Identification of tomato F-box proteins functioning in phenylpropanoid metabolism.

Phenylpropanoids, a class of specialized metabolites, play crucial roles in plant growth and stress adaptation and include diverse phenolic compounds such as flavonoids. Phenylalanine ammonia-lyase (PAL) and chalcone synthase (CHS) are essential enzymes functioning at the entry points of general phenylpropanoid biosynthesis and flavonoid biosynthesis, respectively. In Arabidopsis, PAL and CHS are turned over through ubiquitination-dependent proteasomal degradation. Specific kelch domain-containing F-Box (KFB) proteins as components of ubiquitin E3 ligase directly interact with PAL or CHS, leading to polyubiquitinated PAL and CHS, which in turn influences phenylpropanoid and flavonoid production. Although phenylpropanoids are vital for tomato nutritional value and stress responses, the post-translational regulation of PAL and CHS in tomato remains unknown. We identified 31 putative KFB-encoding genes in the tomato genome. Our homology analysis and phylogenetic study predicted four PAL-interacting SlKFBs, while SlKFB18 was identified as the sole candidate for the CHS-interacting KFB. Consistent with their homolog function, the predicted four PAL-interacting SlKFBs function in PAL degradation. Surprisingly, SlKFB18 did not interact with tomato CHS and the overexpression or knocking out of SlKFB18 did not affect phenylpropanoid contents in tomato transgenic lines, suggesting its irreverence with flavonoid metabolism. Our study successfully discovered the post-translational regulatory machinery of PALs in tomato while highlighting the limitation of relying solely on a homology-based approach to predict interacting partners of F-box proteins.

Transcriptional repression of GTL1 under water-deficit stress promotes anthocyanin biosynthesis to enhance drought tolerance.

The transcription factor GT2-LIKE 1 (GTL1) has been implicated in orchestrating a transcriptional network of diverse physiological, biochemical, and developmental processes. In response to water-limiting conditions, GTL1 is a negative regulator of stomatal development, but its potential rolein other water-deficit responses is unknown. We hypothesized that GTL1 regulates transcriptome changes associated with drought tolerance over leaf developmental stages. To test the hypothesis, gene expression was profiled by RNA-seq analysis in emerging and expanding leaves of wild-type and a drought-tolerant gtl1-4 knockout mutant under well-watered and water-deficit conditions. Our comparative analysis of genotype-treatment combinations within leaf developmental age identified 459 and 1073 differentially expressed genes in emerging and expanding leaves, respectively, as water-deficit responsive GTL1-regulated genes. Transcriptional profiling identified a potential role of GTL1 in two important pathways previously linked to drought tolerance: flavonoid and polyamine biosynthesis. In expanding leaves, negative regulation of GTL1 under water-deficit conditions promotes biosynthesis of flavonoids and anthocyanins that may contribute to drought tolerance. Quantification of polyamines did not support a role for GTL1 in these drought-responsive pathways, but this is likely due to the complex nature of polyamine synthesis and turnover. Our global transcriptome analysis suggests that transcriptional repression of GTL1 by water deficit allows plants to activate diverse pathways that collectively contribute to drought tolerance.

What is going on inside of phytochrome B photobodies?

Plants exhibit an enormous phenotypic plasticity to adjust to changing environmental conditions. For this purpose, they have evolved mechanisms to detect and measure biotic and abiotic factors in their surroundings. Phytochrome B exhibits a dual function, since it serves as a photoreceptor for red and far-red light as well as a thermosensor. In 1999, it was first reported that phytochromes not only translocate into the nucleus but also form subnuclear foci upon irradiation by red light. It took more than 10 years until these phytochrome speckles received their name; these foci were coined photobodies to describe unique phytochrome-containing subnuclear domains that are regulated by light. Since their initial discovery, there has been much speculation about the significance and function of photobodies. Their presumed roles range from pure experimental artifacts to waste deposits or signaling hubs. In this review, we summarize the newest findings about the meaning of phyB photobodies for light and temperature signaling. Recent studies have established that phyB photobodies are formed by liquid-liquid phase separation via multivalent interactions and that they provide diverse functions as biochemical hotspots to regulate gene expression on multiple levels.

High-Reliability and Self-Rectifying Alkali Ion Memristor through Bottom Electrode Design and Dopant Incorporation.

Ionic memristor devices are crucial for efficient artificial neural network computations in neuromorphic hardware. They excel in multi-bit implementation but face challenges like device reliability and sneak currents in crossbar array architecture (CAA). Interface-type ionic memristors offer low variation, self-rectification, and no forming process, making them suitable for CAA. However, they suffer from slow weight updates and poor retention and endurance. To address these issues, the study demonstrated an alkali ion self-rectifying memristor with an alkali metal reservoir formed by a bottom electrode design. By adopting Li metal as the adhesion layer of the bottom electrode, an alkali ion reservoir was formed at the bottom of the memristor layer by diffusion occurring during the atomic layer deposition process for the Na:TiO2 memristor layer. In addition, Al dopant was used to improve the retention characteristics by suppressing the diffusion of alkali cations. In the memristor device with optimized Al doping, retention characteristics of more than 20 h at 125 °C, endurance characteristics of more than 5.5 × 105, and high linearity/symmetry of weight update characteristics were achieved. In reliability tests on 100 randomly selected devices from a 32 × 32 CAA device, device-to-device and cycle-to-cycle variations showed low variation values within 81% and 8%, respectively.

Treatment Outcome of the Brain Metastases in Peri-Rolandic Area: Comparison Between Surgery and Stereotactic Radiosurgery.

BACKGROUND: Brain metastases of peri-Rolandic area is crucial as it directly impacts the quality of life for cancer patients. Surgery or stereotactic radiosurgery (SRS) is considered for peri-Rolandic brain metastases as for other brain metastases. However, the benefit of each treatment modality on functional outcome has not been clearly defined for this tumor. The purpose of this study is to compare the functional course of each treatment and to suggest an effective treatment for patients' quality of life. METHODS: Fifty-two patients who had undergone SRS or surgery for brain metastasis confirmed by enhanced MRI were enrolled retrospectively. Overall survival (OS), progression free survival (PFS), and functional outcomes were estimated using the Kaplan-Meier method, univariate, multivariate analysis, and Cox proportional hazards regression. RESULTS: Median OS and PFS were 13.3 months and 8.9 months in our study population. Treatment modalities were not significant factors for OS and PFS. Extracranial systemic cancer progression was significant factor for both parameters (p=0.030 for OS and p=0.040 for PFS). Median symptom improvement (improvement of at least 1 grade after surgery compared to preoperative state) time was significantly shorter in surgery group than in the SRS group (10.5 days vs. 37.5 days, p=0.034). CONCLUSION: Surgery for brain metastases can contribute to a positive quality of life for the remaining duration of the patient's life.

Low Dielectric Constant Characteristics of Styrene and Maleimide Anhydride Copolymer with Modification for High Frequency Application of Printed Circuit Board.

Recently, due to the intensive and fast progress of the high frequency wireless communication environment, including 5th generation (5G) wireless communication, more robust substrate for printed circuit board (PCB) application, especially with less power consumption, is required. In this study, modified resins based on styrene-maleic anhydride (SMA) copolymer were prepared and evaluated as binder resin to accomplish a low dielectric constant or relative permittivity (εr: <3.0) substrate for the PCB application under ultrahigh frequencies (UHF; 1 GHz~9.4 GHz). The low εr dielectric characteristics of the modified SMA copolymer could be correlated with effects from the stereo-structure of carbon chains or conformational orientation, where the degree of crystallization was analyzed by X-ray diffraction (XRD) and nuclear magnetic resonance (NMR) spectroscopies. Prepreg films of the low εr modified SMA copolymers and their compounds with epoxy resins were also characterized in terms of dielectric loss or dissipation factor (Df), which have shown more noticeable relation with their stereo-structures as well.

Morphological and molecular expression patterns of neural precursor cells derived from human fetal spinal cord in two-, three-dimensional, and organoid culture environments.

Recently, interest in three-dimensional (3D) cell or tissue organoids that may, in vitro, overcome not only the practical problems associated with fetal tissue transplantation, but also provide a potential source for the regeneration of injured spinal cords, has been increasing steadily. In this study, we showed that human neural precursor cells (hNPCs) derived from the fetal spinal cord could be incubated in serum free medium at two dimensional (2D), three dimensional (3D) and tissue organoid-systems. Additionally, we investigated morphological changes over time along with the expression of proteoglycans, collagen, or myelin in 2D, 3D and tissue-like organoids. 2D cells exhibited a spindle-shaped morphology with classic hill and valley growth patterns, while 3D cells grew as clusters of undifferentiated cells and cell sheets (tissue organoids) that gradually rolled up like a carpet without forming a circular cell mass. Immunostaining was performed to demonstrate the expression of TUJ-1, MAP-2, GAD 65/67 and ChAT in 2D cells or tissue-like organoids, which stained positively for them. In addition, we observed the immunoreactivity of HNu, NG2, TUJ-1, and GFAP in tissue-like organoids. The organoid culture system studied in our work may be used as therapeutic agents for spinal cord injury (SCI), and as raw materials needed for development of new medicines to improve human responses and cure diseases.

Four French sheath-based transradial cerebral angiographies in the elderly: A single neurointerventionalist's experience.

BACKGROUND: Catheter angiography via transradial access (TRA) is better at reducing access site complications and morbidity than via transfemoral access (TFA). The rate of periprocedural complications increases in elderly populations and using a smaller sheath can help reduce access site complications. The aim of this study was to assess the feasibility and safety of 4 F sheath-based TRA cerebral angiography in elderly patients (≥65 years) and compare it to TFA cerebral angiography. METHODS: The medical records of elderly patients undergoing diagnostic cerebral angiography with a single neurointerventionalist via TRA (57 cases, from July 2019 to December 2020) versus TFA (69 cases, from January 2018 to June 2019) were retrospectively reviewed. All TRA angiographies were performed via right radial artery access with a 4 F sheath and a 4 F Simmons 2 catheter. RESULTS: There were no significant differences (TRA vs. TFA) in age (71.1 ± 4.0 vs. 72.1 ± 4.6 years, p = 0.189), accessed vessels (3.9 ± 0.5 vs. 3.9 ± 0.6, p = 0.852), fluoroscopy time (7.1 ± 3.3 vs. 7.6 ± 3.5 min, p = 0.068), and radiation exposure (42.1 ± 15.8 vs. 47.0 ± 13.7 Gy-cm2, p = 0.067). However, the procedure duration was significantly shorter in the TRA group (17.2 ± 3.9 vs. 19.0 ± 6.0 min, p = 0.003). Painful groin hematoma occurred in 2 of the 69 cases (2.9%) in the TFA group. In the TRA group, access site complications were not occurred; however, catheter kinks occurred in 2 of 57 cases (3.5%). CONCLUSIONS: The 4 F sheath-based TRA is a feasible option for diagnostic cerebral angiography in elderly patients. However, care should be taken during catheter manipulation.

Anterograde signaling controls plastid transcription via sigma factors separately from nuclear photosynthesis genes.

Light initiates chloroplast biogenesis in Arabidopsis by eliminating PHYTOCHROME-INTERACTING transcription FACTORs (PIFs), which in turn de-represses nuclear photosynthesis genes, and synchronously, generates a nucleus-to-plastid (anterograde) signal that activates the plastid-encoded bacterial-type RNA polymerase (PEP) to transcribe plastid photosynthesis genes. However, the identity of the anterograde signal remains frustratingly elusive. The main challenge has been the difficulty to distinguish regulators from the plethora of necessary components for plastid transcription and other essential chloroplast functions, such as photosynthesis. Here, we show that the genome-wide induction of nuclear photosynthesis genes is insufficient to activate the PEP. PEP inhibition is imposed redundantly by multiple PIFs and requires PIF3's activator activity. Among the nuclear-encoded components of the PEP holoenzyme, we identify four light-inducible, PIF-repressed sigma factors as anterograde signals. Together, our results elucidate that light-dependent inhibition of PIFs activates plastid photosynthesis genes via sigma factors as anterograde signals in parallel with the induction of nuclear photosynthesis genes.

Direct photoresponsive inhibition of a p53-like transcription activation domain in PIF3 by Arabidopsis phytochrome B.

Photoactivated phytochrome B (PHYB) binds to antagonistically acting PHYTOCHROME-INTERACTING transcription FACTORs (PIFs) to regulate hundreds of light responsive genes in Arabidopsis by promoting PIF degradation. However, whether PHYB directly controls the transactivation activity of PIFs remains ambiguous. Here we show that the prototypic PIF, PIF3, possesses a p53-like transcription activation domain (AD) consisting of a hydrophobic activator motif flanked by acidic residues. A PIF3mAD mutant, in which the activator motif is replaced with alanines, fails to activate PIF3 target genes in Arabidopsis, validating the functions of the PIF3 AD in vivo. Intriguingly, the N-terminal photosensory module of PHYB binds immediately adjacent to the PIF3 AD to repress PIF3's transactivation activity, demonstrating a novel PHYB signaling mechanism through direct interference of the transactivation activity of PIF3. Our findings indicate that PHYB, likely also PHYA, controls the stability and activity of PIFs via structurally separable dual signaling mechanisms.

Comparison of Long-Term Angiographic Results of Wide-Necked Intracranial Aneurysms : Endovascular Treatment with Single-Microcatheter Coiling, Double-Microcatheter Coiling, and Stent-Assisted Coiling.

OBJECTIVE: Endovascular treatment of intracranial aneurysms is challenging in case of wide-necked aneurysms because coils are prone to herniate into the parent artery, causing thromboembolic events or vessel occlusion. This study aims to compare long-term angiographic results of wide-necked aneurysms treated by stent-assisted, double-microcatheter, or single-microcatheter groups. METHODS: Between January 2003 and October 2016, 108 aneurysms that were treated with endovascular coil embolization with a neck size wider than 4 mm and a follow-up period of more than 3 years were selected. We performed coil embolization with single-microcatheter, double-microcatheter, and stent-assisted techniques. Angiographic results were evaluated using the Raymond-Roy occlusion classification (RROC). All medical and angiographic records were reviewed retrospectively. RESULTS: Clinical and angiographic analyses were conducted in 108 wide-necked aneurysms. The immediate post-procedural results revealed RROC class I (complete occlusion) in 66 cases (61.1%), class II (residual neck) in 36 cases (33.3%), and class III (residual sac) in six cases (5.6%). The final follow-up results revealed class I in 48 cases (44.4%), class II in 49 cases (45.4%), and class III in 11 cases (10.2%). Of a total of 45 (41.6%) radiologic recurrences, there were 21 cases (19.4%) of major recurrence that required additional treatment, and 24 cases (22.2%) of minor recurrence. The final follow-up angiographic results showed statistically significant differences between the stent-assisted group and the others (p<0.01). CONCLUSION: Long-term follow-up angiography demonstrated that the stent-assisted technique had a better complete occlusion rate than the other two techniques.

PHYTOCHROME-INTERACTING FACTORs trigger environmentally responsive chromatin dynamics in plants.

The interplay between light receptors and PHYTOCHROME-INTERACTING FACTORs (PIFs) serves as a regulatory hub that perceives and integrates environmental cues into transcriptional networks of plants1,2. Although occupancy of the histone variant H2A.Z and acetylation of histone H3 have emerged as regulators of environmentally responsive gene networks, how these epigenomic features interface with PIF activity is poorly understood3-7. By taking advantage of rapid and reversible light-mediated manipulation of PIF7 subnuclear localization and phosphorylation, we simultaneously assayed the DNA-binding properties of PIF7, as well as its impact on chromatin dynamics genome wide. We found that PIFs act rapidly to reshape the H2A.Z and H3K9ac epigenetic landscape in response to a change in light quality. Furthermore, we discovered that PIFs achieve H2A.Z removal through direct interaction with EIN6 ENHANCER (EEN), the Arabidopsis thaliana homolog of the chromatin remodeling complex subunit INO80 Subunit 6 (Ies6). Thus, we describe a PIF-INO80 regulatory module that is an intermediate step for allowing plants to change their growth trajectory in response to environmental changes.

Radiotherapy for brain metastasis and long-term survival.

Patients with brain metastases (BM) can benefit from radiotherapy (RT), although the long-term benefits of RT remain unclear. We searched a Korean national health insurance claims database and identified 135,740 patients with newly diagnosed BM during 2002-2017. Propensity score matching (PSM) was used to evaluate survival according to RT modality, which included whole-brain radiotherapy (WBRT) and/or stereotactic radiosurgery (SRS). The 84,986 eligible patients were followed for a median interval of 6.6 months, and 37,046 patients underwent RT (43.6%). After the PSM, patients who underwent RT had significantly better overall survival after 1 year (42.4% vs. 35.3%, P < 0.001), although there was no significant difference at 2.6 years, and patients who did not undergo RT had better survival after 5 years. Among patients with BM from lung cancer, RT was also associated with a survival difference after 1 year (57.3% vs. 32.8%, P < 0.001) and a median survival increase of 3.7 months. The 1-year overall survival rate was significantly better for SRS than for WBRT (46.4% vs. 38.8%, P < 0.001). Among Korean patients with BM, especially patients with primary lung cancer, RT improved the short-term survival rate, and SRS appears to be more useful than WBRT in this setting.

RCB initiates Arabidopsis thermomorphogenesis by stabilizing the thermoregulator PIF4 in the daytime.

Daytime warm temperature elicits thermomorphogenesis in Arabidopsis by stabilizing the central thermoregulator PHYTOCHROME INTERACTING transcription FACTOR 4 (PIF4), whose degradation is otherwise promoted by the photoreceptor and thermosensor phytochrome B. PIF4 stabilization in the light requires a transcriptional activator, HEMERA (HMR), and is abrogated when HMR's transactivation activity is impaired in hmr-22. Here, we report the identification of a hmr-22 suppressor mutant, rcb-101, which surprisingly carries an A275V mutation in REGULATOR OF CHLOROPLAST BIOGENESIS (RCB). rcb-101/hmr-22 restores thermoresponsive PIF4 accumulation and reverts the defects of hmr-22 in chloroplast biogenesis and photomorphogenesis. Strikingly, similar to hmr, the null rcb-10 mutant impedes PIF4 accumulation and thereby loses the warm-temperature response. rcb-101 rescues hmr-22 in an allele-specific manner. Consistently, RCB interacts directly with HMR. Together, these results unveil RCB as a novel temperature signaling component that functions collaboratively with HMR to initiate thermomorphogenesis by selectively stabilizing PIF4 in the daytime.

Is There Pathological Uniformity between the Periphery and Center of a Gastrointestinal Stromal Tumor?

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors and have some malignant potential. Mitotic count is important for predicting the malignant potential of GISTs. Proper treatment of GISTs requires accurate pathological diagnosis. In general, endoscopic ultrasound-guided fine-needle aspiration and deep biopsy are used for pathological diagnosis of GIST before making decisions about surgery. This study sought to evaluate the pathological uniformity of gastric GISTs for mitotic index of the center and periphery of the GIST. METHODS: We retrospectively reviewed the data of 37 gastric GIST patients who underwent wedge resection at Hanyang University Hospital. We used Armed Forces Institute of Pathology criteria to classify gastric GISTs. To determine the pathological uniformity of gastric GISTs, we compared GIST risk stratification between the center and periphery of GISTs. RESULTS: The mean size of GISTs was 3.56 ± 2.10 cm. Three lesions were located in the antrum, 11 in the fundus, 9 in the cardia, and 14 in the body. The mean age of patients was 58.65 ± 9.44 years; 18 patients were male and 19 were female. Thirty-five patients (94.6%) showed the same level of risk stratification between the center and periphery of gastric GISTs, while two patients (5.4%) presented different levels of risk between the two sites. No significant difference in mitotic count was observed between the two sites (kappa value = 0.863; p = 0.001). CONCLUSIONS: Mitotic index category (either more than five mitoses per high-power field or five or fewer mitoses per high-power field) of GISTs showed good concurrence between the center and periphery.

Learning curve of trans-sacral epiduroscopic laser decompression in herniated lumbar disc disease.

BACKGROUND: Trans-sacral epiduroscopic laser decompression (SELD) using slender epiduroscope and a holmium YAG laser is one of the minimally invasive surgical options for lumbar disc herniation. However, the learning curve of SELD and the effect of surgical proficiency on clinical outcome have not yet been established. We investigated patients with lumbar disc herniation undergoing SELD to report the clinical outcome and learning curve. METHODS: Retrospective analysis of clinical outcome and learning curve were performed at a single center from clinical data collected from November 2015 to November 2018. A total of 82 patients who underwent single-level SELD for lumbar disc herniation with a minimum follow-up of 6.0 months were enrolled. Based on the findings that the cut-off of familiarity was 20 cases according to the cumulative study of operation time, patients were allocated to two groups: early group (n = 20) and late group (n = 62). The surgical, clinical, and radiological outcomes were retrospectively evaluated between the two groups to analyze the learning curve of SELD. RESULTS: According to linear and log regression analyses, the operation time was obtained by the formula: operation time = 58.825-(0.181 × [case number]) (p < 0.001). The mean operation time was significantly different between the two groups (mean 56.95 min; 95% confidence interval [CI], 49.12-64.78 in the early group versus mean 45.34 min; 95% CI, 42.45-48.22 in the late group; p = 0.008, non-parametric Mann-Whitney U test). Baseline characteristics, including demographic data, clinical factors, and findings of preoperative magnetic resonance imaging, did not differ between the two groups. Also, there was no significant difference in terms of surgical outcomes, including complication and failure rates, as well as clinical and radiological outcomes between the two groups. CONCLUSION: The learning curve of SELD was not as steep as that of other minimally invasive spinal surgery techniques, and the experience of surgery was not an influencing factor for outcome variation.

Identifying Genotype-Phenotype Correlations via Integrative Mutation Analysis.

Mutations in protein-coding regions can lead to large biological changes and are associated with genetic conditions, including cancers and Mendelian diseases, as well as drug resistance. Although whole genome and exome sequencing help to elucidate potential genotype-phenotype correlations, there is a large gap between the identification of new variants and deciphering their molecular consequences. A comprehensive understanding of these mechanistic consequences is crucial to better understand and treat diseases in a more personalized and effective way. This is particularly relevant considering estimates that over 80% of mutations associated with a disease are incorrectly assumed to be causative. A thorough analysis of potential effects of mutations is required to correctly identify the molecular mechanisms of disease and enable the distinction between disease-causing and non-disease-causing variation within a gene. Here we present an overview of our integrative mutation analysis platform, which focuses on refining the current genotype-phenotype correlation methods by using the wealth of protein structural information.

Efficacy and safety of decompressive craniectomy with non-suture duraplasty in patients with traumatic brain injury.

BACKGROUND: Decompressive craniectomy is an important surgical treatment for patients with severe traumatic brain injury (TBI). Several reports have been published on the efficacy of non-watertight sutures in duraplasty performed in decompressive craniectomy. This study sought to determine the safety and feasibility of the non-suture dural closure technique in decompressive craniectomy. METHODS: A total of 106 patients were enrolled at a single trauma center between January 2017 and December 2018. We retrospectively collected data and classified the patients into non-suture and suture duraplasty craniectomy groups. We compared the characteristics of patients and their intra/postoperative findings such as operative time, blood loss, imaging findings, complications, and Glasgow Outcome Scale scores. RESULTS: There were 37 and 69 patients in the non-suture and suture duraplasty groups, respectively. There were no significant differences between the two groups concerning general characteristics. The operative time was significantly lower in the non-suture duraplasty group than in the suture duraplasty group (150 min vs. 205 min; p = 0.002). Furthermore, blood loss was significantly less severe in the non-suture duraplasty group than in the suture duraplasty group (1000 mL vs. 1500 mL; p = 0.028). There were no other significant differences. CONCLUSION: Non-suture duraplasty involved shorter operative times and less severe blood losses than suture duraplasty. Other complications and prognoses were similar across groups. Therefore, the non-suture duraplasty in decompressive craniectomy is a safe and feasible surgical technique.