High-luminance one-dimensional integral imaging display based on gradient-width line light sources.

A high-luminance one-dimensional integral imaging display is presented in this paper. A gradient-width line light source array behind an elemental image array is proposed. The widths of the line light sources with equal pitches gradually increased from both sides to center. The viewing ranges generated by the line light sources were enlarged from both sides to the center. The light illuminating the left half of the elemental image array was superimposed on the right side, and the light illuminating the right half of the elemental image array was superimposed on the left side. The viewing zone was related to the leftmost and rightmost line light sources, and the luminance was improved by enlarging the other line light sources.

Factors associated with SARS-CoV-2 vaccine hesitancy after stroke: a cross-sectional study.

BACKGROUND: The vaccination status of post-stroke patients, who are at high risk of severe outcomes from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a significant concern, yet it remains unclear. We aimed to explore the vaccination status, factors associated with vaccine hesitancy, and adverse effects after vaccination among post-stroke patients. METHODS: This multi-center observational study enrolled hospitalized post-stroke patients from six Chinese hospitals (Oct 1, 2020 - Mar 31, 2021), examining vaccine uptake and self-reported reasons for vaccine hesitancy, utilizing logistic regression to investigate risk factors for vaccine hesitancy, and recording any adverse reactions post-vaccination. RESULTS: Of the total 710 post-stroke patients included in the study, 430 (60.6%) had completed the recommended full-3 dose SARS-CoV-2 vaccination, with 176 (24.8%) remaining unvaccinated. The most common reasons for vaccine hesitancy were concerns about vaccine side effects (41.5%) and impaired mobility (33.9%). Logistic regression identified advanced age (aOR = 1.97, 95%CI: 1.36-2.85, P = 0.001), lower Barthel Index score (aOR = 0.88, 95%CI: 0.82-0.93, P = 0.018), higher Modified Rankin Scale score (aOR = 1.85, 95%CI: 1.32-2.56, P = 0.004), and poorer usual activity level of EuroQol 5-Dimension (aOR = 2.82, 95%CI: 1.51-5.28, P = 0.001) as independent risk factors for vaccine hesitancy. Approximately 14.8% reported minor adverse reactions, mainly pain at the injection site. CONCLUSION: We found that post-stroke patients have insufficient SARS-CoV-2 vaccination rates, with key risk factors for vaccine hesitancy including concerns about side effects, advanced age, and functional impairments. No severe adverse reactions were observed among the vaccinated population.

Diagnostic Value of Clear Cell Likelihood Score v1.0 and v2.0 for Common Subtypes of Small Renal Masses: A Multicenter Comparative Study.

BACKGROUND: Clear cell likelihood score (ccLS) is reliable for diagnosing small renal masses (SRMs). However, the diagnostic value of Clear cell likelihood score version 1.0 (ccLS v1.0) and v2.0 for common subtypes of SRMs might be a potential score extension. PURPOSE: To compare the diagnostic performance and interobserver agreement of ccLS v1.0 and v2.0 for characterizing five common subtypes of SRMs. STUDY TYPE: Retrospective. POPULATION: 797 patients (563 males, 234 females; mean age, 53 ± 12 years) with 867 histologically proven renal masses. FIELD STRENGTH/SEQUENCES: 3.0 and 1.5 T/T2 weighted imaging, T1 weighted imaging, diffusion-weighted imaging, a dual-echo chemical shift (in- and opposed-phase) T1 weighted imaging, multiphase dynamic contrast-enhanced imaging. ASSESSMENT: Six abdominal radiologists were trained in the ccLS algorithm and independently scored each SRM using ccLS v1.0 and v2.0, respectively. All SRMs had definite pathological results. The pooled area under curve (AUC), accuracy, sensitivity, and specificity were calculated to evaluate the diagnostic performance of ccLS v1.0 and v2.0 for characterizing common subtypes of SRMs. The average κ values were calculated to evaluate the interobserver agreement of the two scoring versions. STATISTICAL TESTS: Random-effects logistic regression; Receiver operating characteristic analysis; DeLong test; Weighted Kappa test; Z test. The statistical significance level was P < 0.05. RESULTS: The pooled AUCs of clear cell likelihood score version 2.0 (ccLS v2.0) were statistically superior to those of ccLS v1.0 for diagnosing clear cell renal cell carcinoma (ccRCC) (0.907 vs. 0.851), papillary renal cell carcinoma (pRCC) (0.926 vs. 0.888), renal oncocytoma (RO) (0.745 vs. 0.679), and angiomyolipoma without visible fat (AMLwvf) (0.826 vs. 0.766). Interobserver agreement for SRMs between ccLS v1.0 and v2.0 is comparable and was not statistically significant (P = 0.993). CONCLUSION: The diagnostic performance of ccLS v2.0 surpasses that of ccLS v1.0 for characterizing ccRCC, pRCC, RO, and AMLwvf. Especially, the standardized algorithm has optimal performance for ccRCC and pRCC. ccLS has potential as a supportive clinical tool. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Diagnosis of colorectal cancer based on folate receptor-positive circulating tumor cell analysis: a retrospective cohort study.

BACKGROUND: Early diagnosis and treatment are crucial to improve the prognosis of colorectal cancer (CRC). At present, there is a lack of an accurate CRC screening factor. We conducted folate receptor-positive circulating tumor cell analysis (FR + CTC analysis) in distinguishing CRC from benign colorectal diseases to evaluate the diagnostic efficiency. METHODS: Clinical data of patients admitted to The First Affiliated Hospital of Anhui Medical University from January 2021 to July 2022 were retrospectively collected. Levels of FR + CTC and other indicators were analyzed. Receiver operating characteristic (ROC) analysis was performed to assess the diagnostic performance of these molecular biomarkers. RESULTS: Data of 103 patients with CRC and 54 patients with benign colorectal diseases were collected. FR + CTC levels were observed significantly higher in CRC patients than in patients with benign colorectal diseases (P < 0.001). FR + CTC level was correlated with tumor diameter, differentiation, T-stage, pathological stage, clinical stage, and intravascular tumor thrombus in patients with CRC (P < 0.05). The optimal cutoff value of FR + CTC level for diagnosing CRC patients was 7.66 FU/3 ml, with a sensitivity of 85.4%, a specificity of 74.1%, and an Area Under Curve (AUC) of 0.855 (95% CI 0.77-0.923). In < 50-years old patients with CRC, the diagnostic efficiency of FR + CTC was excellent, with an AUC of 0.936 (95% CI 0.877-0.995). CONCLUSION: FR + CTC counting has excellent diagnostic efficiency in screening of CRC. FR + CTC count can also predict the tumor stage of CRC patients before surgery, and guide the choice of treatment.

"Dramatic Growth" of Microbial Aerosols for Visualization and Accurate Counting of Bioaerosols.

While the global COVID-19 pandemic has subsided, microbial aerosol detection has become of high concern. Timely, accurate, and highly sensitive monitoring of microbial aerosols in indoor air is the basis for effective prevention and control of infectious diseases. At present, no commercial equipment or reliable technology can simultaneously control the detection time and limit at 6 h and 102 CFU/mL, respectively. Based on the "safety size range" of particulate matter in the air, we propose a new method of microbial dilation detection, which enables the pathogen to grow rapidly and dramatically into a polymeric microsphere, larger in size than the coexisting aerosol particles. "Like a crane standing among chickens", the microorganism can be easily visualized and counted. Different from routine chemical and biological sensing technologies, this method can achieve absolute counting of microbial particles, and the simple principles can be developed into devices for different life scenarios.

Kerr-lens mode-locked femtosecond Yb:CALYO oscillator with more than 20-W average power.

We report on the demonstration of a pure Kerr-lens mode-locked Yb:CALYO laser which can directly deliver sub-200 fs pulses with more than 20-W average power. With an incident pump power of 89 W, 153-fs pulses were generated with an average power of 21.5 W at a repetition rate of 77.9 MHz. The corresponding peak power and single pulse energy were 1.6 MW and 0.27 µJ, respectively. The stable operation of the mode-locking was confirmed by very small fluctuations in both spectrum and output power recorded over an hour. Second harmonic generation (SHG) was conducted with 59% conversion efficiency, which indicated that the high-power mode-locking pulses are of good quality. Stable Kerr-lens mode-locking (KLM) with 156-fs pulse duration and 27.2-W average power was also achieved with 109-W pump power. To the best of our knowledge, this is the highest average output power ever reported from a femtosecond mode-locked bulk oscillator.

Differentiation between renal epithelioid angiomyolipoma and clear cell renal cell carcinoma using clear cell likelihood score.

PURPOSE: Clear cell likelihood score (ccLS) may be a reliable diagnostic method for distinguishing renal epithelioid angiomyolipoma (EAML) and clear cell renal cell carcinoma (ccRCC). In this study, we aim to explore the value of ccLS in differentiating EAML from ccRCC. METHODS: We performed a retrospective analysis in which 27 EAML patients and 60 ccRCC patients underwent preoperative magnetic resonance imaging (MRI) at our institution. Two radiologists trained in the ccLS algorithm scored independently and the consistency of their interpretation was evaluated. The difference of the ccLS score was compared between EAML and ccRCC in the whole study cohort and two subgroups [small renal masses (SRM; ≤ 4 cm) and large renal masses (LRM; > 4 cm)]. RESULTS: In total, 87 patients (59 men, 28 women; mean age, 55±11 years) with 90 renal masses (EAML: ccRCC = 1: 2) were identified. The interobserver agreement of two radiologists for the ccLS system to differentiate EAML from ccRCC was good (k = 0.71). The ccLS score in the EAML group and the ccRCC group ranged from 1 to 5 (73.3% in scores 1-2) and 2 to 5 (76.7% in scores 4-5), respectively, with statistically significant differences (P < 0.001). With the threshold value of 2, ccLS can distinguish EAML from ccRCC with the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 87.8%, 95.0%, 73.3%, 87.7%, and 88.0%, respectively. The AUC (area under the curve) was 0.913. And the distribution of the ccLS score between the two diseases was not affected by tumor size (P = 0.780). CONCLUSION: The ccLS can distinguish EAML from ccRCC with high accuracy and efficiency.

High average power amplification of femtosecond pulses based on the Yb:CaYAlO4 crystal.

In this paper, we demonstrated the direct amplification of femtosecond pulses with the Yb:CaYAlO4 crystal for the first time. A compact and simple two-stage amplifier delivered amplified pulses with the average powers of 55.4 W for σ-polarization and 39.4 W for π-polarization at the center wavelengthes of 1032 nm and 1030 nm, corresponding to 28.3% and 16.3% optical-to-optical efficiencies, respectively. These are to the best of our knowledge the highest value achieved with a Yb:CaYAlO4 amplifier. Upon using a compressor consisting of prisms and GTI mirrors, a pulse duration of 166-fs was measured. Thanks to the good thermal management, the beam quality (M2) parameters <1.3 along each axis were maintained in each stage.

Efficacy and outcome of extensive intraoperative peritoneal lavage plus surgery vs surgery alone with advanced gastric cancer patients.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors. After resection, one of the major problems is its peritoneal dissemination and recurrence. Some free cancer cells may still exist after resection. In addition, the surgery itself may lead to the dissemination of tumor cells. Therefore, it is necessary to remove residual tumor cells. Recently, some researchers found that extensive intraoperative peritoneal lavage (EIPL) plus intraperitoneal chemotherapy can improve the prognosis of patients and eradicate peritoneal free cancer for GC patients. However, few studies explored the safety and long-term outcome of EIPL after curative gastrectomy. AIM: To evaluate the efficacy and long-term outcome of advanced GC patients treated with EIPL. METHODS: According to the inclusion and exclusion criteria, a total of 150 patients with advanced GC were enrolled in this study. The patients were randomly allocated to two groups. All patients received laparotomy. For the non-EIPL group, peritoneal lavage was washed using no more than 3 L of warm saline. In the EIPL group, patients received 10 L or more of saline (1 L at a time) before the closure of the abdomen. The surviving rate analysis was compared by the Kaplan-Meier method. The prognostic factors were carried out using the Cox appropriate hazard pattern. RESULTS: The basic information in the EIPL group and the non-EIPL group had no significant difference. The median follow-up time was 30 mo (range: 0-45 mo). The 1- and 3-year overall survival (OS) rates were 71.0% and 26.5%, respectively. The symptoms of ileus and abdominal abscess appeared more frequently in the non-EIPL group (P < 0.05). For the OS of patients, the EIPL, Borrmann classification, tumor size, N stage, T stage and vascular invasion were significant indicators. Then multivariate analysis revealed that EIPL, tumor size, vascular invasion, N stage and T stage were independent prognostic factors. The prognosis of the EIPL group was better than the non-EIPL group (P < 0.001). The 3-year survival rate of the EIPL group (38.4%) was higher than the non-EIPL group (21.7%). For the recurrence-free survival (RFS) of patients, the risk factor of RFS included EIPL, N stage, vascular invasion, type of surgery, tumor location, Borrmann classification, and tumor size. EIPL and tumor size were independent risk factors. The RFS curve of the EIPL group was better than the non-EIPL group (P = 0.004), and the recurrence rate of the EIPL group (24.7%) was lower than the non-EIPL group (46.4%). The overall recurrence rate and peritoneum recurrence rate in the EIPL group was lower than the non-EIPL group (P < 0.05). CONCLUSION: EIPL can reduce the possibility of perioperative complications including ileus and abdominal abscess. In addition, the overall survival curve and RFS curve were better in the EIPL group.

Fast Charge-Transport Interface on Primary Particles Boosts High-Rate Performance of Li-Rich Mn-Based Cathode Materials.

A Li-rich Mn-based layered oxide cathode (LLO) is one of the most promising cathode materials for achieving high-energy lithium-ion batteries. Nevertheless, the intrinsic problems including sluggish kinetics, oxygen evolution, and structural degradation lead to unsatisfactory performance in rate capability, initial Coulombic efficiency, and stability of LLO. Herein, different from the current typical surface modification, an interfacial optimization of primary particles is proposed to improve the simultaneous transport of ions and electrons. The modified interfaces containing AlPO4 and carbon can effectively increase the Li+ diffusion coefficient and decrease the interfacial charge-transfer resistance, thereby achieving fast charge-transport kinetics. Moreover, the in situ high-temperature X-ray diffraction confirms that the modified interface can improve the thermal stability of LLO by inhibiting the lattice oxygen release on the surface of the delithiated cathode material. In addition, the chemical and visual analysis of the cathode-electrolyte interface (CEI) composition clarifies that a highly stable and conductive CEI film generated on the modified electrode can facilitate interfacial kinetic transmission during cycling. As a result, the optimized LLO cathode exhibits a high initial Coulombic efficiency of 87.3% at a 0.2C rate and maintains superior high-rate stability with a capacity retention of 88.2% after 300 cycles at a 5C high rate.

Engineering a SERS Sensing Nanoplatform with Self-Sterilization for Undifferentiated and Rapid Detection of Bacteria.

The development of a convenient, sensitive, rapid and self-sterilizing biosensor for microbial detection is important for the prevention and control of foodborne diseases. Herein, we designed a surface-enhanced Raman scattering (SERS) sensing nanoplatform based on a capture-enrichment-enhancement strategy to detect bacteria. The gold-Azo@silver-cetyltrimethylammonium bromide (Au-Azo@Ag-CTAB) SERS nanotags were obtained by optimizing the synthesis process conditions. The results showed that the modification of CTAB enabled the nanotags to bind to different bacteria electrostatically. This SERS sensing nanoplatform was demonstrated to be fast (15 min), accurate and sensitive (limit of detection (LOD): 300 and 400 CFU/mL for E. coli and S. aureus, respectively). Of note, the excellent endogenous antibacterial activity of CTAB allowed the complete inactivation of bacteria after the assay process, thus effectively avoiding secondary contamination.

High-Aperture-Ratio Dual-View Integral Imaging Display.

Low aperture ratio is a problem in the conventional dual-view integral imaging (DVII) display using a point light source array. A high-aperture-ratio DVII display using a gradient width point light source array is reported in this work. The elemental Images 1 and 2, which are alternatively aligned on a liquid crystal panel, are illuminated by the light rays emitted from an assigned point light source. The optical path is optimized by optimizing the widths of the point light sources. The aperture ratio of the proposed DVII display was demonstrated as 1.88 times the conventional DVII display. Experiments showed that the vertical viewing range is related to the vertical width of the first row point light source, whereas the aperture ratio is related to the vertical widths of all point light sources. By optimizing the widths of the point light sources, the aperture ratio is enhanced without loss of viewing range.

Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases.

BACKGROUND: Dysregulated activation of the inflammasome is involved in various human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) have been designed and developed, none of the inhibitors are clinically available. Growing evidence suggests that targeting apoptosis-associated speck-like protein containing a CARD (ASC), the oligomerization of which is the key event for the assembly of inflammasome, may be another promising therapeutic strategy. Lonidamine (LND), a small-molecule inhibitor of glycolysis used as an antineoplastic drug, has been evidenced to have anti-inflammation effects. However, its anti-inflammatory mechanism is still largely unknown. METHODS: Middle cerebral artery occlusion (MCAO), experimental autoimmune encephalomyelitis (EAE) and LPS-induced sepsis mice models were constructed to investigate the therapeutic and anti-inflammasome effects of LND. The inhibition of inflammasome activation and ASC oligomerization by LND was evaluated using western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) in murine bone marrow-derived macrophages (BMDMs). Direct binding of LND with ASC was assessed using molecular mock docking, surface plasmon resonance (SPR), and drug affinity responsive target stability (DARTS). RESULTS: Here, we find that LND strongly attenuates the inflammatory injury in experimental models of inflammasome-associated diseases including autoimmune disease-multiple sclerosis (MS), ischemic stroke and sepsis. Moreover, LND blocks diverse types of inflammasome activation independent of its known targets including hexokinase 2 (HK2). We further reveal that LND directly binds to the inflammasome ligand ASC and inhibits its oligomerization. CONCLUSIONS: Taken together, our results identify LND as a broad-spectrum inflammasome inhibitor by directly targeting ASC, providing a novel candidate drug for the treatment of inflammasome-driven diseases in clinic.

Model established based on blood markers predicts overall survival in patients after radical resection of types II and III adenocarcinoma of the esophagogastric junction.

BACKGROUND: In recent years, the incidence of types II and III adenocarcinoma of the esophagogastric junction (AEG) has shown an obvious upward trend worldwide. The prognostic prediction after radical resection of AEG has not been well established. AIM: To establish a prognostic model for AEG (types II and III) based on routine markers. METHODS: A total of 355 patients who underwent curative AEG at The First Affiliated Hospital of Anhui Medical University from January 2014 to June 2015 were retrospectively included in this study. Univariate and multivariate analyses were performed to identify the independent risk factors. A nomogram was constructed based on Cox proportional hazards models. The new score models was analyzed by C index and calibration curves. The receiver operating characteristic (ROC) curve was used to compare the predictive accuracy of the scoring system and tumor-node-metastasis (TNM) stage. Overall survival was calculated using the Kaplan-Meier curve amongst different risk AEG patients. RESULTS: Multivariate analysis showed that TNM stage (hazard ratio [HR] = 2.286, P = 0.008), neutrophil-to-lymphocyte ratio (HR = 2.979, P = 0.001), and body mass index (HR = 0.626, P = 0.026) were independent prognostic factors. The new scoring system had a higher concordance index (0.697), and the calibration curves of the nomogram were reliable. The area under the ROC curve of the new score model (3-year: 0.725, 95% confidence interval [CI]: 0.676-0.777; 5-year: 0.758, 95%CI: 0.708-0.807) was larger than that of TNM staging (3-year: 0.630, 95%CI: 0.585-0.684; 5-year: 0.665, 95%CI: 0.616-0.715). CONCLUSION: Based on the serum markers and other clinical indicators, we have developed a precise model to predict the prognosis of patients with AEG (types II and III). The new prognostic nomogram could effectively enhance the predictive value of the TNM staging system. This scoring system can be advantageous and helpful for surgeons and patients.

Case report: A rare combination of right aortic arch with right patent ductus arteriosus and right tracheal bronchus causing impaired respiratory function.

A right aortic arch with concomitant right patent ductus arteriosus and right tracheal bronchus is a rare congenital anomaly. Herein, the respiratory and circulatory functions of the child were normal at early ages, and imaging examination indicated that conservative treatment was suitable. However, with the growth and development of the child, the right tracheal bronchus was oppressed by the right arterial duct. We performed a cut and ligation of the right patent ductus arteriosus to relieve the pressure on the right tracheal bronchus. At the 6-month follow-up, the child had recovered well and exhibited no symptoms of respiratory restriction. Therefore, we believe that early interventions should be considered for this rare anatomic presentation to benefit the patient's respiratory and circulatory systems. Our experience provides a foundational reference for future cases.

A Nucleophilic Chemical Probe Targeting Electrophilic Functional Groups in an Untargeted Way to Explore Cysteine Modulators in Natural Products.

The vital roles of biologically relevant cysteines have been discovered from proteins that are promising targets for new drugs or chemical tools. Therefore, new electrophilic small molecules that can covalently modulate these cysteines have attracted immense interest. Because of their extremely wide chemical diversity, electrophilic natural products (NPs) have been studied as promising sources of cysteine modulators. Previous studies have developed chemical probes to facilitate the detection and isolation of electrophilic NPs. To address the problems with the current methods, including their low sensitivity, high false-positive rate, and dependence on performing manual processing with a plethora of spectra, we report a chemical probe that can first covalently capture electrophilic NPs from natural resources and then produce sensitive reporter ion signals that are specific for the detected NPs. We applied this untargeted method to explore electrophilic NPs from natural resources and found that the complexity of electrophilic NPs was beyond our expectations. We used this chemical probe to identify a new electrophilic furanosesterterpene (BG-1) from an extract of Ginkgo biloba that targets the Cys207 of acyl-CoA thioesterase 7 (ACOT7).

MicroRNA-4487 regulates vascular smooth muscle cell proliferation, migration and apoptosis by targeting RAS p21 protein activator 1.

BACKGROUND: Dysregulation of microRNA (miRNA) is involved in the pathogenesis of a variety of diseases, including atherosclerosis (AS). However, the role of miRNA-4487 (miR-4487) in the development of AS is not fully clarified. This study is intended to investigate the regulatory effects of miR-4487 on the proliferation, migration and apoptosis of vascular smooth muscle cells (VSMCs) and the related mechanisms. METHODS: Oxidized low-density lipoprotein (ox-LDL) was employed to induce the dysfunction of VSMCs. Subsequently, miR-4487 expression was detected by quantitative real-time PCR. Afterward, the expression levels of RAS p21 protein activator 1 (RASA1) and apoptosis-related proteins (Bcl-2, Bax, Cleaved caspase 3, Cleaved caspase 9) were detected by Western blotting. The proliferation, migration and apoptosis of VSMCs were then detected by CCK-8, BrdU, Transwell and flow cytometry assays, respectively. Moreover, a dual-luciferase reporter gene assay was executed to verify the targeting between miR-4487 to the RASA1 3'-untranslated region (3'-UTR). RESULTS: ox-LDL treatment increased miR-4487 expression and decreased RASA1 expression in VSMCs. Additionally, ox-LDL treatment promoted the proliferation and migration of VSMCs, but inhibited apoptosis. Besides, the effects of ox-LDL treatment on the proliferation, migration and apoptosis of VSMCs were attenuated by the transfection of miR-4487 inhibitors. Furthermore, miR-4487 directly targeted the 3'-UTR of RASA1 mRNA and repressed the expression level of RASA1. Also, RASA1 knockdown reversed the effects of miR-4487 inhibition on VSMCs. CONCLUSION: MiR-4487 promotes VSMCs viability and migration and inhibits apoptosis by targeting RASA1 in VSMCs, by which it promotes the pathogenesis of AS.

The evolution paths of some reprehensive scaffolds of RORγt modulators, a perspective from medicinal chemistry.

The ligand binding domain (LBD) of retinoid-related orphan nuclear receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to cure autoimmune diseases via modulating the IL-17 and IL-22 production by Th17 cells. Diverse chemical scaffolds of these small molecules have been discovered by multiple groups with methods such as high throughput screening (HTS) and virtual screening. These different scaffolds are further developed by medicinal chemists to afford lead compounds the best of which enter clinical trials. In this review, we summarize these chemical scaffolds and their evolution paths according to the groups in which they have been discovered or studied. We combine the data of the chemistry, biological assays and structural biology of each chemical scaffold, in order to afford insight to develop new RORγt modulators with higher potency, less toxicity and elucidated working mechanism.

5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development.

Retinoic­acid­receptor­related orphan nuclear hormone receptor gamma t (RORγt), a critical transcriptional factor of Th17 cells, is a potential therapeutic target for Th17-mediated autoimmune diseases. In addition, RORγt is essential for thymocyte survival and lymph node development, and RORγt inhibition or deficiency causes abnormal thymocyte development, thymus lymphoma, and lymph node defect. Recent study demonstrated that specific regulation of Th17 differentiation related to the hinge region of RORγt. In this research, we investigated the effect of RORγt inhibitor, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative (TTP), in the therapy of lupus nephritis and its safety on thymocyte development. We demonstrated that TTP repressed the development of Th17 cells and ameliorated the autoimmune disease manifestation in the pristane-induced lupus nephritis mice model. The treatment of TTP in the mice did not interfere with thymocyte development, including total thymocyte number and proportion of CD4+CD8+ double-positive populations in the thymus, and had no substantial effects on the pathogenesis of thymoma. The TTP had a stronger affinity with full-length RORγt protein compared with the truncated RORγt LBD region via surface plasmon resonance, which indicated TTP binding to RORγt beyond LBD region. Molecular docking computation showed that the best binding pocket of TTP to RORγt is located in the hinge region of RORγt. In summary, as a RORγt inhibitor, TTP had a potential to develop the clinical medicine for treating Th17-mediated autoimmune diseases with low safety risk for thymocyte development.