Early postnatal development of the primary visual areas 17 and 18 of the cat cerebral cortex: An SMI-32 study.

Using anti-neurofilament H non-phosphorylated antibodies (SMI-32) as markers for the neuronal maturation level and Y channel responsible for motion processing, we investigated early postnatal development of the primary visual areas 17 and 18 in cats aged 0, 10, 14, and 34 days and in adults. Two analyzed parameters of SMI-32-immunolabeling were used: the total proportion of SMI-32-labeling and the density of labeled neurons. (i) The developmental time course of the total proportion of SMI-32-labeling shows the general increase in the accumulation of heavy-chain neurofilaments. This parameter showed a different time course for cortical layer development; the maximal increment in the total labeling in layer V occurred between the second and fifth postnatal weeks and in layers II-III and VI after the fifth postnatal week. In addition, the delay in accumulation of SMI-32-labeling was shown in layer V of the area 17 periphery representation during the first two postnatal weeks. (ii) The density of SMI-32-labeled neurons decreased in all layers of area 18, but was increased, decreased, or had a transient peak in layers II-III, V, and VI of area 17, respectively. The transient peak is in good correspondence with some transient neurochemical features previously revealed for different classes of cortical and thalamic neurons and reflects the time course of the early development of the thalamocortical circuitry. Some similarities between the time courses for the development of SMI-32-labeling in areas 17/18 and in A- and C-laminae of the LGNd allow us to propose heterochronous postnatal development of two Y sub-channels.

The self-compatibility is acquired after polyploidization: a case study of Brassica napus self-incompatible trilinear hybrid breeding system.

Self-incompatibility plays a vital role in angiosperms, by preventing inbreeding depression and maintaining genetic diversity within populations. Following polyploidization, many angiosperm species transition from self-incompatibility to self-compatibility. Here, we investigated the S-locus in Brassicaceae and identified distinct origins for the sRNA loci, SMI and SMI2 (SCR Methylation Inducer 1 and 2), within the S-locus. The SMI loci were found to be widespread in Cruciferae, whereas the SMI2 loci were exclusive to Brassica species. Additionally, we discovered four major S-haplotypes (BnS-1, BnS-6, BnS-7, and BnS-1300) in rapeseed. Overexpression of BnSMI-1 in self-incompatible Brassica napus ('S-70S1300S6 ') resulted in a significant increase in DNA methylation in the promoter regions of BnSCR-6 and BnSCR-1300, leading to self-compatibility. Conversely, by overexpressing a point mutation of BnSmi-1 in the 'S-70S1300S6 ' line, we observed lower levels of DNA methylation in BnSCR-6 and BnSCR-1300 promoters. Furthermore, the overexpression of BnSMI2-1300 in the 'SI-326S7S6 ' line inhibited the expression of BnSCR-7 through transcriptional repression of the Smi2 sRNA from the BnS-1300 haplotype. Our study demonstrates that the self-compatibility of rapeseed is determined by S-locus sRNA-mediated silencing of SCR after polyploidization, which helps to further breed self-incompatible or self-compatible rapeseed lines, thereby facilitating the utilization of heterosis.

Thyroid ultrasound and its ancillary techniques.

Ultrasound (US) of the thyroid has been used as a diagnostic tool since the late 1960s. US is the most important imaging tool for diagnosing thyroid disease. In the majority of cases a correct diagnosis can already be made in synopsis of the sonographic together with clinical findings and basal thyroid hormone parameters. However, the characterization of thyroid nodules by US remains challenging. The introduction of Thyroid Imaging Reporting and Data Systems (TIRADSs) has improved diagnostic accuracy of thyroid cancer significantly. Newer techniques such as elastography, superb microvascular imaging (SMI), contrast enhanced ultrasound (CEUS) and multiparametric ultrasound (MPUS) expand diagnostic options and tools further. In addition, the use of artificial intelligence (AI) is a promising tool to improve and simplify diagnostics of thyroid nodules and there is evidence that AI can exceed the performance of humans. Combining different US techniques with the introduction of new software, the use of AI, FNB as well as molecular markers might pave the way for a completely new area of diagnostic accuracy in thyroid disease. Finally, interventional ultrasound using US-guided thermal ablation (TA) procedures are increasingly proposed as therapy options for benign as well as malignant thyroid diseases.

GPCRs in the round: SMA-like copolymers and SMALPs as a platform for investigating GPCRs.

G-protein-coupled receptors (GPCRs) are the largest family of membrane proteins, regulate a plethora of physiological responses and are the therapeutic target for 30-40% of clinically-prescribed drugs. They are integral membrane proteins deeply embedded in the plasma membrane where they activate intracellular signalling via coupling to G-proteins and ß-arrestin. GPCRs are in intimate association with the bilayer lipids and that lipid environment regulates the signalling functions of GPCRs. This complex lipid 'landscape' is both heterogeneous and dynamic. GPCR function is modulated by bulk membrane properties including membrane fluidity, microdomains, curvature, thickness and asymmetry but GPCRs are also regulated by specific lipid:GPCR binding, including cholesterol and anionic lipids. Understanding the molecular mechanisms whereby GPCR signalling is regulated by lipids is a very active area of research currently. A major advance in membrane protein research in recent years was the application of poly(styrene-co-maleic acid) (SMA) copolymers. These spontaneously generate SMA lipid particles (SMALPs) encapsulating membrane protein in a nano-scale disc of cell membrane, thereby removing the historical need for detergent and preserving lipid:GPCR interaction. The focus of this review is how GPCR-SMALPs are increasing our understanding of GPCR structure and function at the molecular level. Furthermore, an increasing number of 'second generation' SMA-like copolymers have been reported recently. These are reviewed from the context of increasing our understanding of GPCR molecular mechanisms. Moreover, their potential as a novel platform for downstream biophysical and structural analyses is assessed and looking ahead, the translational application of SMA-like copolymers to GPCR drug discovery programmes in the future is considered.

Clinical application of intraoperative ultrasound superb microvascular imaging in brain tumors resections: contributing to the achievement of total tumoral resection.

BACKGROUND: To investigate whether the intraoperative superb microvascular imaging(SMI) technique helps evaluate lesion boundaries compared with conventional grayscale ultrasound in brain tumor surgery and to explore factors that may be associated with complete radiographic resection. METHODS: This study enrolled 57 consecutive brain tumor patients undergoing surgery. During the operation, B-mode and SMI ultrasound evaluated the boundaries of brain tumors. MRI before and within 48h after surgery was used as the gold standard to evaluate gross-total resection(GTR). The ultrasound findings and GTR results were analyzed to determine the imaging factors related to GTR. RESULTS: A total of 57 patients were enrolled in the study, including 32 males and 25 females, with an average age of 53.4 ± 14.1 years old(range 19 ~ 80). According to the assessment criteria of MRI, before and within 48 h after the operation, 37(63.9%) cases were classified as GTR, and 20(35.1%) cases were classified as GTR. In comparing tumor interface definition between B-mode and SMI mode, SMI improved HGG boundary recognition in 5 cases(P = 0.033). The results showed that the tumor size ≥ 5 cm and unclear ultrasonic boundary were independent risk factors for nGTR (OR>1, P<0.05). CONCLUSIONS: As an innovative intraoperative doppler technique in neurosurgery, SMI can effectively demarcate the tumor's boundary and help achieve GTR as much as possible.

Quantitative evaluation of ocular vascularity and correlation analysis in patients with diabetic retinopathy by SMI and OCTA.

AIMS: To find potential relation between retrobulbar vessels and fundus microvessels and to detect sensitive and effective clinical indicators in predicting the progress of diabetic retinopathy (DR), ocular hemodynamics were measured using superb microvascular imaging (SMI) and ultrawide-field optical coherence tomography angiography (UWF-OCTA). METHODS: Observational, cross-sectional study evaluating ocular hemodynamics in patients with DR by SMI (Aplio i900, Canon Medical) and UWF-OCTA (BM-400 K BMizar, Tupai Medical Technology). The peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) of the central retinal artery (CRA), posterior ciliary artery (PCA), and ophthalmic artery (OA) were measured by SMI. UWF-OCTA evaluated the fundus vascular parameters. A correlation analysis was used to determine the correlation between SMI and UWF-OCTA parameters. RESULTS: One hundred thirty-nine eyes of 139 diabetic patients were included: 29 without DR (NDR), 36 with mild to moderate nonproliferative DR (M-NPDR), 37 with severe NPDR (S-NPDR), and 37 with proliferative DR (PDR). PSV and EDV of retrobulbar vessels decreased from NDR to S-NPDR while increasing PDR. RI of OA showed a decreasing trend in the progression of DR, but other vessels didn't show the same trend. ROC curve analysis showed that CRAPSV, CRAEDV, PCAEDV, OAPSV, and OAEDV had diagnostic value distinguishing M-NPDR and S-NPDR. The correlation analysis observed a significant association between the SMI parameters of CRA and PCA and UWF-OCTA parameters. CRA hemodynamics were more associated with fundus vascular parameters, especially the retina, in the NDR group than in the M-NPDR group. In contrast, PCA consistently correlated with fundus vascular parameters, especially in the choroid, from the NDR to the M-NPDR group. However, OA showed a poor correlation with OCTA parameters. CONCLUSION: The velocity of retrobulbar vessels, mainly the CRA, may serve as a valuable predictor for assessing the progress of DR. The use of SMI in diabetic patients may help identify patients at risk of developing retinopathy.

Relationship between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD): A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease. Identifying MASLD risk factors could help early intervention and reduce the burden of the disease. Previous studies investigated the association between sarcopenia and NAFLD. Several trials were published after the last meta-analysis with indecisive results. This is an updated meta-analysis which aims to assess the association between sarcopenia, MASLD, and MASLD-related fibrosis. METHODS: Relevant trials published on PubMed, Web of Science, Scopus, and Cochrane Library databases until October 2022 were included. We included studies in which skeletal mass index (SMI) or sarcopenia was compared between patients with and without NAFLD now MASLD. Also, studies comparing fibrosis between MASLD patients with and without sarcopenia were included. Data were pooled as odds ratios (ORs) and 95 % confidence intervals (CIs) using Review Manager Software. RESULTS: A total of 25 studies were included. The incidence of sarcopenia was significantly higher in MASLD than controls (OR, 1.25; 95 % CI, 1.08-1.44; P = 0.003). SMI odds showed no significant difference between NAFLD patients and controls (OR, 1.02; 95 % CI, 0.91-1.15; P = 0.7). NAFLD patients with sarcopenia had higher odds of fibrosis than NAFLD patients without sarcopenia (OR, 1.49; 95 % CI, 1.03-2.14; P = 0.03). CONCLUSIONS: Sarcopenia increased MASLD's probability and was associated with a higher probability of liver fibrosis in MASLD patients. However, SMI had no predictive value of MASLD occurrence.

Drowning in the ripple effect: identifying a syndemic network of health experience (with modifiable health behaviours) using the UK Biobank.

A Syndemic model of health experience in severe mental illness (SMI) involving modifiable health behaviour contributors has been theorised but has not yet been investigated. Over the next 10 years mental ill-health and suicidal behaviours have been predicted to increase which will decrease health experience and increase hospitalisation and associated costs. This paper investigated a Syndemic model of health experience in people with SMI informed by physical activity levels, exposure to nature, personal resilience levels, drugs related (tobacco smoking and alcohol consumption), and sleep behaviours using UK Biobank data. Results implementing SEM indicate partial evidence for a Syndemic model, with personal resilience being at its centre. Contrary to previous findings, drugs related behaviours did not play an important role in the model. Implementing a Syndemic framework approach to current health care strategies could be beneficial in the development of self-management strategies for people with SMI. This is the first paper using SEM analyses to investigate SMI under the Syndemic theory paradigm.

Spatial transcriptomics: Technologies, applications and experimental considerations.

The diverse cell types of an organ have a highly structured organization to enable their efficient and correct function. To fully appreciate gene functions in a given cell type, one needs to understand how much, when and where the gene is expressed. Classic bulk RNA sequencing and popular single cell sequencing destroy cell structural organization and fail to provide spatial information. However, the spatial location of gene expression or of the cell in a complex tissue provides key clues to comprehend how the neighboring genes or cells cross talk, transduce signals and work together as a team to complete the job. The functional requirement for the spatial content has been a driving force for rapid development of the spatial transcriptomics technologies in the past few years. Here, we present an overview of current spatial technologies with a special focus on the commercially available or currently being commercialized technologies, highlight their applications by category and discuss experimental considerations for a first spatial experiment.

An ADPLL-Based GFSK Modulator with Two-Point Modulation for IoT Applications.

To establish ubiquitous and energy-efficient wireless sensor networks (WSNs), short-range Internet of Things (IoT) devices require Bluetooth low energy (BLE) technology, which functions at 2.4 GHz. This study presents a novel approach as follows: a fully integrated all-digital phase-locked loop (ADPLL)-based Gaussian frequency shift keying (GFSK) modulator incorporating two-point modulation (TPM). The modulator aims to enhance the efficiency of BLE communication in these networks. The design includes a time-to-digital converter (TDC) with the following three key features to improve linearity and time resolution: fast settling time, low dropout regulators (LDOs) that adapt to process, voltage, and temperature (PVT) variations, and interpolation assisted by an analog-to-digital converter (ADC). It features a digital controlled oscillator (DCO) with two key enhancements as follows: ΔΣ modulator dithering and hierarchical capacitive banks, which expand the frequency tuning range and improve linearity, and an integrated, fast-converging least-mean-square (LMS) algorithm for DCO gain calibration, which ensures compliance with BLE 5.0 stable modulation index (SMI) requirements. Implemented in a 28 nm CMOS process, occupying an active area of 0.33 mm2, the modulator demonstrates a wide frequency tuning range of from 2.21 to 2.58 GHz, in-band phase noise of -102.1 dBc/Hz, and FSK error of 1.42% while consuming 1.6 mW.

The added value of superb microvascular imaging for renal cortical thickness measurement in chronic kidney disease.

PURPOSE: The aim of this study was to evaluate renal parenchymal thickness and renal cortical thickness measurements on brightness mode ultrasound (B-mode US) and B-mode US + Superb Microvascular Imaging (SMI) technique, comparing with computed tomography (CT) or magnetic resonance imaging (MRI) serving as a reference standard. METHODS: Renal parenchymal thickness and renal cortical thickness measurements were obtained from B-mode US, B-mode US + SMI, and CT/MRI in a group of healthy subjects and a group of patients with chronic kidney disease (CKD). The mean differences and correlations of renal parenchymal thickness and renal cortical thickness were analyzed using dependent pair t-test and Pearson's correlation, respectively. RESULTS: The mean difference in renal cortical thickness measurements between B-mode US + SMI and CT/MRI was lower than the mean difference between B-mode US alone and CT/MRI. Additionally, renal cortical thickness measured using B-mode US + SMI showed a stronger correlation with values obtained from CT/MRI than values measured using standard B-mode US alone. CONCLUSION: The measurement of renal cortical thickness by B-mode US + SMI is more accurate than that by B-mode US alone.

Factors to Improve Reverse Integration: A Mixed Method Embedded Design Study.

Individuals with serious mental illness face inequity in receiving primary care services. The Substance Abuse and Mental Health Services Administration (SAMHSA) granted funds to Certified Community Behavioral Health Clinics (CCBHC) to integrate primary care and behavioral health specialties to increase access to care. This mixed method study aimed to measure the SAMHSA-defined levels of reverse integration at a CCBHC at one point in time. Providers and patients provided feedback through semi-structured interviews. Qualitative data was investigated for themes, while the quantitative data was run through inferential analysis with the Kruskal Wallis H test. Clinically meaningful results showed people using primary care at the integrated clinic were more satisfied and were more apt to continue seeing their current providers than those receiving non-integrated care. The CCBHC achieved level 4 integration; factors investigated confirmed proximity alone does not necessitate integration without effective communication and implementation of practice changes.

Inner Structure of the Lateral Geniculate Complex of Adult and Newborn Acomys cahirinus.

Acomys cahirinus is a unique Rodentia species with several distinctive physiological traits, such as precocial development and remarkable regenerative abilities. These characteristics render A. cahirinus increasingly valuable for regenerative and developmental physiology studies. Despite this, the structure and postnatal development of the central nervous system in A. cahirinus have been inadequately explored, with only sporadic data available. This study is the first in a series of papers addressing these gaps. Our first objective was to characterize the structure of the main visual thalamic region, the lateral geniculate complex, using several neuronal markers (including Ca2+-binding proteins, glutamic acid decarboxylase enzyme, and non-phosphorylated domains of heavy-chain neurofilaments) to label populations of principal neurons and interneurons in adult and newborn A. cahirinus. As typically found in other rodents, we identified three subdivisions in the geniculate complex: the dorsal and ventral lateral geniculate nuclei (LGNd and LGNv) and the intergeniculate leaflet (IGL). Additionally, we characterized internal diversity in the LGN nuclei. The "shell" and "core" regions of the LGNd were identified using calretinin in adults and newborns. In adults, the inner and outer parts of the LGNv were identified using calbindin, calretinin, parvalbumin, GAD67, and SMI-32, whereas in newborns, calretinin and SMI-32 were employed for this purpose. Our findings revealed more pronounced developmental changes in LGNd compared to LGNv and IGL, suggesting that LGNd is less mature at birth and more influenced by visual experience.

Outcomes of a Virtual 10-Week COVID-19 and Psychosis Program in an HMO: A Mixed Methods Quality Improvement Project.

Virtual clinical services became the primary treatment modality in a large U.S. HMO psychiatry department during the COVID-19 pandemic. A mixed methods quality improvement project was developed to address psychosis, severe anxiety, and stressors unique to COVID-19 and sheltering in place. The purpose was to determine if a virtual 10-week pilot program combining psychoeducation, skills-based training, experiential exercises using third-wave CBT, and process questions would decrease symptoms and hospitalization rates and improve quality of life. Pre- and postmeasure scores on pandemic-related stress (the PRSF), perceived stress (PSS), and general patient health (PHQ-9) were gathered from five patients in the Department of Psychiatry at Kaiser Permanente in Oakland, California. Qualitative interviews explored patients' perceptions of program benefits. Mean, median, and range on the pre- and postprogram assessments and paired samples t tests for means were calculated. Quantitative results were not statistically significant: p = 0.32 (Revised PRSF), p = 0.34 (PSS), p = 0.94 (PHQ-9). In interviews, most participants reported a decrease in pandemic-related stress. Half reported a decrease in general perceived stress. Half reported no change. Self-assessment reflected perceptions of benefits from this 10-week program, using words such as useful and important. The virtual program helped relieve pandemic-related stress and improved overall quality of life. The results show promise for expanding the program to other hospitals providing services for this diagnostic population.

Genome-Wide Identification and Functional Analysis of Salvia miltiorrhiza MicroRNAs Reveal the Negative Regulatory Role of Smi-miR159a in Phenolic Acid Biosynthesis.

MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs in plants. They play critical functions in various biological processes during plant growth and development. Salvia miltiorrhiza is a well-known traditional Chinese medicinal plant with significant medicinal, economic, and academic values. In order to elucidate the role of miRNAs in S. miltiorrhiza, six small RNA libraries from mature roots, young roots, stems, mature leaves, young leaves and flowers of S. miltiorrhiza and one degradome library from mixed tissues were constructed. A total of 184 miRNA precursors, generating 137 known and 49 novel miRNAs, were genome-widely identified. The identified miRNAs were predicted to play diversified regulatory roles in plants through regulating 891 genes. qRT-PCR and 5' RLM-RACE assays validated the negative regulatory role of smi-miR159a in SmMYB62, SmMYB78, and SmMYB80. To elucidate the function of smi-miR159a in bioactive compound biosynthesis, smi-miR159a transgenic hairy roots were generated and analyzed. The results showed that overexpression of smi-miR159a caused a significant decrease in rosmarinic acid and salvianolic acid B contents. qRT-PCR analysis showed that the targets of smi-miR159a, including SmMYB62, SmMYB78, and SmMYB80, were significantly down-regulated, accompanied by the down-regulation of SmPAL1, SmC4H1, Sm4CL1, SmTAT1, SmTAT3, SmHPPR1, SmRAS, and SmCYP98A14 genes involved in phenolic acid biosynthesis. It suggests that smi-miR159a is a significant negative regulator of phenolic acid biosynthesis in S. miltiorrhiza.

Surface Topography, Microbial Adhesion, and Immune Responses in Silicone Mammary Implant-Associated Capsular Fibrosis.

Breast cancer is the most common cancer in women globally, often necessitating mastectomy and subsequent breast reconstruction. Silicone mammary implants (SMIs) play a pivotal role in breast reconstruction, yet their interaction with the host immune system and microbiome remains poorly understood. This study investigates the impact of SMI surface topography on host antimicrobial responses, wound proteome dynamics, and microbial colonization. Biological samples were collected from ten human patients undergoing breast reconstruction with SMIs. Mass spectrometry profiles were analyzed for acute and chronic wound proteomes, revealing a nuanced interplay between topography and antimicrobial response proteins. 16S rRNA sequencing assessed microbiome dynamics, unveiling topography-specific variations in microbial composition. Surface topography alterations influenced wound proteome composition. Microbiome analysis revealed heightened diversity around rougher SMIs, emphasizing topography-dependent microbial invasion. In vitro experiments confirmed staphylococcal adhesion, growth, and biofilm formation on SMI surfaces, with increased texture correlating positively with bacterial colonization. This comprehensive investigation highlights the intricate interplay between SMI topography, wound proteome dynamics, and microbial transmission. The findings contribute to understanding host-microbe interactions on SMI surfaces, essential for optimizing clinical applications and minimizing complications in breast reconstruction.

Factor structure of posttraumatic stress disorder (PTSD) in persons with serious mental illness.

BACKGROUND: Trauma and posttraumatic stress disorder (PTSD) are common among individuals with serious mental illness (SMI; e.g., schizophrenia, schizoaffective disorder, bipolar disorder, treatment refractory major depressive disorder), with resultant functional impairment. Previous studies have not evaluated the factor structure of the PTSD Checklist (PCL) among persons with SMI. AIMS: This study evaluated the factor structure of the PCL in two large SMI samples from public mental health treatment sectors screened for PTSD using the PCL. METHODS: Four different models of PTSD were tested using confirmatory factor analyses. RESULTS: Results indicated that the DSM-5 4-factor model (intrusion, avoidance, numbing, and hyperarousal) had the best fit. Further, the DSM-5 4-factor model demonstrated measurement invariance. CONCLUSIONS: Results supported the suitability of the DSM-5 4-factor model of PTSD among people with SMI.

Sensorimotor integration and motor learning during a novel visuomotor tracing task in young adults with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that has noted alterations to motor performance and coordination, potentially affecting learning processes and the acquisition of motor skills. This work will provide insight into the role of altered neural processing and sensorimotor integration (SMI) while learning a novel visuomotor task in young adults with ADHD. This work compared adults with ADHD (n = 12) to neurotypical controls (n = 16), using a novel visuomotor tracing task, where participants used their right-thumb to trace a sinusoidal waveform that varied in both frequency and amplitude. This learning paradigm was completed in pre, acquisition, and post blocks, where participants additionally returned and completed a retention and transfer test 24 h later. Right median nerve short latency somatosensory-evoked potentials (SEPs) were collected pre and post motor acquisition. Performance accuracy and variability improved at post and retention measures for both groups for both normalized (P < 0.001) and absolute (P < 0.001) performance scores. N18 SEP: increased in the ADHD group post motor learning and decreased in controls (P < 0.05). N20 SEP: increased in both groups post motor learning (P < 0.01). P25: increased in both groups post motor learning (P < 0.001). N24: increased for both groups at post measures (P < 0.05). N30: decreased in the ADHD group and increased in controls (P < 0.05). These findings suggest that there may be differences in cortico-cerebellar and prefrontal processing in response to novel visuomotor tasks in those with ADHD.NEW & NOTEWORTHY Alterations to somatosensory-evoked potentials (SEPs) were present in young adults with attention-deficit/hyperactivity disorder (ADHD), when compared with neurotypical controls. The N18 and N30 SEP peak had differential changes between groups, suggesting alterations to olivary-cerebellar-M1 processing and SMI in those with ADHD when acquiring a novel visuomotor tracing task. This suggests that short-latency SEPs may be a useful biomarker in the assessment of differential responses to motor acquisition in those with ADHD.

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl- efflux signaling pathway.

BACKGROUND: Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease. METHODS: In this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice. RESULTS: The expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl- efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model. CONCLUSIONS: Therefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

Glycogen synthase 3 (GSK-3) regulation of PD-1 expression and and its therapeutic implications.

The past few years have witnessed exciting progress in the application of immune check-point blockade (ICB) for the treatment of various human cancers. ICB was first used against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to demonstrate durable anti-tumor responses followed by ICB against programmed cell death-1 (PD-1) or its ligand, PD-L1. Present approaches involve the use of combinations of blocking antibodies against CTLA-4, PD-1 and other inhibitory receptors (IRs) such as TIM3, TIGIT and LAG3. Despite this success, most patients are not cured by ICB therapy and there are limitations to the use of antibodies including cost, tumor penetration, the accessibility of receptors, and clearance from the cell surface as well as inflammatory and autoimmune complications. Recently, we demonstrated that the down-regulation or inhibition of glycogen synthase kinase 3 (GSK-3) down-regulates PD-1 expression in infectious diseases and cancer (Taylor et al., 2016 Immunity 44, 274-86; 2018 Cancer Research 78, 706-717; Krueger and Rudd 2018 Immunity 46, 529-531). In this Review, we outline the use of small molecule inhibitors (SMIs) that target intracellular pathways for co-receptor blockade in cancer immunotherapy.