Nuclear accessibility of transcription factors controls gene expression, co‐regulated by Ran‐dependent nuclear localization and a competitive regulatory network. Here, we reveal that nuclear import ...factor‐facilitated transcriptional repression attenuates ribosome biogenesis under chronic salt stress. Kap114p, one of the karyopherin‐βs (Kap‐βs) that mediates nuclear import of yeast TATA‐binding protein (yTBP), exhibits a yTBP‐binding affinity four orders of magnitude greater than its counterparts and suppresses binding of yTBP with DNA. Our crystal structure of Kap114p reveals an extensively negatively charged concave surface, accounting for high‐affinity basic‐protein binding. KAP114 knockout in yeast leads to a high‐salt growth defect, with transcriptomic analyses revealing that Kap114p modulates expression of genes associated with ribosomal biogenesis by suppressing yTBP binding to target promoters, a trans‐repression mechanism we attribute to reduced nuclear Ran levels under salinity stress. Our findings reveal that Ran integrates the nuclear transport pathway and transcription regulatory network, allowing yeast to respond to environmental stresses.
Synopsis
This study reveals that the karyopherin Kap114p facilitates transcriptional repression and attenuates ribosome biogenesis under chronic salt stress.
Crystal structure of Kap114p reveals that it structurally resembles Cse1p.
Kap114p displays a very high affinity towards yTBP and suppresses binding of yTBP to DNA.
Kap114p modulates the expression of genes associated with ribosomal biogenesis via trans‐repression of yTBP‐mediated transcription under salinity stress.
Ran integrates the nuclear transport pathway and transcription regulatory network, allowing yeast to respond to environmental stresses.
This study reveals that the karyopherin Kap114p facilitates transcriptional repression and attenuates ribosome biogenesis under chronic salt stress.
Activation of proliferation of Schwann cells is crucial for axonal guidance and successful nerve regeneration following peripheral nerve injury (PNI). Considering melatonin plays an important role in ...proliferative regulation of central glial cells, the present study determined whether melatonin can effectively promote Schwann cell proliferation and improve nerve regeneration after PNI. The spontaneous immortalized rat Schwann cell line (RSC 96 cells) was first analyzed by quantitative polymerase chain reaction (QPCR) to detect the potential existence of melatonin receptors. The melatonin receptor‐mediated signaling responsible for proliferation was examined by measuring the phosphorylation of extracellular signal‐regulated kinases (ERK1/2) pathway. The in vivo model of PNI was performed by the end‐to‐side neurorrhaphy. The quantity of Schwann cells as well as the number of re‐innervated motor end plates (MEP) on target muscles was examined to represent the functional recovery of injured nerves. QPCR results indicated that MT1 is the dominant receptor in Schwann cells. Immunoblotting and proliferation assay revealed an enhanced phosphorylation of ERK1/2 and increased number of RSC 96 cells following melatonin administration. Nonselective melatonin receptor antagonist (luzindole) treatment significantly suppressed all the above findings, suggesting that the proliferative effects of melatonin were mediated by a receptor‐dependent pathway. In vivo results corresponded well with in vitro findings in which melatonin effectively increased the amount of proliferated Schwann cells and re‐innervated MEP on target muscles following PNI. As melatonin successfully improves nerve regeneration by promoting Schwann cell proliferation, therapeutic use of melatonin may thus serve as a promising strategy to counteract the PNI‐induced neuronal disability.
Abstract
The transcription factor TATA-box binding protein (TBP) modulates gene expression in nuclei. This process requires the involvement of nuclear transport receptors, collectively termed ...karyopherin-β (Kap-β) in yeast, and various regulatory factors. In previous studies we showed that Kap114p, a Kap-β that mediates nuclear import of yeast TBP (yTBP), modulates yTBP-dependent transcription. However, how Kap114p associates with yTBP to exert its multifaceted functions has remained elusive. Here, we employ single-particle cryo-electron microscopy to determine the structure of Kap114p in complex with the core domain of yTBP (yTBP
C
). Remarkably, Kap114p wraps around the yTBP
C
N-terminal lobe, revealing a structure resembling transcriptional regulators in complex with TBP, suggesting convergent evolution of the two protein groups for a common function. We further demonstrate that Kap114p sequesters yTBP away from promoters, preventing a collapse of yTBP dynamics required for yeast responses to environmental stress. Hence, we demonstrate that nuclear transport receptors represent critical elements of the transcriptional regulatory network.
New Findings
What is the central question of this study?
Imbalance of activities between GABAergic and glutamatergic systems is involved in epilepsy. It is not known whether simultaneously increasing ...GABAergic and decreasing glutamatergic activity using valproic acid and ceftriaxone, respectively, leads to better seizure control.
What is the central question of this study?
Ceftriaxone suppressed seizure and cognitive deficits and restored neuronal density and the number of newborn cells in the hippocampus in a rat model of epilepsy. Combined treatment with ceftriaxone and valproic acid showed additive effects in seizure suppression.
The pathophysiology of epilepsy is typically considered as an imbalance between inhibitory GABA and excitatory glutamate neurotransmission. Valproic acid (Val), a GABA agonist, is one of the first‐line antiepileptic drugs in the treatment of epilepsy, but it exhibits adverse effects. Ceftriaxone (CEF) elevates expression of glutamate transporter‐1, enhances the reuptake of synaptic glutamate, increases the number of newborn cells and exhibits neuroprotective effects in animal studies. In this study, we evaluated effects of the combination of CEF and Val on behavioural and neuronal measures in a rat epilepsy model. Male Wistar rats were injected i.p. with pentylenetetrazol (35 mg/kg, every other day for 13 days) to induce the epilepsy model. Ceftriaxone (10 or 50 mg/kg), Val (50 or 100 mg/kg) or the combination of CEF and Val were injected daily after the fourth pentylenetetrazol injection for seven consecutive days. Epileptic rats exhibited seizure and impairments in motor and cognitive functions. Treatment with CEF and Val reduced the seizure and enhanced motor and cognitive functions in a dose‐dependent manner. The combination of CEF (10 mg/kg) and Val (50 mg/kg) improved behaviours considerably. Histologically, compared with control animals, epileptic rats exhibited lower neuronal density and a reduction in hippocampal newborn cells but higher apoptosis in the basolateral amygdala, all of which were restored by the treatment with CEF, Val or the combination of CEF and Val. The study findings demonstrated that the combination of low doses of CEF and Val has beneficial effects on seizure suppression, neuroprotection and improvement in motor and cognitive functions in epilepsy.
Remodeling of the extracellular matrix (ECM) in the tumor microenvironment promotes glioma progression. Chondroitin sulfate (CS) proteoglycans appear in the ECM and on the cell surface, and can be ...catalyzed by dermatan sulfate epimerase to form chondroitin sulfate/dermatan sulfate (CS/DS) hybrid chains. Dermatan sulfate epimerase 1 (DSE) is overexpressed in many types of cancer, and CS/DS chains mediate several growth factor signals. However, the role of DSE in gliomas has never been explored. In the present study, we determined the expression of DSE in gliomas by consulting a public database and conducting immunohistochemistry on a tissue array. Our investigation revealed that DSE was upregulated in gliomas compared with normal brain tissue. Furthermore, high DSE expression was associated with advanced tumor grade and poor survival. We found high DSE expression in several glioblastoma cell lines, and DSE expression directly mediated DS chain formation in glioblastoma cells. Knockdown of DSE suppressed the proliferation, migration, and invasion of glioblastoma cells. In contrast, overexpression of DSE in GL261 cells enhanced these malignant phenotypes and in vivo tumor growth. Interestingly, we found that DSE selectively regulated heparin-binding EGF-like growth factor (HB-EGF)-induced signaling in glioblastoma cells. Inhibiting epidermal growth factor receptor (EGFR) and ErbB2 with afatinib suppressed DSE-enhanced malignant phenotypes, establishing the critical role of the ErbB pathway in regulating the effects of DSE expression. This evidence indicates that upregulation of DSE in gliomas contributes to malignant behavior in cancer cells. We provide novel insight into the significance of DS chains in ErbB signaling and glioma pathogenesis.
Monocots are a major taxon within flowering plants, have unique morphological traits, and show an extraordinary diversity in lifestyle. To improve our understanding of monocot origin and evolution, ...we generate chromosome-level reference genomes of the diploid Acorus gramineus and the tetraploid Ac. calamus, the only two accepted species from the family Acoraceae, which form a sister lineage to all other monocots. Comparing the genomes of Ac. gramineus and Ac. calamus, we suggest that Ac. gramineus is not a potential diploid progenitor of Ac. calamus, and Ac. calamus is an allotetraploid with two subgenomes A, and B, presenting asymmetric evolution and B subgenome dominance. Both the diploid genome of Ac. gramineus and the subgenomes A and B of Ac. calamus show clear evidence of whole-genome duplication (WGD), but Acoraceae does not seem to share an older WGD that is shared by most other monocots. We reconstruct an ancestral monocot karyotype and gene toolkit, and discuss scenarios that explain the complex history of the Acorus genome. Our analyses show that the ancestors of monocots exhibit mosaic genomic features, likely important for that appeared in early monocot evolution, providing fundamental insights into the origin, evolution, and diversification of monocots.
Osteoarthritis and hidradenitis suppurativa (HS) share a common inflammatory pathway. However, whether patients with HS have higher risk developing osteoarthritis remained unclear.
A retrospective ...cohort design was adopted in this study. Electronic medical records had been retrieved from the US collaborative network in the TriNetX research network. A propensity score matching of 1:1 was performed to match for covariates. In total, 50,931 patients with HS and the same amount of non-HS controls were identified for analyses. Hazard ratio (HR) of osteoarthritis in patient with HS was calculated.
Risk of patients with HS developing osteoarthritis was 1.37-fold higher than that of non-HS controls 95% confidence interval (CI), 1.21-1.55 when followed up for 1 year. The significance remained when the follow-up periods were extended to 3 years and 5 years. When osteoarthritis was stratified on occurring sites, the HR of knee osteoarthritis was 1.19 (95% CI, 1.09-1.29) and the HR of hip osteoarthritis was 1.17 (95% CI, 1.01-1.35) in the 5-year follow-up. The 5-year risk of osteoarthritis remained significant in sensitivity models.
Patients with HS were of high risk of developing osteoarthritis compared with people without HS. The clinical association was recommended to be considered while approaching patients with HS.
Double-eyelid blepharoplasty is the most popular cosmetic surgery in Taiwan. The creation of a small palpebral fold along with reduction of eyelid fullness makes the eye look slightly larger, thereby ...leading to an appearance of youthfulness, alertness, and vitality. Herein, we propose a method of combining the techniques of arcade buried suture and forceps, which is designed to create a more physiologically natural double eyelid.
We conducted a retrospective review of 45 patients who underwent double-eyelid surgery between December 2015 and December 2019. The procedures were performed by one senior surgeon using arcade suture upper blepharoplasty combined with the forceps technique. The patients' age ranged from 18 to 38 years (mean, 28 years). Ninety-one percent of the patients were women and were undergoing surgery for cosmetic reasons.
Of the 45 patients who underwent arcade suture upper blepharoplasty with the forceps technique, no patients developed stitch abscess or granuloma, obvious asymmetry, disappearance of line, chemosis, and corneal injury. The follow-up period ranged from 3 months to 4 years (mean, 32 months). Patient satisfaction was very high.
The arcade suture upper blepharoplasty combined with the forceps technique is a simple method for establishing a durable double eyelid without serious complication and providing excellent results.
This study aimed to investigate the survival analysis of extramammary Paget's disease (EMPD) in a Taiwanese population and to provide data for comparison with other studies in various locations and ...racial populations.
We retrospectively analyzed the medical records of 63 patients with EMPD who were surgically treated from 2002 to 2019 at a single institution. The primary endpoint was the 5-year overall survival rate of EMPD, and the secondary endpoint was recurrence-free 5-year survival. Independent variables included patients' demographic data, concurrent malignancy (i.e., non-EMPD-related cancers), tumor size, distant metastasis, and surgery and/or radiation.
Of all the 63 patients, 8 cases were excluded. A total of 43 patients (78.18%) were male, and 12 were female, with a mean age of 72.67 years (range 44-89 years). The most common affected anatomic site was the penoscrotal region (22 patients, 40.00%), followed by the perianal and perineal regions (17 patients, 30.91%). Among the 55 patients, 41 patients (74.55%) were diagnosed with at least one underlying disease, whereas the most common underlying disease was cardiovascular disease (30 patients, 54.55%). The overall survival rate was 80.00% at 36 months and 65.45% at the end of follow-up. EMPD with deep dermal invasion was a significant poor prognostic factor of overall survival in cause-specific hazard model (sub-hazard ratio (HR) 5.167, p = 0.0015, 95% confidence interval (CI) 1.876-14.230). Patients with regional metastasis or distant metastasis had poorer prognosis of 5-year survival (sub-HR 4.513, p = 0.0028, CI 1.683-12.103). The limitations of this study include its retrospective nature and sample size.
In our series, EMPD with metastasis and deep dermal invasion was the significant harmful factors in both overall 5-year survival and 5-year recurrence-free survival. The surgical excision is not associated with a low risk of local recurrence or overall survival, and long-term follow-up is still needed.
Understanding the three‐dimensional (3D) structure of the human skull is imperative for medical courses. However, medical students are overwhelmed by the spatial complexity of the skull. Separated ...polyvinyl chloride (PVC) bone models have advantages as learning tools, but they are fragile and expensive. This study aimed to reconstruct 3D‐printed skull bone models (3D‐PSBs) using polylactic acid (PLA) with anatomical characteristics for spatial recognition of the skull. Student responses to 3D‐PSB application were investigated through a questionnaire and tests to understand the requirement of these models as a learning tool. The students were randomly divided into 3D‐PSB (n = 63) and skull (n = 67) groups to analyze pre‐ and post‐test scores. Their knowledge was improved, with the gain scores of the 3D‐PSB group (50.0 ± 3.0) higher than that of the skull group (37.3 ± 5.2). Most students agreed that using 3D‐PSBs with quick response codes could improve immediate feedback on teaching (88%; 4.41 ± 0.75), while 85.9% of the students agreed that individual 3D‐PSBs clarified the structures hidden within the skull (4.41 ± 0.75). The ball drop test revealed that the mechanical strength of the cement/PLA model was significantly greater than that of the cement or PLA model. The prices of the PVC, cement, and cement/PLA models were 234, 1.9, and 10 times higher than that of the 3D‐PSB model, respectively. These findings imply that low‐cost 3D‐PSB models could revolutionize skull anatomical education by incorporating digital technologies like the QR system into the anatomical teaching repertoire.
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