Constitutive activation mechanism of a class C GPCR.

Class C G-protein-coupled receptors (GPCRs) are activated through binding of agonists to the large extracellular domain (ECD) followed by rearrangement of the transmembrane domains (TMDs). GPR156, a class C orphan GPCR, is unique because it lacks an ECD and exhibits constitutive activity. Impaired GPR156-Gi signaling contributes to loss of hearing. Here we present the cryo-electron microscopy structures of human GPR156 in the Go-free and Go-coupled states. We found that an endogenous phospholipid molecule is located within each TMD of the GPR156 dimer. Asymmetric binding of Gα to the phospholipid-bound GPR156 dimer restructures the first and second intracellular loops and the carboxy-terminal part of the elongated transmembrane 7 (TM7) without altering dimer conformation. Our findings reveal that GPR156 is a transducer for phospholipid signaling. Constant binding of abundant phospholipid molecules and the G-protein-induced reshaping of the cytoplasmic face provide a basis for the constitutive activation of GPR156.

Early onset diagnosis in Alzheimer's disease patients via amyloid-ß oligomers-sensing probe in cerebrospinal fluid.

Amyloid-ß (Aß) oligomers are implicated in the onset of Alzheimer's disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aß oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aß during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aß self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients' CSF revealed a marked change of log (I/I0) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies.

Cooled radiofrequency ablation of genicular nerves for knee osteoarthritis.

Knee osteoarthritis (OA) is a prevalent and debilitating musculoskeletal condition that significantly affects the quality of life of millions of individuals worldwide. In recent years, cooled radiofrequency ablation (CRFA) has become a viable treatment option for knee OA. This review thoroughly evaluated the existing literature on CRFA therapy for knee OA. It delved into the mechanisms behind CRFA, evaluated its clinical efficacy, and investigated potential avenues for future research and application. The insights gained from this review are crucial for healthcare professionals, researchers, and policymakers, offering an updated perspective on CRFA's role as a viable therapeutic option for knee OA.

Association between fatty infiltration in the cervical multifidus and treatment response following cervical interlaminar epidural steroid injection.

Background: Recent attention has been directed towards fatty infiltration in the cervical extensor muscles for predicting clinical outcomes in several cervical disorders. This study aimed to investigate the potential association between fatty infiltration in the cervical multifidus and treatment response following cervical interlaminar epidural steroid injection (CIESI) in patients with cervical radicular pain. Methods: The data of patients with cervical radicular pain who received CIESIs between March 2021 and June 2022 were reviewed. A responder was defined as a patient with a numerical rating scale decrease of ≥ 50% from the baseline to three months after the procedure. The presence of fatty infiltration in the cervical multifidus was assessed, along with patient characteristics, and cervical spine disease severity. To assess cervical sarcopenia, fatty infiltration in the bilateral multifidus muscles was evaluated at the C5-C6 level using the Goutallier classification. Results: Among 275 included patients, 113 (41.1%) and 162 (58.9%) were classified as non-responders and responders, respectively. The age, severity of disc degeneration, and grade of cervical multifidus fatty degeneration were significantly lower in responders. Multivariate logistic regression analysis revealed that pre-procedural symptoms (radicular pain with neck pain, odd ratio [OR] = 0.527, P = 0.024) and high-grade cervical multifidus fatty degeneration (Goutallier grade 2.5-4, OR = 0.320, P = 0.005) were significantly associated with an unsuccessful response to CIESI. Conclusions: These results suggest high-grade cervical multifidus fatty infiltration is an independent predictor of poor response to CIESI in patients with cervical radicular pain.

One-dimensional nanomaterials for cancer therapy and diagnosis.

One-dimensional (1-D) nanomaterials possess unique shape-dependent phyicochemical properties and are increasingly recognized as promising materials for nanotechnology. 1-D nanomaterials can be classified according to their shape, such as nanorods, nanotubes, nanowires, self-assembled nanochains, etc., and have been applied in electronics, photonics, and catalysis. The biological characteristics of 1-D nanomaterials, including high drug loading efficiency, prolonged blood circulation, the ability to capture cancer cells, unique cellular uptake mechanisms, efficient photothermal conversion, and material tunability, have aided in extending their potential to biomedical applications, particularly in cancer therapy and diagnosis. This review highlights a novel perspective on emerging 1-D nanomaterials for cancer therapy and diagnosis by introducing the definition of 1-D nanomaterials, their shape-dependent physicochemical properties, biomedical applications, and recent advances in cancer therapy and diagnosis. This review also proposes unexplored potential nanomaterial types and therapeutic applications for 1-D nanomaterials. In particular, the most significant and exciting advances in recent years, including ultrasound-enabled sonodynamic therapy, magnetic field-based therapy, and bioresponsive 1-D nanomaterials for intracellular self-assembly in situ, are discussed along with novel therapeutic concepts, such as piezoelectric 1-D nanomaterials, nanozyme-based nanomedicine, and others.

Impact of Sarcopenia on Percutaneous Epidural Balloon Neuroplasty in Patients with Lumbar Spinal Stenosis: A Retrospective Analysis.

Background and Objectives: With the aging population, the incidence of degenerative lumbar spinal stenosis (LSS) is increasing. Sarcopenia is an age-related muscular decrease. Although epidural balloon neuroplasty is effective in patients with LSS refractory to conventional treatments, its effect has not been assessed in patients with sarcopenia. Therefore, this study evaluated the effect of epidural balloon neuroplasty in patients with LSS and sarcopenia. Materials and Methods: This retrospective study reviewed the following details from the electronic medical records: patient characteristics, including sex, age, body mass index, diabetes, hypertension, stenosis grading, pain duration, location, pain intensity, and medications. Back and leg pain intensity was evaluated before and after the procedure at one, three, and six months during the follow-up period. A generalized estimating equations model was used at six months follow-up. Patients were divided into sarcopenia and non-sarcopenia groups using the cross-sectional area of the psoas muscle at the level of L3 on magnetic resonance imaging. Results: A total of 477 patients were included (sarcopenia group: 314 patients, 65.8%; non-sarcopenia group: 163 patients, 34.2%). Age, sex, body mass index, and medication quantification scale III were statistically different between both groups. The generalized estimating equations analyses-with unadjusted and adjusted estimation-revealed a significantly reduced pain intensity after the procedure compared to the baseline in both groups. The difference in pain intensity between both groups was not statistically different. Conclusions: Percutaneous epidural balloon neuroplasty may be considered for patients with chronic lumbar LSS regardless of accompanying sarcopenia.

A dual-action niclosamide-based prodrug that targets cancer stem cells and inhibits TNBC metastasis.

Chemotherapy typically destroys the tumor mass but rarely eradicates the cancer stem cells (CSCs) that can drive metastatic recurrence. A key current challenge is finding ways to eradicate CSCs and suppress their characteristics. Here, we report a prodrug, Nic-A, created by combining a carbonic anhydrase IX (CAIX) inhibitor, acetazolamide, with a signal transducer and transcriptional activator 3 (STAT3) inhibitor, niclosamide. Nic-A was designed to target triple-negative breast cancer (TNBC) CSCs and was found to inhibit both proliferating TNBC cells and CSCs via STAT3 dysregulation and suppression of CSC-like properties. Its use leads to a decrease in aldehyde dehydrogenase 1 activity, CD44high/CD24low stem-like subpopulations, and tumor spheroid-forming ability. TNBC xenograft tumors treated with Nic-A exhibited decreased angiogenesis and tumor growth, as well as decreased Ki-67 expression and increased apoptosis. In addition, distant metastases were suppressed in TNBC allografts derived from a CSC-enriched population. This study thus highlights a potential strategy for addressing CSC-based cancer recurrence.

Contralateral oblique view can prevent dural puncture in fluoroscopy-guided cervical epidural access: a prospective observational study.

INTRODUCTION: Although the contralateral oblique (CLO) view at 50°±5° is clinically useful for cervical epidural access, no previous studies have confirmed its safety. This prospective observational study was conducted to assess the safety profile, including the risk of dural puncture, in fluoroscopically guided cervical epidural access using the CLO view. METHODS: In cervical epidural access using the CLO view, the incidence of dural puncture was investigated as the primary outcome. Other intraprocedural complications, including intravascular entry, subdural entry, spinal cord injury and vasovagal injury, and postprocedural complications were investigated as secondary outcomes. Procedural variables including first-pass success, final success, needling time, total number of needle passes and false loss of resistance (LOR) were evaluated. RESULTS: Of the 393 patients who underwent cervical interlaminar epidural access were included for analysis, no instances of dural puncture or spinal cord injury were observed. The incidence of intravascular entry, vasovagal reaction and subdural entry were 3.1%, 0.5% and 0.3%, respectively. All procedures were successfully performed, with 85.0% of first-pass success rate. The mean needling time was 133.8 (74.9) s. The false-positive and false-negative LOR rates were 8.2% and 2.0%, respectively. All needle tips were visualized clearly during the procedure. CONCLUSIONS: The fluoroscopy-guided CLO view at 50°±5° avoided dural puncture or spinal cord injury and decreased the incidence of false LOR during cervical epidural access with a paramedian approach. TRIAL REGISTRATION NUMBER: NCT04774458.

Recent developments in carbon dots: a biomedical application perspective.

Recently, newly developed carbon-based nanomaterials known as carbon dots (CDs) have generated significant interest in nanomedicine. However, current knowledge regarding CD research in the biomedical field is still lacking. An overview of the most recent development of CDs in biomedical research is given in this review article. Several crucial CD applications, such as biosensing, bioimaging, cancer therapy, and antibacterial applications, are highlighted. Finally, CD-based biomedicine's challenges and future potential are also highlighted to enrich biomedical researchers' knowledge about the potential of CDs and the need for overcoming various technical obstacles.

Wavelength engineerable porous organic polymer photosensitizers with protonation triggered ROS generation.

Engineering excitation wavelength of photosensitizers (PSs) for enhanced reactive oxygen species (ROS) generation has inspired new windows for opportunities, enabling investigation of previously impracticable biomedical and photocatalytic applications. However, controlling the wavelength corresponding to operating conditions remains challenging while maintaining high ROS generation. To address this challenge, we implement a wavelength-engineerable imidazolium-based porous organic photocatalytic ROS generation system (KUP system) via a cost-effective one-pot reaction. Remarkably, the optimal wavelength for maximum performance can be tuned by modifying the linker, generating ROS despite the absence of metal ions and covalently attached heavy atoms. We demonstrate that protonated polymerization exclusively enables photosensitization and closely interacts with oxygen related to the efficiency of photosensitizing. Furthermore, superior tumor eradication and biocompatibility of the KUP system were confirmed through bioassays. Overall, the results document an unprecedented polymerization method capable of engineering wavelength, providing a potential basis for designing nanoscale photosensitizers in various ROS-utilizing applications.

Effectiveness of percutaneous epidural neuroplasty using a balloon catheter in patients with chronic spinal stenosis accompanying mild spondylolisthesis: a longitudinal cohort study.

Background: Degenerative lumbar spondylolisthesis (DLS) is frequently associated with lumbar spinal stenosis (LSS) and conservative treatments such as epidural steroid injection do not have long-term benefits in LSS patients with DLS. This study evaluated the effectiveness of percutaneous epidural neuroplasty using a balloon catheter in patients with LSS and DLS. Methods: Patients' sex, age, body mass index, diabetes, hypertension, stenosis grading, pain duration, location, pain intensity, and medications were retrieved from electronic medical records. At 1, 3, and 6 months following the procedure, data on pain severity, medication usage, and physical functional status were analyzed. A generalized estimating equations model was used at the six-month follow-up. Patients were divided into those with DLS (the spondylolisthesis group) and those without DLS (the no spondylolisthesis group) to evaluate whether the effects of percutaneous epidural neuroplasty using a balloon catheter were different. Results: A total of 826 patients were included (spondylolisthesis: 433 patients, 52.4%; no spondylolisthesis: 393 patients, 47.6%). Age, body mass index, hypertension, pain location, and stenosis grading were statistically different between the two groups. The generalized estimating equations analyses with unadjusted and adjusted estimation revealed a significant improvement in the estimated mean numerical rating scale of pain intensities compared to that at baseline in both groups (P < 0.001). Any adverse events that occurred were minor and temporary. Conclusions: Percutaneous epidural neuroplasty using a balloon catheter may be an alternative treatment option for patients with chronic LSS, regardless of accompanying DLS, who have had failed conservative management.

Percutaneous epidural balloon neuroplasty: a narrative review of current evidence.

Percutaneous epidural balloon neuroplasty (PEBN) can be used to perform balloon decompression combined with percutaneous epidural neuroplasty (PEN), leading to significant pain relief and functional improvement in patients with lumbar spinal stenosis. Several studies have demonstrated the effectiveness of PEBN and supported its relatively long-term outcomes (at least 6 months, sustained for up to 12 months). Balloon neuroplasty appears to be superior to conventional PEN. Moreover, it has been shown to be effective in patients unresponsive to conventional PEN or in those with post lumbar surgery syndrome. In addition, balloon neuroplasty achieved successful outcomes regardless of the approach used, such as retrodiscal, transforaminal, contralateral interlaminar, or caudal. Chronic lumbar radicular pain without back pain, neurogenic claudication, and minimal neuropathic component were favorable predictors of successful PEBN from a symptomatic perspective. A short duration of pain after lumbar surgery, lumbar foraminal stenosis caused primarily by degenerative disc, mild foraminal stenosis, and perineural adhesion by degenerative discs were associated with successful outcomes of PEBN from pathological aspects. Ballooning ≥ 50% of the target sites and complete contrast dispersion after ballooning seemed to be crucial for successful outcomes from a technical perspective. In addition, PEBN was effective regardless of the accompanying redundant nerve roots or a mild degree of spondylolisthesis. Studies on balloon neuroplasty have reported occasional minor and self-limiting complications; however, no PEBN-related significant complications have been reported. Given the present evidence, balloon neuroplasty appears to be a safe and effective procedure with minimal complications for the treatment of lumbar spinal stenosis.

Glucose-driven TOR-FIE-PRC2 signalling controls plant development.

Nutrients and energy have emerged as central modulators of developmental programmes in plants and animals1-3. The evolutionarily conserved target of rapamycin (TOR) kinase is a master integrator of nutrient and energy signalling that controls growth. Despite its key regulatory roles in translation, proliferation, metabolism and autophagy2-5, little is known about how TOR shapes developmental transitions and differentiation. Here we show that glucose-activated TOR kinase controls genome-wide histone H3 trimethylation at K27 (H3K27me3) in Arabidopsis thaliana, which regulates cell fate and development6-10. We identify FERTILIZATION-INDEPENDENT ENDOSPERM (FIE), an indispensable component of Polycomb repressive complex 2 (PRC2), which catalyses H3K27me3 (refs. 6-8,10-12), as a TOR target. Direct phosphorylation by TOR promotes the dynamic translocation of FIE from the cytoplasm to the nucleus. Mutation of the phosphorylation site on FIE abrogates the global H3K27me3 landscape, reprogrammes the transcriptome and disrupts organogenesis in plants. Moreover, glucose-TOR-FIE-PRC2 signalling modulates vernalization-induced floral transition. We propose that this signalling axis serves as a nutritional checkpoint leading to epigenetic silencing of key transcription factor genes that specify stem cell destiny in shoot and root meristems and control leaf, flower and silique patterning, branching and vegetative-to-reproduction transition. Our findings reveal a fundamental mechanism of nutrient signalling in direct epigenome reprogramming, with broad relevance for the developmental control of multicellular organisms.

Effectiveness of Epidural Balloon Neuroplasty in Patients With Chronic Spinal Stenosis Accompanied by Redundant Nerve Roots: A Longitudinal Cohort Study.

BACKGROUND: Symptomatic patients with chronic lumbar spinal stenosis (LSS) accompanied by redundant nerve roots (RNR) have poor treatment outcomes. Recently, epidural balloon neuroplasty has been shown to be effective in patients with chronic LSS. OBJECTIVE: To evaluate the effectiveness of epidural balloon neuroplasty in patients with chronic LSS accompanied by RNR. STUDY DESIGN: Retrospective cohort study. SETTING: A single pain clinic of a tertiary medical center in Seoul, Republic of Korea. METHODS: Patients with chronic LSS were divided into groups with (RNR group) and without RNR (non-RNR group). The generalized estimating equations (GEE) model was used to evaluate the effectiveness of epidural balloon neuroplasty in both groups based on Numeric Rating Scale (NRS-11) score for pain intensity, Medication Quantification Scale III (MQS III), and proportion of functional improvement at one, 3, and 6 months postprocedure. RESULTS: GEE analyses showed a significant reduction of pain intensity in NRS-11 and functional improvement compared to baseline throughout the 6-month follow-up period in both groups (P < 0.001), without differences between groups. After adjusting for potential confounding variables, the NRS-11 of leg pain one month after the procedure in the RNR group was reduced less than that in the non-RNR group (P = 0.016), although we did not find a significant time and group interaction. After adjustment, less functional improvement was observed 3 months after the procedures in the RNR group than in the non-RNR group (P = 0.001), with a significant interaction between time and group (P = 0.003). The estimated mean MQS III values were unchanged at 6 months regardless of adjustment in both groups. LIMITATIONS: Retrospective design and a lack of information on adjuvant nonpharmacologic therapies. CONCLUSION: Epidural balloon neuroplasty may be an effective option for reducing pain in patients with chronic LSS accompanied by RNR.

HEAT SHOCK TRANSCRIPTION FACTOR B2b acts as a transcriptional repressor of VIN3, a gene induced by long-term cold for flowering.

Vernalization, an acceleration of flowering after long-term winter cold, is an intensively studied flowering mechanism in winter annual plants. In Arabidopsis, Polycomb Repressive Complex 2 (PRC2)-mediated suppression of the strong floral repressor, FLOWERING LOCUS C (FLC), is critical for vernalization and a PHD finger domain protein, VERNALIZATION INSENSITIVE 3 (VIN3), recruits PRC2 on FLC chromatin. The level of VIN3 was found to gradually increase in proportion to the length of cold period during vernalization. However, how plants finely regulate VIN3 expression according to the cold environment has not been completely elucidated. As a result, we performed EMS mutagenesis using a transgenic line with a minimal promoter of VIN3 fused to the GUS reporter gene, and isolated a mutant, hyperactivation of VIN3 1 (hov1), which showed increased GUS signal and endogenous VIN3 transcript levels. Using positional cloning combined with whole-genome resequencing, we found that hov1 carries a nonsense mutation, leading to a premature stop codon on the HEAT SHOCK TRANSCRIPTION FACTOR B2b (HsfB2b), which encodes a repressive heat shock transcription factor. HsfB2b directly binds to the VIN3 promoter, and HsfB2b overexpression leads to reduced acceleration of flowering after vernalization. Collectively, our findings reveal a novel fine-tuning mechanism to regulate VIN3 for proper vernalization response.

Comparison of the contralateral oblique view with the lateral view for mid-thoracic epidural access under fluoroscopic guidance: a randomized controlled trial.

BACKGROUND: The fluoroscopic-guided epidural access is occasionally challenging; therefore, the contralateral oblique (CLO) view has emerged as an alternative approach. The CLO view appears to be optimal for mid-thoracic epidural access; however, evidence on its utility is lacking. Therefore, we aimed to evaluate the clinical usefulness of the CLO view at 60°±5° compared with the lateral (LAT) view using fluoroscopic-guided mid-thoracic epidural access. METHODS: Patients were randomly allocated to undergo mid-thoracic epidural access under the fluoroscopic LAT view (LAT group) or CLO view (CLO group). The primary outcome was the first-pass success rate of mid-thoracic epidural access. The secondary outcomes were procedural pain intensity, patient satisfaction, needling time, number of needle passes, and radiation dose. RESULTS: Seventy-nine patients were included. The first-pass success rate was significantly higher in the CLO group than in the LAT group (68.3% vs 34.2%, difference: 34.1%; 95% CI 13.3 to 54.8; p=0.003). Procedural pain intensity was significantly lower in the CLO group than in the LAT group. Patient satisfaction was significantly greater in the CLO group than in the LAT group. The needling time and the number of needle passes were significantly lower in the CLO group than in the LAT group. Radiation dose in the CLO group was significantly reduced compared with that in the LAT group. CONCLUSIONS: The fluoroscopic CLO view at 60°±5° increased the success rate and patient satisfaction and reduced the procedural time and patient discomfort compared with the LAT view when performing mid-thoracic epidural access. Therefore, the CLO view at 60°±5° can be considered for mid-thoracic epidural access under fluoroscopic guidance. TRIAL REGISTRATION NUMBER: KCT0004926.

Picomolar-sensitive ß-amyloid fibril fluorophores by tailoring the hydrophobicity of biannulated π-elongated dioxaborine-dyes.

The pathological origin of Alzheimer's disease (AD) is still shrouded in mystery, despite intensive worldwide research efforts. The selective visualization of ß-amyloid (Aß), the most abundant proteinaceous deposit in AD, is pivotal to reveal AD pathology. To date, several small-molecule fluorophores for Aß species have been developed, with increasing binding affinities. In the current work, two organic small-molecule dioxaborine-derived fluorophores were rationally designed through tailoring the hydrophobicity with the aim to enhance the binding affinity for Aß1-42 fibrils -while concurrently preventing poor aqueous solubility-via biannulate donor motifs in D-π-A dyes. An unprecedented sub-nanomolar affinity was found (K d = 0.62 ± 0.33 nM) and applied to super-sensitive and red-emissive fluorescent staining of amyloid plaques in cortical brain tissue ex vivo. These fluorophores expand the dioxaborine-curcumin-based family of Aß-sensitive fluorophores with a promising new imaging agent.

Comparison of contralateral oblique view with the lateral view for fluoroscopic-guided cervical epidural steroid injection: a randomized clinical trial.

BACKGROUND: Cervical epidural steroid injection is associated with rare but potentially catastrophic complications. The contralateral oblique (CLO) view may be a safe and feasible alternative to the lateral (LAT) view for fluoroscopic-guided cervical epidural steroid injection. However, evidence for the clinical usefulness of the CLO view for cervical epidural steroid injection is lacking. We assessed the clinical usefulness of the CLO view for cervical epidural steroid injection in managing cervical herniated intervertebral discs. METHODS: Patients were randomly assigned to receive fluoroscopic-guided cervical epidural steroid injection under LAT view or CLO view at 50±5° degrees groups. The primary outcome was the needling time comparison between the two groups. Secondary outcomes were comparison of first-attempt success rate, needle tip visualization and location, total number of needle passes, final success rate, crossover success rate and false-positive/negative loss of resistance. Complications and radiation dose were also compared. RESULTS: The needling time significantly decreased in the CLO than in the LAT group. The first-attempt success rate was significantly higher in the CLO compared with the LAT group. The needle tip was clearly visualized (p<0.001) and located more often on (or just anterior to) the ventral interlaminar line (p<0.001) in the CLO than in the LAT group. There were significantly fewer needle passes (p=0.019) in the CLO than in the LAT group. There were no significant differences in the final success, crossover success, false-positive/negative loss of resistance or radiation dose between the groups. Two (5.9%) cases in the LAT group experienced complications. CONCLUSION: The CLO view may be recommended for fluoroscopic-guided cervical epidural steroid injection, considering its better clinical usefulness over the LAT view.

Calix[n]triazolium based turn-on fluorescent sensing ensemble for selective adenosine monophosphate (AMP) detection.

A novel calix[n]triazolium was synthesized and exhibited excellent selectivity for AMP. The binding between calix[n]triazolium and chromenolate anions forms a non-fluorescent complex and the resulting supramolecular ensemble selectively detects AMP in water and induces "turn-on" fluorescence. The sensing platform is the first macrocyclic system to discriminate AMP from ADP and ATP through fluorescence changes.