective medium theory. We also assess the optical and thermal performance of each RCs.

Prenatal cocaine exposure and self-reported behavioral adjustments from ages 12 to 21: environmental pathways.

BACKGROUND: In a birth-cohort study, we followed offspring with prenatal cocaine exposure (PCE) to investigate longitudinal associations of PCE with self-reported behavioral adjustment from early adolescence to emerging adulthood (EA). Environmental pathways (family functioning, non-kinship care, maltreatment) were specified as potential mediators of PCE. METHODS: Participants were 372 (190 PCE; 47% male), primarily Black, low socioeconomic status, enrolled at birth. Internalizing and externalizing behaviors were assessed using Youth Self-Report at ages 12 and 15 and Adult Self-Report at age 21. Extended random-intercept cross-lagged panel modeling was used to account for potential bidirectional relationships between internalizing and externalizing behaviors over time, examining potential mediators. RESULTS: Adjusting for covariates, significant indirect effects were found for each mediator at different ages. For family functioning, these were both internalizing (ß = 0.83, p = 0.04) and externalizing behaviors (ß = 1.58, p = 0.02) at age 12 and externalizing behaviors at age 15 (ß = 0.51, p = 0.03); for non-kinship care, externalizing behaviors at ages 12 (ß = 0.63, p = 0.02) and 15 (ß = 0.20, p = 0.03); and for maltreatment, both internalizing and externalizing behaviors at ages 15 (ß = 0.64, p = 0.02 for internalizing; ß = 0.50, p = 0.03 for externalizing) and 21 (ß = 1.39, p = 0.01 for internalizing; ß = 1.11, p = 0.01 for externalizing). Direct associations of PCE with internalizing and externalizing behaviors were not observed, nor cross-lagged relationships between internalizing and externalizing behaviors. CONCLUSIONS: Negative associations of PCE with behavioral adjustment persist into EA via environmental pathways, specifying intervention points to disrupt adverse pathways toward healthy development.

Upper turnaround point in a reentry circuit of the idiopathic left posterior fascicular ventricular tachycardia.

BACKGROUND: The anatomic extent of the reentry circuit in idiopathic left posterior fascicular ventricular tachycardia (LPF-VT) is yet to be fully elucidated. We hypothesized that entrainment mapping could be used to delineate the reentry circuit of an LPF-VT, especially including the upper turnaround point. METHODS: Twenty-three consecutive LPF-VT patients (mean age, 29 ± 9 years, 18 males) were included. We performed overdrive pacing with entrainment attempts at the left bundle branch (LBB) and the left His bundle (HB) region. RESULTS: Overdrive pacing from the LBB region showed concealed fusion in all 23 patients (post-pacing interval [PPI], 322.1 ± 64.3 ms; tachycardia cycle length [TCL], 319.0 ± 61.6 ms; PPI-TCL, 3.1 ± 4.6 ms) with a long stimulus-to-QRS interval (287.9 ± 58.0 ms, approximately 90% of the TCL). Pacing from the same LBB region at a slightly faster pacing rate showed manifest fusion with antidromic conduction to the LBB and minimal in-and-out time to the LBB potential (PPI-TCL, 21.3 ± 13.7 ms). Overdrive pacing from the left HB region showed manifest fusion with a long PPI-TCL (53.9 ± 22.5 ms). CONCLUSIONS: Our pacing study results suggest that the upper turnaround point in a reentry circuit of the LPF-VT may extend to the proximal His-Purkinje conduction system near the LBB region but below the left HB region. The LPF may constitute the retrograde limb of the reentry circuit.

Prevalence and risk factors of low vitamin D levels in children and adolescents with familial hypokalemic periodic paralysis.

Patients with familial hypokalemic periodic paralysis (HOKPP) experience episodes of reversible immobility and are at an increased risk of limited sunlight exposure, potentially leading to vitamin D deficiency. However, there is a lack of data on vitamin D levels in this population. We investigated serum vitamin D levels and their associated factors in children with HOKPP. This study included 170 genetically-confirmed children with HOKPP, aged 3-18 years, and 170 age-, sex-, and body mass index (BMI)-matched healthy controls from the Korean Channelopathy Study, a prospective controlled investigation. Anthropometric and clinical characteristics were recorded, and serum levels of calcium, ionized calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D, and intact parathyroid hormone (PTH) were analyzed. Vitamin D deficiency (< 20 ng/mL) was observed in 87.0% of the patients compared to 45.5% of the controls (P < 0.05) during the summer-fall season. During the winter-spring season, 91.7% of the patients and 73.4% of the controls were deficient (P < 0.05). A strong positive correlation was found between onset age of the first paralytic attack and vitamin D levels (r = 0.78, P < 0.01). Conversely, the frequency and duration of paralytic attacks were negatively correlated with vitamin D levels (r = -0.82 and r = -0.65, P < 0.01, respectively). Age, BMI, age at onset, frequency and duration of attacks, and PTH levels were independently associated with vitamin D levels (ß = -0.10, -0.12, 0.19, -0.27, -0.21, and -0.13, P < 0.05, respectively). CONCLUSIONS: Vitamin D deficiency was highly prevalent in children with HOKPP, and vitamin D levels correlated with various disease characteristics. We recommend routine screening for vitamin D levels in these patients to address this prevalent deficiency. Considering the high prevalence of vitamin D deficiency observed, further research on other diseases characterized by reversible immobility is warranted. WHAT IS KNOWN: • A correlation between immobility and low serum vitamin D levels has been established. However, the vitamin D status of patients with familial hypokalemic periodic paralysis (HOKPP) who experience periods of reversible immobility remains unknown. WHAT IS NEW: • Vitamin D deficiency was highly prevalent in children with HOKPP, and vitamin D levels correlated with various disease characteristics.

Respiratory rate­oxygenation (ROX) index for predicting high-flow nasal cannula failure in patients with and without COVID-19.

BACKGROUND: The predictive value of the respiratory rate­oxygenation (ROX) index for a high-flow nasal cannula (HFNC) in patients with COVID-19 with acute hypoxemic respiratory failure (AHRF) may differ from patients without COVID-19 with AHRF, but these patients have not yet been compared. We compared the diagnostic accuracy of the ROX index for HFNC failure in patients with AHRF with and without COVID-19 during acute emergency department (ED) visits. METHODS: We performed a retrospective analysis of patients with AHRF treated with an HFNC in an ED between October 2020 and April 2022. The ROX index was calculated at 1, 2, 4, 6, 12, and 24 h after HFNC placement. The primary outcome was the failure of the HFNC, which was defined as the need for subsequent intubation or death within 72 h. A receiver operating characteristic (ROC) curve was used to evaluate discriminative power of the ROX index for HFNC failure. RESULTS: Among 448 patients with AHRF treated with an HFNC in an ED, 78 (17.4%) patients were confirmed to have COVID-19. There was no significant difference in the HFNC failure rates between the non-COVID-19 and COVID-19 groups (29.5% vs. 33.3%, p = 0.498). The median ROX index was higher in the non-COVID-19 group than in the COVID-19 group at all time points. The prognostic power of the ROX index for HFNC failure as evaluated by the area under the ROC curve was generally higher in the COVID-19 group (0.73-0.83) than the non-COVID-19 group (0.62-0.75). The timing of the highest prognostic value of the ROX index for HFNC failure was at 4 h for the non-COVID-19 group, whereas in the COVID-19 group, its performance remained consistent from 1 h to 6 h. The optimal cutoff values were 6.48 and 5.79 for the non-COVID-19 and COVID-19 groups, respectively. CONCLUSIONS: The ROX index had an acceptable discriminative power for predicting HFNC failure in patients with AHRF with and without COVID-19 in the ED. However, the higher ROX index thresholds than those in previous publications involving intensive care unit (ICU) patients suggest the need for careful monitoring and establishment of a new threshold for patients admitted outside the ICU.

Can DNA Methylation Profiling Classify Histologic Subtypes and Grades in Soft Tissue Sarcoma?

BACKGROUND: A clear classification of the subtype and grade of soft tissue sarcoma is important for predicting prognosis and establishing treatment strategies. However, the rarity and heterogeneity of these tumors often make diagnosis difficult. In addition, it remains challenging to predict the response to chemotherapy and prognosis. Thus, we need a new method to help diagnose soft tissue sarcomas and determine treatment strategies in conjunction with traditional methods. Genetic alterations can be found in some subtypes of soft tissue sarcoma, but many other types show dysregulated gene expression attributed to epigenetic changes, such as DNA methylation status. However, research on DNA methylation profiles in soft tissue sarcoma is still insufficient to provide information to assist in diagnosis and therapeutic decisions. QUESTIONS/PURPOSES: (1) Do DNA methylation profiles differ between normal tissue and soft tissue sarcoma? (2) Do DNA methylation profiles vary between different histologic subtypes of soft tissue sarcoma? (3) Do DNA methylation profiles differ based on tumor grade? METHODS: Between January 2019 and December 2022, we treated 85 patients for soft tissue sarcomas. We considered patients whose specimens were approved for pilot research by the Human Biobank of St. Vincent's Hospital, The Catholic University of Korea, as potentially eligible. Based on this, 41% (35 patients) were eligible; 1% (one patient) was excluded because of gender mismatch between clinical and genetic data after controlling for data quality. Finally, 39 specimens (34 soft tissue sarcomas and five normal samples) were included from 34 patients who had clinical data. All tissue samples were collected intraoperatively. The five normal tissue samples were from muscle tissues. There were 20 female patients and 14 male patients, with a median age of 58 years (range 19 to 82 years). Genomic DNA was extracted from frozen tissue, and DNA methylation profiles were obtained. Genomic annotation of DNA methylation sites and hierarchical cluster analysis were performed to interpret results from DNA methylation profiling. A t-test was used to analyze different methylation probes. Benjamini-Hochberg-adjusted p value calculations were used to account for bias resulting from evaluating thousands of methylation sites. RESULTS: The most common histologic subtypes were liposarcoma (n = 10) and leiomyosarcoma (n = 9). The tumor grade was Fédération Nationale des Centres de Lutte Contre Le Cancer Grades 1, 2, and 3 in 3, 15, and 16 patients, respectively. DNA methylation profiling demonstrated differences between soft tissue sarcoma and normal tissue as 21,188 cytosine-phosphate-guanine sites. Despite the small number of samples, 72 of these sites showed an adjusted p value of < 0.000001, suggesting a low probability of statistical errors. Among the 72 sites, 70 exhibited a hypermethylation pattern in soft tissue sarcoma, with only two sites showing a hypomethylation pattern. Thirty of 34 soft tissue sarcomas were distinguished from normal samples using hierarchical cluster analysis. There was a different methylation pattern between leiomyosarcoma and liposarcoma at 7445 sites. Using the data, hierarchical clustering analysis showed that liposarcoma was distinguished from leiomyosarcoma. When we used the same approach and included other subtypes with three or more samples, only leiomyosarcoma and myxofibrosarcoma were separated from the other subtypes, while liposarcoma and alveolar soft-part sarcoma were mixed with the others. When comparing DNA methylation profiles between low-grade (Grade 1) and high-grade (Grades 2 and 3) soft tissue sarcomas, a difference in methylation pattern was observed at 144 cytosine-phosphate-guanine sites. Among these, 132 cytosine-phosphate-guanine sites exhibited hypermethylation in the high-grade group compared with the low-grade group. Hierarchical clustering analysis showed a division into two groups, with most high-grade sarcomas (28 of 31) separated from the low-grade group and few (3 out of 31) clustered together with the low-grade group. However, three high-grade soft tissue sarcomas were grouped with the Grade 1 cluster, and all of these sarcomas were Grade 2. When comparing Grades 1 and 2 to Grade 3, Grade 3 tumors were separated from Grades 1 and 2. CONCLUSION: We observed a different DNA methylation pattern between soft tissue sarcomas and normal tissues. Liposarcoma was distinguished from leiomyosarcoma using methylation profiling. High-grade soft tissue sarcoma samples showed a hypermethylation pattern compared with low-grade ones. Our findings indicate the need for research using methylation profiling to better understand the diverse biological characteristics of soft tissue sarcoma. Such research should include studies with sufficient samples and a variety of subtypes, as well as analyses of the expression and function of related genes. Additionally, efforts to link this research with clinical data related to treatment and prognosis are necessary. LEVEL OF EVIDENCE: Level III, diagnostic study.

Comparison of High- and Low-Dose Rivaroxaban Regimens in Elderly East Asian Patients With Atrial Fibrillation.

BACKGROUND: In the Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban 20 mg was the on-label dose, and the dose-reduction criterion for rivaroxaban was a creatinine clearance of < 50 mL/min. Some Asian countries are using reduced doses label according to the J-ROCKET AF trial. The aim of this study was to assess the safety and efficacy of a high-dose rivaroxaban regimen (HDRR, 20/15 mg) and low-dose rivaroxaban regimen (LDRR, 15/10 mg) among elderly East Asian patients with atrial fibrillation (AF) in real-world practice. METHODS: This study was a multicenter, prospective, non-interventional observational study designed to evaluate the efficacy and safety of rivaroxaban in AF patients > 65 years of age with or without renal impairment. RESULTS: A total of 1,093 patients (mean age, 72.8 ± 5.8 years; 686 [62.9%] men) were included in the analysis, with 493 patients allocated to the HDRR group and 598 patients allocated to the LDRR group. A total of 765 patients received 15 mg of rivaroxaban (203 in the HDRR group and 562 in the LDRR group). There were no significant differences in the incidence rates of major bleeding (adjusted hazard ratio [HR], 0.64; 95% confidential interval [CI], 0.21-1.93), stroke (adjusted HR, 3.21; 95% CI, 0.54-19.03), and composite outcomes (adjusted HR, 1.13; 95% CI, 0.47-2.69) between the HDRR and LDRR groups. CONCLUSION: This study revealed the safety and effectiveness of either dose regimen of rivaroxaban in an Asian population for stroke prevention of AF. Considerable numbers of patients are receiving LDRR therapy in real-world practice in Asia. Both regimens were safe and effective for these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04096547.

Genetic variation for grain nutritional profile and yield potential in sorghum and the possibility of selection for drought tolerance under irrigated conditions.

BACKGROUND: Increasing grain nutritional value in sorghum (Sorghum bicolor) is a paramount breeding objective, as is increasing drought resistance (DR), because sorghum is grown mainly in drought-prone areas. The genetic basis of grain nutritional traits remains largely unknown. Marker-assisted selection using significant loci identified through genome-wide association study (GWAS) shows potential for selecting desirable traits in crops. This study assessed natural variation available in sorghum accessions from around the globe to identify novel genes or genomic regions with potential for improving grain nutritional value, and to study associations between DR traits and grain weight and nutritional composition. RESULTS: We dissected the genetic architecture of grain nutritional composition, protein content, thousand-kernel weight (TKW), and plant height (PH) in sorghum through GWAS of 163 unique African and Asian accessions under irrigated and post-flowering drought conditions. Several QTLs were detected. Some were significantly associated with DR, TKW, PH, protein, and Zn, Mn, and Ca contents. Genomic regions on chromosomes 1, 2, 4, 8, 9, and 10 were associated with TKW, nutritional, and DR traits; colocalization patterns of these markers indicate potential for simultaneous improvement of these traits. In African accessions, markers associated with TKW were mapped to six regions also associated with protein, Zn, Ca, Mn, Na, and DR, suggesting the potential for simultaneous selection for higher grain nutrition and TKW. Our results indicate that it may be possible to select for increased DR on the basis of grain nutrition and weight potential. CONCLUSIONS: This study provides a valuable resource for selecting landraces for use in plant breeding programs and for identifying loci that may contribute to grain nutrition and weight with the hope of producing cultivars that combine improved yield traits, nutrition, and DR.

Identification of cerebral cortices processing acceleration, velocity, and position during directional reaching movement with deep neural network and explainable AI.

Cerebral cortical representation of motor kinematics is crucial for understanding human motor behavior, potentially extending to efficient control of the brain-computer interface. Numerous single-neuron studies have found the existence of a relationship between neuronal activity and motor kinematics such as acceleration, velocity, and position. Despite differences between kinematic characteristics, it is hard to distinguish neural representations of these kinematic characteristics with macroscopic functional images such as electroencephalography (EEG) and magnetoencephalography (MEG). The reason might be because cortical signals are not sensitive enough to segregate kinematic characteristics due to their limited spatial and temporal resolution. Considering different roles of each cortical area in producing movement, there might be a specific cortical representation depending on characteristics of acceleration, velocity, and position. Recently, neural network modeling has been actively pursued in the field of decoding. We hypothesized that neural features of each kinematic parameter could be identified with a high-performing model for decoding with an explainable AI method. Time-series deep neural network (DNN) models were used to measure the relationship between cortical activity and motor kinematics during reaching movement. With DNN models, kinematic parameters of reaching movement in a 3D space were decoded based on cortical source activity obtained from MEG data. An explainable artificial intelligence (AI) method was then adopted to extract the map of cortical areas, which strongly contributed to decoding each kinematics from DNN models. We found that there existed differed as well as shared cortical areas for decoding each kinematic attribute. Shared areas included bilateral supramarginal gyri and superior parietal lobules known to be related to the goal of movement and sensory integration. On the other hand, dominant areas for each kinematic parameter (the contralateral motor cortex for acceleration, the contralateral parieto-frontal network for velocity, and bilateral visuomotor areas for position) were mutually exclusive. Regarding the visuomotor reaching movement, the motor cortex was found to control the muscle force, the parieto-frontal network encoded reaching movement from sensory information, and visuomotor areas computed limb and gaze coordination in the action space. To the best of our knowledge, this is the first study to discriminate kinematic cortical areas using DNN models and explainable AI.

Cortical maps of somatosensory perception in human.

Tactile and movement-related somatosensory perceptions are crucial for our daily lives and survival. Although the primary somatosensory cortex is thought to be the key structure of somatosensory perception, various cortical downstream areas are also involved in somatosensory perceptual processing. However, little is known about whether cortical networks of these downstream areas can be dissociated depending on each perception, especially in human. We address this issue by combining data from direct cortical stimulation (DCS) for eliciting somatosensation and data from high-gamma band (HG) elicited during tactile stimulation and movement tasks. We found that artificial somatosensory perception is elicited not only from conventional somatosensory-related areas such as the primary and secondary somatosensory cortices but also from a widespread network including superior/inferior parietal lobules and premotor cortex. Interestingly, DCS on the dorsal part of the fronto-parietal area including superior parietal lobule and dorsal premotor cortex often induces movement-related somatosensations, whereas that on the ventral one including inferior parietal lobule and ventral premotor cortex generally elicits tactile sensations. Furthermore, the HG mapping results of the movement and passive tactile stimulation tasks revealed considerable similarity in the spatial distribution between the HG and DCS functional maps. Our findings showed that macroscopic neural processing for tactile and movement-related perceptions could be segregated.

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

DREB1A/CBF3 Is Repressed by Transgene-Induced DNA Methylation in the Arabidopsis ice1 -1 Mutant.

DREB1/CBFs are key transcription factors involved in plant cold stress adaptation. The expression of DREB1/CBFs triggers a cold-responsive transcriptional cascade, after which many stress tolerance genes are expressed. Thus, elucidating the mechanisms of cold stress-inducible DREB1/CBF expression is important to understand the molecular mechanisms of plant cold stress responses and tolerance. We analyzed the roles of a transcription factor, INDUCER OF CBF EXPRESSION1 (ICE1), that is well known as an important transcriptional activator in the cold-inducible expression of DREB1A/CBF3 in Arabidopsis (Arabidopsis thaliana). ice1-1 is a widely accepted mutant allele known to abolish cold-inducible DREB1A expression, and this evidence has strongly supported ICE1-DREB1A regulation for many years. However, in ice1-1 outcross descendants, we unexpectedly discovered that ice1-1 DREB1A repression was genetically independent of the ice1-1 allele ICE1(R236H). Moreover, neither ICE1 overexpression nor double loss-of-function mutation of ICE1 and its homolog SCRM2 altered DREB1A expression. Instead, a transgene locus harboring a reporter gene in the ice1-1 genome was responsible for altering DREB1A expression. The DREB1A promoter was hypermethylated due to the transgene. We showed that DREB1A repression in ice1-1 results from transgene-induced silencing and not genetic regulation by ICE1. The ICE1(R236H) mutation has also been reported as scrm-D, which confers constitutive stomatal differentiation. The scrm-D phenotype and the expression of a stomatal differentiation marker gene were confirmed to be linked to the ICE1(R236H) mutation. We propose that the current ICE1-DREB1 regulatory model should be revalidated without the previous assumptions.

Long-term outcome of thoracoscopic ablation and radiofrequency catheter ablation for persistent atrial fibrillation as a de novo procedure.

AIMS: Limited data are available regarding the efficacy of thoracoscopic ablation as the first procedure for persistent atrial fibrillation (AF). We sought to compare the long-term efficacy of thoracoscopic ablation vs. radiofrequency (RF) catheter ablation as the first procedure for persistent AF. METHODS AND RESULTS: Between February 2011 and December 2020, 575 patients who underwent ablation for persistent AF were studied. Among them, thoracoscopic ablation was performed in 281 patients, RF catheter ablation in 228, and hybrid ablation in 66. Rhythm, clinical, and safety outcomes during 7-year follow-up were compared. The patients who underwent thoracoscopic ablation were older, had a higher prevalence of stroke, and had a larger left atrial volume than those who underwent RF catheter ablation. In the propensity score-matched population (n = 306), incidences of atrial tachyarrhythmia recurrence were 51.4% in the thoracoscopic ablation group and 62.5% in the RF catheter ablation group [adjusted hazard ratio (HR) 0.869, 95% confidence interval (CI) 0.618-1.223, P = 0.420]. Stroke and total procedural adverse events were not significantly different between thoracoscopic and RF catheter ablation (2.7 vs. 2.5%, P = 0.603, and 7.1 vs. 4.8%, P = 0.374, respectively). The hybrid ablation group showed similar rhythm outcomes compared with both the thoracoscopic and the RF catheter ablation groups. At the redo procedure, pulmonary vein gaps were more frequently observed in the RF catheter ablation group (32.6%) than in the thoracoscopic ablation group (7.9%) and in the hybrid ablation group (8.8%) (P < 0.001). CONCLUSION: As a first procedure in persistent AF, thoracoscopic ablation and RF catheter ablation showed comparable efficacy, clinical, and safety outcomes during long-term follow-up.

Oral anticoagulants and concurrent rifampin administration in tuberculosis patients with non-valvular atrial fibrillation.

BACKGROUND: Evidence and guidelines for Non-vitamin K antagonist oral anticoagulants (NOACs) use when prescribing concurrent rifampin for tuberculosis treatment in patients with non-valvular atrial fibrillation (NVAF) are limited. METHODS: Using the Korean National Health Insurance Service database from January 2009 to December 2018, we performed a population-based retrospective cohort study to assess the net adverse clinical events (NACE), a composite of ischemic stroke or systemic embolism and major bleeding, of NOACs compared with warfarin among NVAF patients taking concurrent rifampin administration for tuberculosis treatment. After a propensity matching score (PSM) analysis, Cox proportional hazards regression was performed in matched cohorts to investigate the clinical outcomes. RESULTS: Of the 735 consecutive patients selected, 465 (63.3%) received warfarin and 270 (36.7%) received NOACs. Among 254 pairs of patients after PSM, the crude incidence rate of NACE was 25.6 in NOAC group and 32.8 per 100 person-years in warfarin group. There was no significant difference between NOAC and warfarin use in NACE (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.48-1.14; P = 0.172). Major bleeding was the main driver of NACE, and NOAC use was associated with a statistically significantly lower risk of major bleeding than that with warfarin use (HR, 0.63; 95% CI, 0.40-1.00; P = 0.0499). CONCLUSIONS: In our population-based study, there was no statically significant difference in the occurrence of NACE between NOAC and warfarin use. NOAC use may be associated with a lower risk of major bleeding than that with warfarin use.

Role of cathepsin D induced by Porphyromonas gingivalis lipopolysaccharide in periodontitis.

Periodontitis is an inflammatory disease of tooth-supporting tissues caused by oral bacteria. Periodontal ligament loss and alveolar bone destruction occur in progressive periodontitis. Since gingival crevicular fluids (GCF) reflects the inflammatory environment of the periodontal pocket, it is a very important specimen for developing targets for periodontitis diagnosis. An antibody array was performed using GCF collected from healthy participants and patients with periodontitis to identify the proteolytic enzymes involved in periodontitis. Of 21 targets on the antibody array membrane, kallikrein 6 (KLK6), kallikrein 10 (KLK10), cathepsin A (CathA), and cathepsin D (CathD) showed higher levels in periodontitis GCF than in GCF from healthy participants. Lipopolysaccharide stimulation of Porphyromonas gingivalis (PG-LPS) in immortalized gingival fibroblasts only increased CathD protein levels among the four targets. The substrate cleavage activity of CathD was increased in PG-LPS-treated immortalized gingival fibroblast extract. The PG-LPS-induced substrate cleavage effect was abolished by the CathD inhibitor pepstatin A. Osteoclast formation was promoted by treatment with conditioned media from PG-LPS- treated immortalized gingival fibroblasts but inhibited by the CathD inhibitor pepstatin A. These results suggest that PG-LPS affected the osteoclast formation process by increasing CathD expression in cells around the alveolar bone, thereby participating in periodontitis progression.