Charcot arthropathy of the knee accompanied by tethered cord syndrome and lumbosacral fur sinus.

Charcot arthropathy is a rare disease in clinic, which is easy to be misdiagnosed and delayed diagnosis. Imaging examination plays a key role in the diagnosis of Charcot arthropathy. It is important to improve the early diagnosis rate and strive for early treatment to improve the quality of life of these patients. Here we reported a rare case of charcot knee (CK) accompanied by tethered cord syndrome and lumbosacral fur sinus, who presented with joint destruction, joint deformity and multiple free bodies and received joint free bodies removal and joint replacement surgery with acceptable short and midterm follow-up results.

Application of the "Plan-Do-Check-Action" plan in improving the pass rate of the "National Medical Licensing Examination".

BACKGROUND: The National Medical Licensing Examination (NMLE) is the only objective, standardized metric to evaluate whether a medical student possessing the professional knowledge and skills necessary to work as a physician. However, the overall pass rate of NMLE in our hospital in 2021 was much lower than that of Peking Union Medical College Hospital, which was required to be further improved. METHODS: To find the reasons for the unsatisfactory performance in 2021, the quality improvement team (QIT) organized regular face-to-face meetings for in-depth discussion and questionnaire, and analyzed the data by "Plato analysis" and "Brainstorming method". After finding out the reasons, the "Plan-Do-Check-Action" (PDCA) cycle was continued to identify and solve problems, which included the formulation and implementation of specific training plans by creating the "Gantt charts", the check of effects, and continuous improvements from 2021 to 2022. Detailed information about the performance of students in 2021 and 2022, and the attendance, assessment, evaluation and suggestions from our hospital were provided by the relevant departments, and the pass rate-associated data was collected online. RESULTS: After the PDCA plan, the pass rate of NMLE in our hospital increased by 10.89% from 80.15% in 2021 to 91.04% in 2022 (P = 0.0109), with the pass rate of skill examination from 95.59% in 2021 to 99.25% in 2022 (P = 0.0581) and theoretical examination from 84.5% in 2021 to 93.13% in 2022 (P = 0.027). Additionally, the mean scores of all examinees increased with the theoretical examination score increasing from 377.0 ± 98.76 in 2021 to 407.6 ± 71.94 in 2022 (P = 0.004). CONCLUSIONS: Our results showed a success application of the PDCA plan in our hospital which improved the pass rate of the NMLE in 2022, and the PDCA plan may provide a practical framework for future medical education and further improve the pass rate of NMLE in the next year.

Angelicin improves osteoporosis in ovariectomized rats by reducing ROS production in osteoclasts through regulation of the KAT6A/Nrf2 signalling pathway.

BACKGROUND: Angelicin, which is found in Psoralea, can help prevent osteoporosis by stopping osteoclast formation, although the precise mechanism remains unclear. METHODS: We evaluated the effect of angelicin on the oxidative stress level of osteoclasts using ovariectomized osteoporosis model rats and RAW264.7 cells. Changes in the bone mass of the femur were investigated using H&E staining and micro-CT. ROS content was investigated by DHE fluorescence labelling. Osteoclast-related genes and proteins were examined for expression using Western blotting, immunohistochemistry, tartrate-resistant acid phosphatase staining, and real-time quantitative PCR. The influence of angelicin on osteoclast development was also evaluated using the MTT assay, double luciferin assay, chromatin immunoprecipitation, immunoprecipitation and KAT6A siRNA transfection. RESULTS: Rats treated with angelicin had considerably higher bone mineral density and fewer osteoclasts. Angelicin prevented RAW264.7 cells from differentiating into osteoclasts in vitro when stimulated by RANKL. Experiments revealed reduced ROS levels and significantly upregulated intracellular KAT6A, HO-1, and Nrf2 following angelicin treatment. The expression of genes unique to osteoclasts, such as MMP9 and NFATc1, was also downregulated. Finally, KAT6A siRNA transfection increased intracellular ROS levels while decreasing KAT6A, Nrf2, and HO-1 protein expression in osteoclasts. However, in the absence of KAT6A siRNA transfection, angelicin greatly counteracted this effect in osteoclasts. CONCLUSIONS: Angelicin increased the expression of KAT6A. This enhanced KAT6A expression helps to activate the Nrf2/HO-1 antioxidant stress system and decrease ROS levels in osteoclasts, thus inhibiting oxidative stress levels and osteoclast formation.

Experimental and Theoretical Investigations of Direct and Indirect Band Gaps of WSe2.

Low-dimension materials such as transition metal dichalcogenides (TMDCs) have received extensive research interest and investigation for electronic and optoelectronic applications. Due to their unique widely tunable band structures, they are good candidates for next-generation optoelectronic devices. Particularly, their photoluminescence properties, which are fundamental for optoelectronic applications, are highly sensitive to the nature of the band gap. Monolayer TMDCs in the room temperature range have presented a direct band gap behavior and bright photoluminescence. In this work, we investigate a popular TMDC material WSe2's photoluminescence performance using a Raman spectroscopy laser with temperature dependence. With temperature variation, the lattice constant and the band gap change dramatically, and thus the photoluminescence spectra are changed. By checking the photoluminescence spectra at different temperatures, we are able to reveal the nature of direct-to-indirect band gap in monolayer WSe2. We also implemented density function theory (DFT) simulations to computationally investigate the band gap of WSe2 to provide comprehensive evidence and confirm the experimental results. Our study suggests that monolayer WSe2 is at the transition boundary between the indirect and direct band gap at room temperature. This result provides insights into temperature-dependent optical transition in monolayer WSe2 for quantum control, and is important for cultivating the potential of monolayer WSe2 in thermally tunable optoelectronic devices operating at room temperature.

Discovery of pyridazinone derivatives bearing tetrahydroimidazo[1,2-a]pyrazine scaffold as potent inhibitors of transient receptor potential canonical 5 to ameliorate hypertension-induced renal injury in rats.

Transient receptor potential canonical 5 (TRPC5) is a calcium-permeable non-selective cation channel involved in various pathophysiological processes, including renal injury. Recently, GFB-887, an investigational pyridazinone TRPC5 inhibitor, demonstrated significant therapeutic potential in a Phase II clinical trial for focal segmental glomerulosclerosis (FSGS), a rare and severe form of chronic kidney disease (CKD). In the current study, based on the structure of GFB-887, we conducted extensive structural modification to explore novel TRPC5 inhibitors with desirable drug-like properties and robust nephroprotective efficacy. A series of pyridazinone derivatives featuring a novel tetrahydroimidazo[1,2-a]pyrazine scaffold were synthesized and their activities were evaluated in HEK-293 cells stably expressing TRPC5 using a fluorescence-based Ca2+ mobilization assay. Among these compounds, compound 12 is turned out to be a potent TRPC5 inhibitor with apparent affinity comparable to the parent compound GBF-887. Compound 12 is highly selective on TRPC4/5 over TRPC3/6/7 and hERG channels, along with acceptable pharmacokinetic properties and a favorable safety profile. More importantly, in a rat model of hypertension-induced renal injury, oral administration of compound 12 (10 mg/kg, BID) efficaciously reduced mean blood pressure, inhibited proteinuria, and protected podocyte damage. These findings further confirmed the potential of TRPC5 inhibitors on the CKD treatment and provided compound 12 to be a valuable tool for exploring TRPC4/5 pathophysiology.

Thin-film lithium niobate circulator-free dispersion compensator in a time-lens system for femtosecond-pulse generation.

We demonstrate a circulator-free thin-film lithium niobate (TFLN) dispersion compensator based on the cascading 2 × 2 multimode interferometer (MMI) and two identical chirped Bragg gratings (CBGs). The cascaded MMI-CBG structure provides a dispersion value of 920 ps/nm/m over a 20 nm bandwidth covering 1537 to 1557 nm, featuring a compact footprint of 1 mm × 0.7 mm. Utilizing this device within a TFLN electro-optic time-lens system, we successfully generate 863-fs pulses at a 37 GHz repetition rate. Our compact, scalable, low-loss, and circulator-free dispersion compensator is the building block for the efficient generation of high-peak-power femtosecond laser pulses.

Soft-in-Rigid Strategy Promoting Rapid and High-Capacity Lithium Storage by Chemical Scissoring.

Large and rapid lithium storage is hugely demanded for high-energy/power lithium-ion batteries; however, it is difficult to achieve these two indicators simultaneously. Sn-based materials with a (de)alloying mechanism show low working potential and high theoretical capacity, but the huge volume expansion and particle agglomeration of Sn restrict cyclic stability and rate capability. Herein, a soft-in-rigid concept was proposed and achieved by chemical scissoring where a soft Sn-S bond was chosen as chemical tailor to break the Ti-S bond to obtain a loose stacking structure of 1D chain-like Sn1.2Ti0.8S3. The in situ and ex situ (micro)structural characterizations demonstrate that the Sn-S bonds are reduced into Sn domains and such Sn disperses in the rigid Ti-S framework, thus relieving the volume expansion and particle agglomeration by chemical and physical shielding. Benefiting from the merits of large-capacity Sn with an alloying mechanism and high-rate TiS2 with an intercalation mechanism, the Sn1.2Ti0.8S3 anode offers a high specific capacity of 963.2 mA h g-1 at 0.1 A g-1 after 100 cycles and a reversible capacity of 250 mA h g-1 at 10 A g-1 after 3900 cycles. Such a strategy realized by chemical tailoring at the structural unit level would broaden the prospects for constructing joint high-capacity and high-rate LIB anodes.

Microplastics or micro-bioplastics released by wrinkling paper cup.

Paper cups have been widely used such as in the fast-food industry for drinking and are generally made of disposable material. To make the paper cup waterproof and prevent leakage, a thin layer of plastic such as polylactic acid (PLA) is commonly coated onto the inner wall surface. This plastic layer can potentially release debris as microplastics, particularly when the cup is wrinkled/crumpled to break and peel off the coating layer, which is tested herein. Using scanning electron microscope (SEM), the broken coating layer can be clearly observed. We then identify the coating material as plastic using mass and Raman spectra. We further employ Raman imaging to identify the released and fallen down debris as microplastics. We cross-check Raman image with SEM image to benefit each other and increase the analysis certainty, because Raman imaging can identify plastic via hyper spectrum to increase the signal-to-noise ratio, while SEM can visualise plastic with a high resolution down to micro-/nano- size. We then employ particle analysis algorithm to estimate the release amount, at approximate 180 microplastic/wrinkle, or micro-bioplastic if considering the main material of PLA as a bioplastic. Overall, we should not wrinkle the paper cup to avoid the potential release of microplastics or micro-bioplastics particularly before and during the drinking process, and the characterisation in this report might be helpful for further research on microplastics.

A Nanoparticle Vaccine Displaying Conserved Epitopes of the Preexisting Neutralizing Antibody Confers Broad Protection against SARS-CoV-2 Variants.

The rapid development of the SARS-CoV-2 vaccine has been used to prevent the spread of coronavirus 2019 (COVID-19). However, the ongoing and future pandemics caused by SARS-CoV-2 variants and mutations underscore the need for effective vaccines that provide broad-spectrum protection. Here, we developed a nanoparticle vaccine with broad protection against divergent SARS-CoV-2 variants. The corresponding conserved epitopes of the preexisting neutralizing (CePn) antibody were presented on a self-assembling Helicobacter pylori ferritin to generate the CePnF nanoparticle. Intranasal immunization of mice with CePnF nanoparticles induced robust humoral, cellular, and mucosal immune responses and a long-lasting immunity. The CePnF-induced antibodies exhibited cross-reactivity and neutralizing activity against different coronaviruses (CoVs). CePnF vaccination significantly inhibited the replication and pathology of SARS-CoV-2 Delta, WIV04, and Omicron strains in hACE2 transgenic mice and, thus, conferred broad protection against these SARS-CoV-2 variants. Our constructed nanovaccine targeting the conserved epitopes of the preexisting neutralizing antibodies can serve as a promising candidate for a universal SARS-CoV-2 vaccine.

[Comparsion of bone setting technique combined with percutaneous vertebroplasty and percutaneous kyphoplasty for the treatment of osteoporotic vertebral compression fractures].

OBJECTIVE: To explore clinical efficacy of osteoplasty combined with percutaneous vertebroplasty(PVP) and percutaneous kyphoplasty (PKP) alone in treating osteoporosis vertebral compression fractures (OVCFs). METHODS: The clinical data of 80 patients with single-level OVCFs treated from January 2021 to June 2022 were retrospectively analyzed, and were divided into treatment group and control group according to different surgical methods, 40 patients in each group. In treatment group, there were 24 males and 16 females, aged from 60 to 83 years old with an average of (70.43±7.31) years old;bone mineral density ranged from -3.30 to -2.50 SD with an average of(-2.84±0.24) SD;1 patient with T10, 4 patients with T11, 11 patients with T12, 7 patients with L1, 7 patients with L2, 5 patients with L3, 3 patients with L4, 2 patients with L5;bone setting technique combined with PVP were performed. In control group, there were 27 males and 13 females, aged from 60 to 82 years old with an average of (68.98±6.94) years old;bone mineral density ranged from -3.40 to -2.50 SD with an average of (-2.76±0.23) SD;2 patients with T10, 3 patients with T11, 13 patients with T12, 11 patients with L1, 5 patients with L2, 3 patients with L3, 2 patients with L4, 1 patient with L5;simple PKP were peformed. Visual analogue scale (VAS) and lumbar Oswestry disability index (ODI) were compared between two groups before operation, 3 days, 3 and 12 months after operation. The changes of local kyphotic angle, vertebral wedge angle and vertebral anterior margin height ratio were compared between two groups before operation, 3 days and 12 months after operation. RESULTS: All patients were successfully completed operation. Treatment group were followed up from 13 to 22 months with an average of (16.82±2.14) months, and control group were followed up from 13 to 23 months with an average of (16.45±2.56) months. Three patients were occurred bone cement leakage in treatment group, while 1 patient were occurred bone cement leakage and 1 patient occurred sensory disturbance of lower limb skin in control group;there were no significant difference in complications between two groups (P>0.05). There were no significant difference in preoperative VAS and ODI between two groups (P>0.05). At 3 days after operation, VAS of treatment group 3.68±0.62 was significantly higher than that of control group 4.00±0.72 (P<0.05). There were no significant difference in VAS and ODI between two groups at 3 and 12 months after operation (P>0.05). There were no significant difference in local kyphotic angle, vertebral wedge angle and vertebral anterior margin height between two groups at 3 days and 12 months after operation (P>0.05). CONCLUSION: Compared with PKP, bone setting manipulation combined with PVP for the treatment of OVCFs has advantages in early postoperative pain relief. In terms of vertebral height recovery, bone setting manipulation combined with PVP and PKP alone have similar clinical effects.

The long-term efficacy of eltrombopag in children with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is the most common autoimmune disorder characterized by decreased platelet counts and impaired platelet production. Eltrombopag has been demonstrated to be safe and effective for children with ITP. It is reported eltrombopag can achieve a sustained response off treatment. However, data on its overall efficacy and safety profile are scarce in children. This study aimed to investigate the long-term efficacy of eltrombopag in children with ITP. Treatment overall response (OR), complete response (CR), response (R), durable response (DR), no response (NR), treatment free remission (TFR), and relapse rate, were assessed in 103 children with ITP during eltrombopag therapy. The OR rate, CR rate, R rate, DR rate, NR rate, TFR rate, and relapse rate were 67.0%, 55.3%, 11.7%, 56.3%, 33.0%, 60%, 36.2%, respectively. Importantly, we discovered that newly diagnosed ITP patients showed a higher DR rate, TFR rate and lower relapse rate compared to persistent and chronic ITP patients. Furthermore, the CR rate, DR rate, and TFR rate of 5 patients under six months were 100%. None of them suffered relapse. The most common adverse event (AEs) was hepatotoxicity (7.77%). Our study highlighted the critical role of eltrombopag as the second-line treatment in children with ITP who were intolerant to first-line therapy.

Outcomes of a Double-Cup Construct to Treat Paprosky 3A and 3B Acetabular Defects at a Mean of 39 Months.

BACKGROUND: Modular reconstruction systems based on porous tantalum (PT) prosthetic components have been increasingly used for the treatment of complex acetabular bone defects in revision total hip arthroplasty. We report a novel technique that applies a revision cup as a "super-augment" to form a "double-cup" construct for Paprosky type III defects. METHODS: A retrospective review was conducted on revision total hip arthroplasty cases, comparing those treated with double-cup constructs (DC group, n = 48) to those treated with PT shells and augments (PT group, n = 48). All procedures were performed at the same institute between 2017 and 2022. Clinical outcome evaluation utilized the Harris Hip Score, Oxford Hip Score, and the 36-Item Short Form Survey. Preoperative and postoperative radiographic assessments measured hip center of rotation (COR) position and leg length discrepancy. Additionally, postoperative complications and implant survivorship were monitored during the follow-up period. RESULTS: The clinical outcomes improved substantially in both groups, which showed no significant difference in the Harris Hip Score (P = .786), the Oxford Hip Score (P = .570), and the 36-Item Short Form Survey (P = .691). Compared to the PT group, the reconstruction COR was significantly closer to the anatomic COR (vertical distance: 2.630 versus 7.355 mm, P = .0034; horizontal distance: 1.881 versus -6.413 mm, P < .0001) in Paprosky 3B type defects. Additionally, postoperative leg length discrepancy was less in the DC group (-8.252 versus -1.821 mm, P = .0008). Dislocation was the main complication in the DC group, and only 1 patient received re-revision due to repeated dislocation. The cumulative survival rate of the DC group (100%; 95% confidence interval 100) was better than the PT group (83.4%; 95% confidence interval 70.5 to 98.6) when re-revisions for aseptic loosening were the endpoint (P = .046). CONCLUSIONS: The DC is a reliable revision technique for the reconstruction of Paprosky type III bone defects. Although dislocation remains challenging, the biomechanically superior restoration achieved by this technique lowers the risk of aseptic loosening.

Microplastics and nanoplastics released from injection syringe, solid and liquid dimethylpolysiloxane (PDMS).

For a plastic syringe, a stopper at the end of plunger is usually made of polydimethylsiloxane (PDMS, and co-ingredients). To reduce friction and prevent leakage between the stopper and barrel, short chain polymer of liquid PDMS is also used as lubricant. Consequently, an injection process can release solid PDMS debris from the stopper and barrel, and liquid PDMS droplets from the lubricant, both of which are confirmed herein as solid and liquid micro(nano)plastics. From molecular spectrum perspective to directly visualise those micro(nano)plastics, Raman imaging was employed to analyse hundreds-to-thousands of spectra (hyper spectrum or hyperspectral matrix) and significantly enhance signal-to-noise ratio. From morphology perspective to provide high resolution of image, scanning electron microscopy (SEM) was engaged to cross-check with Raman images and increase assignment / quantification certainty. The weak Raman imaging signal of nanoplastics was extracted using image deconvolution algorithm to remove the background noise and average the signal variation. To increase the result's representativeness and avoid quantification bias, multiple syringes were tested and multiple areas were randomly scanned toward statistical results. It was estimated that thousands of microplastics and millions of nanoplastics of solid/liquid PDMS might be injected when using a plastic syringe of 1 mL. Overall, Raman imaging (along with algorithm and SEM) can be helpful for further research on micro(nano)plastics, and it should be cautious to use plastic syringe due to the increasing concern on the emerging contamination of not only solid but also liquid micro(nano)plastics.

Anti-TL1A monoclonal antibody modulates the dysregulation of Th1/Th17 cells and attenuates granuloma formation in sarcoidosis by inhibiting the PI3K/AKT signaling pathway.

Sarcoidosis is a systemic granulomatous disease characterized by non-caseating epithelioid cell granulomas. One of its immunological hallmarks is the differentiation of CD4 + naïve T cells into Th1/Th17 cells, accompanied by the release of numerous pro-inflammatory cytokines. The TL1A/DR3 signaling pathway plays a crucial role in activating effector lymphocytes, thereby triggering pro-inflammatory responses. The primary aim of this investigation was to scrutinize the impact of anti-TL1A monoclonal antibody on the dysregulation of Th1/Th17 cells and granuloma formation in sarcoidosis. Initially, the abnormal activation of the TL1A/DR3 signaling pathway in pulmonary tissues of sarcoidosis patients was confirmed using qPCR and immunohistochemistry techniques. Subsequently, employing a murine model of sarcoidosis, the inhibitory effects of anti-TL1A monoclonal antibody on the TL1A/DR3 signaling pathway in sarcoidosis were investigated through qPCR, immunohistochemistry, and Western blot experiments. The influence of anti-TL1A monoclonal antibody on granulomas was assessed through HE staining, while their effects on sarcoidosis Th1/Th17 cells and associated cytokine mRNA levels were evaluated using flow cytometry and qPCR, respectively. Immunofluorescence and Western blot experiments corroborated the inhibitory effects of anti-TL1A monoclonal antibody on the aberrant activation of the PI3K/AKT signaling pathway in sarcoidosis. The findings of this study indicate that the TL1A/DR3 signaling pathway is excessively activated in sarcoidosis. Anti-TL1A monoclonal antibody effectively inhibit this abnormal activation in sarcoidosis, thereby alleviating the dysregulation of Th1/Th17 cells and reducing the formation of pulmonary granulomas. This effect may be associated with the inhibition of the downstream PI3K/AKT signaling pathway. Anti-TL1A monoclonal antibody hold promise as a potential novel therapeutic intervention for sarcoidosis.

Transcriptome profiling of fast/glycolytic and slow/oxidative muscle fibers in aging and obesity.

Aging and obesity pose significant threats to public health and are major contributors to muscle atrophy. The trends in muscle fiber types under these conditions and the transcriptional differences between different muscle fiber types remain unclear. Here, we demonstrate distinct responses of fast/glycolytic fibers and slow/oxidative fibers to aging and obesity. We found that in muscles dominated by oxidative fibers, the proportion of oxidative fibers remains unchanged during aging and obesity. However, in muscles dominated by glycolytic fibers, despite the low content of oxidative fibers, a significant decrease in proportion of oxidative fibers was observed. Consistently, our study uncovered that during aging and obesity, fast/glycolytic fibers specifically increased the expression of genes associated with muscle atrophy and inflammation, including Dkk3, Ccl8, Cxcl10, Cxcl13, Fbxo32, Depp1, and Chac1, while slow/oxidative fibers exhibit elevated expression of antioxidant protein Nqo-1 and downregulation of Tfrc. Additionally, we noted substantial differences in the expression of calcium-related signaling pathways between fast/glycolytic fibers and slow/oxidative fibers in response to aging and obesity. Treatment with a calcium channel inhibitor thapsigargin significantly increased the abundance of oxidative fibers. Our study provides additional evidence to support the transcriptomic differences in muscle fiber types under pathophysiological conditions, thereby establishing a theoretical basis for modulating muscle fiber types in disease treatment.

From inflammation to bone formation: the intricate role of neutrophils in skeletal muscle injury and traumatic heterotopic ossification.

Neutrophils are emerging as an important player in skeletal muscle injury and repair. Neutrophils accumulate in injured tissue, thus releasing inflammatory factors, proteases and neutrophil extracellular traps (NETs) to clear muscle debris and pathogens when skeletal muscle is damaged. During the process of muscle repair, neutrophils can promote self-renewal and angiogenesis in satellite cells. When neutrophils are abnormally overactivated, neutrophils cause collagen deposition, functional impairment of satellite cells, and damage to the skeletal muscle vascular endothelium. Heterotopic ossification (HO) refers to abnormal bone formation in soft tissue. Skeletal muscle injury is one of the main causes of traumatic HO (tHO). Neutrophils play a pivotal role in activating BMPs and TGF-ß signals, thus promoting the differentiation of mesenchymal stem cells and progenitor cells into osteoblasts or osteoclasts to facilitate HO. Furthermore, NETs are specifically localized at the site of HO, thereby accelerating the formation of HO. Additionally, the overactivation of neutrophils contributes to the disruption of immune homeostasis to trigger HO. An understanding of the diverse roles of neutrophils will not only provide more information on the pathogenesis of skeletal muscle injury for repair and HO but also provides a foundation for the development of more efficacious treatment modalities for HO.

Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives.

Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.

PM2.5 exposure inhibits osteoblast differentiation by increasing the ubiquitination and degradation of Smad4.

Increasing epidemiological evidence has shown that PM2.5 exposure is significantly associated with the occurrence of osteoporosis. It has been well demonstrated that PM2.5 exposure enhanced the differentiation and function of osteoclasts by indirectly causing chronic inflammation, while the mechanism in osteoblasts remains unclear. In our study, toxic effects were evaluated by direct exposure of 20-80µg/ml PM2.5 to MC3T3-E1 cells and BMSCs. The results showed that PM2.5 exposure did not affect cell viability via proliferation and apoptosis, but significantly inhibited osteoblast differentiation in a dose-dependent manner. Osteogenic transcription factors Runx2 and Sp7 and other biomarkers Alp and Ocn decreased after PM2.5 exposure. RNA-seq revealed TGF-ß signaling was involved in PM2.5 exposure inhibited osteoblast differentiation, which led to P-Smad1/5 and P-Smad2 reduction in the nucleus by increasing the ubiquitination and degradation of Smad4. At last, the inflammation response increased in MC3T3-E1 cells with PM2.5 exposure. Moreover, the mRNA levels of Mmp9 increased in bone marrow-derived macrophage cells treated with the conditional medium collected from MC3T3-E1 cells exposed to PM2.5. Overall, these results indicated that PM2.5 exposure inhibits osteoblast differentiation and concurrently increases the maturation of osteoclasts. Our study provides in-depth mechanistic insights into the direct impact of PM2.5 exposure on osteoblast, which would indicate the unrecognized role of PM2.5 on osteoporosis.