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Fluctuations in host cell growth poses a significant challenge to synthetic gene circuits, often disrupting circuit function. Existing solutions typically rely on circuit redesign with alternative topologies or additional control elements, yet a broadly applicable approach remains elusive. Here, we introduce a new strategy based on liquid-liquid phase separation (LLPS) to stabilize circuit performance. By engineering a self-activating circuit with transcription factors (TF) fused to an intrinsically disordered region (IDR), we enable the formation of TF condensates at the promoter region, maintaining local TF concentration despite growth-mediated dilution. This condensate formation preserves bistable memory in the self-activating circuit, demonstrating that phase separation can robustly counteract growth fluctuations, offering a novel design principle for resilient synthetic circuits., Competing Interests: Competing Interests The authors declare no competing interests.

Objective: To summarize the clinical and genetic characteristics of mental retardation disorder (MRD) with TRIO gene variant in children. Methods: Case series study. The data of 9 children with TRIO gene variants were collected retrospectively from August 2019 to March 2024 in Department of Neurology, Beijing Children's Hospital, Capital Medical University and Department of Pediatrics, the Third Affiliated Hospital of Zhengzhou University. The data included gender, age, intellectual and motor development, appearance, seizures, neuroimaging and genetic results. The clinical features and genotype-phenotype correlations were summarized. Results: Of the 9 children, 6 boys and 3 girls, 4 MRD63 children presented with moderate to severe developmental delays accompanied by macrocephaly; 5 MRD44 children had mild to moderate developmental delays with microcephaly. A total of 5 children had dysmorphic facial features (flat occiput, thick eyebrows, unibrow, large ears, short fingers, pale skin, yellow hair, and strabismus), 2 children experienced seizures (1 child with myoclonic seizure and 1 with absence seizure), 4 children had feeding difficulties, 1 child had congenital cataracts, 1 child had congenital heart disease, 1 child had recurrent infections, and 1 child had tiger-striped changes in the fundus examination. TRIO gene variants carried by the 9 children were all de novo, involving 8 variant sites, including 7 missense variants and 1 frameshift variant, c.3232C>T/p.R1078W (2 cases), c.3920A>G/p.Y1307C, c.4112A>T/p.H1371L, c.4283G>T/p.R1428L, c.4394A>G/p.N1465S, c.6041T>C/p.I2014T, c.6821G>A/p.R2274H, c.7027delC/p.Q2343Sfs*70. Among them, 2 sites are located in the Spectrin domain, 4 sites are in the GEFD1 domain, 2 sites are in the GEFD2 domain, and 1 site (frameshift variant) is in the PH2-SH3 domain. The individual with frameshift variant exhibit absence seizures, mild developmental delay, and the mildest phenotype. The child with myoclonic seizures was treated with valproic acid and levetiracetam for seizure control, while the child with absence epilepsy was treated with valproic acid and lamotrigine for seizure control. All 9 children underwent regular rehabilitation exercises, making slow progress. Conclusions: TRIO gene related MRD is characterized by varying degrees of developmental delay, and often accompanied by macrocephaly or microcephaly, dysmorphic facial features, and with or without seizures. The main variant types are missense variants, which are mostly concentrated in the Spectran domain and GEFD domain. p. R1078W may be a relative hotspot variant. The phenotype caused by the frameshift variant is relatively milder.

The successful integration of engineered gene circuits into host cells remains a significant challenge in synthetic biology due to circuit-host interactions, such as growth feedback, where the circuit influences cell growth and vice versa. Understanding the dynamics of circuit failures and identifying topologies resilient to growth feedback are crucial for both fundamental and applied research. Utilizing transcriptional regulation circuits with adaptation as a paradigm, we systematically study more than four hundred topological structures and uncover various categories of failures. Three dynamical mechanisms of circuit failures are identified: continuous deformation of the response curve, strengthened or induced oscillations, and sudden switching to coexisting attractors. Our extensive computations also uncover a scaling law between a circuit robustness measure and the strength of growth feedback. Despite the negative effects of growth feedback on the majority of circuit topologies, we identify several circuits that maintain optimal performance as designed, a feature important for applications.

Background: The morphology of tumor thrombus varies from person to person and it may affect surgical methods and tumor prognosis. However, studies on the morphology of tumor thrombus are limited. The purpose of our study was to evaluate the impact of tumor thrombus morphology on surgical complexity., Methods: We retrospectively reviewed the clinical data of 229 patients with renal cell carcinoma combined with inferior vena cava (IVC) tumor thrombus who underwent surgical treatment at Peking University Third Hospital between January 2014 and December 2021. The patients were divided into floating morphology (107 patients) and filled morphology (122 patients) tumor thrombi groups. Chi-square and Mann-Whitney U tests were used for categorical and continuous variables, respectively. Postoperative complications were evaluated using the Clavien-Dindo surgical complication classification method., Results: Patients with filled morphology tumor thrombus required more surgical techniques than those with floating morphology tumor thrombus, which was reflected in more open surgeries (P < 0.001), more IVC interruptions (P <0.001), lesser use of the delayed occlusion of the proximal inferior vena cava (DOPI) technique (P < 0.001), and a greater need for cut-off of the short hepatic vein (P < 0.001) and liver dissociation (P = 0.001). Filled morphology significantly increased the difficulty of surgery in patients with renal cell carcinoma with tumor thrombus, reflected in longer operation time (P < 0.001), more surgical blood loss (P <0.001), more intra-operative blood transfusion (P < 0.001), and longer postoperative hospital stay (P < 0.001). Filled morphology tumor thrombus also led to more postoperative complications (53% vs. 20%; P < 0.001)., Conclusion: Compared with floating morphology thrombus, filled morphology thrombus significantly increased the difficulty of surgery in patients with renal cell carcinoma with IVC tumor thrombus., (© 2024. The Author(s).)

Cells provide dynamic platforms for executing exogenous genetic programs in synthetic biology, resulting in highly context-dependent circuit performance. Recent years have seen an increasing interest in understanding the intricacies of circuit-host relationships, their influence on the synthetic bioengineering workflow, and in devising strategies to alleviate undesired effects. We provide an overview of how emerging circuit-host interactions, such as growth feedback and resource competition, impact both deterministic and stochastic circuit behaviors. We also emphasize control strategies for mitigating these unwanted effects. This review summarizes the latest advances and the current state of host-aware and resource-aware design of synthetic gene circuits., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Hemorrhage is the most common major complication after liver biopsy. Hemothorax is one type of bleeding and is very rare and dangerous. Several cases of hemothorax subsequent to liver biopsy have been documented, primarily attributed to injury of the intercostal artery or inferior phrenic artery and a few resulting from lung tissue damage; however, no previous case report of hemothorax caused by injury of musculophrenic artery after liver biopsy has been reported., Case Presentation: A 45-year-old native Chinese woman diagnosed with primary biliary cirrhosis due to long-term redness in urination and abnormal blood test indicators was admitted to our hospital for an ultrasound-guided liver biopsy to clarify pathological characteristics and disease staging. A total of 2 hours after surgery, the patient complained of discomfort in the right chest and abdomen. Ultrasound revealed an effusion in the right thorax and hemothorax was strongly suspected. The patient was immediately referred to the interventional department for digital subtraction angiography. Super-selective angiography of the right internal thoracic artery was performed which revealed significant contrast medium extravasation from the right musculophrenic artery, the terminal branch of the internal thoracic artery. Embolization was performed successfully. The vital signs of the patient were stabilized after the transarterial embolization and supportive treatment., Conclusion: This case draws attention to the musculophrenic artery as a potential source of hemorrhage after percutaneous liver biopsy., (© 2024. The Author(s).)

The rational design and optimization of heterogeneous interface for low loading noble metal HER eletrocatalysts to facilitate the upscaling of alkaline water/seawater electrolysis is highly challenging. Herein, we present a facile deep corrosion strategy induced by NaBH 4 to precisely construct an ultrasmall Ru nanoparticle-decorated Ni/NiO hybrid (r-Ru-Ni/NiO) with highly dispersed triple-phase heterostructures. Remarkably, it exhibits superior activity with only 53 mV and 70 mV at 100 mA cm -2 for hydrogen evolution reaction (HER) in alkaline water and seawater, respectively, surpassing the performance of Pt/C (109.7 mV, 100 mA cm -2 , 1 M KOH). It is attributed to collaborative optimization of electroactive interfaces between well-distributed ultrasmall Ru nanoparticles and Ni/NiO hybrid. Moreover, the assembled r-Ru-Ni/NiO system just require 2.03 V at 1000 mA cm -2 in anion exchange membrane (AEM) electrolyzer, outperforming a RuO 2 /NF || Pt/C system, while exhibiting outstanding stability at high current densities. This study offers a logical design for accurate construction of interfacial engineering, showing promise for large-scale hydrogen production via electrochemical water splitting., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gene circuits within the same host cell often experience coupling, stemming from the competition for limited resources during transcriptional and translational processes. This resource competition introduces an additional layer of noise to gene expression. Here we present three multi-module antithetic control strategies: negatively competitive regulation (NCR) controller, alongside local and global controllers, aimed at reducing the gene expression noise within the context of resource competition. Through stochastic simulations and fluctuation-dissipation theorem (FDT) analysis, our findings highlight the superior performance of the NCR antithetic controller in reducing noise levels. Our research provides an effective control strategy for attenuating resource-driven noise and offers insight into the development of robust gene circuits.

Sepsis is a life-threatening condition that occurs when the body responds to an infection but subsequently triggers widespread inflammation and impaired blood flow. These pathologic responses can rapidly cause multiple organ dysfunction or failure either one by one or simultaneously. The fundamental common mechanisms involved in sepsis-induced multiple organ dysfunction remain unclear. Here, employing quantitative global and phosphoproteomics, we examine the liver's temporal proteome and phosphoproteome changes after moderate sepsis induced by cecum ligation and puncture. In total, 4593 global proteins and 1186 phosphoproteins according to 3275 phosphosites were identified. To characterize the liver-kidney comorbidity after sepsis, we developed a mathematical model and performed cross-analyses of liver and kidney proteome data obtained from the same set of mice. Beyond immune response, we showed the commonly disturbed pathways and key regulators of the liver-kidney comorbidity are linked to energy metabolism and consumption. Our data provide open resources to understand the communication between the liver and kidney as they work to fight infection and maintain homeostasis., (© 2024 Federation of American Societies for Experimental Biology.)

Objective: To summarize the clinical and prognostic features of children with opsoclonus-myoclonus-ataxia syndrome (OMAS). Methods: A total of 46 patients who met the diagnostic criteria of OMAS in the Department of Neurology, Beijing Children's Hospital from June 2015 to June 2023 were retrospectively analyzed. Centralized online consultations or telephone visits were conducted between June and August 2023. The data of the children during hospitalization and follow-up were collected, including clinical manifestations, assistant examination, treatment and prognosis. According to the presence or absence of tumor, the patients were divided into two groups. The chi-square test or Mann-Whitney U test was used to compare the differences between the two groups. Univariate Logistic regression was used to analyze the factors related to OMAS recurrence and prognosis. Results: There were 46 patients, with 25 males and the onset age of 1.5 (1.2, 2.4) years. Twenty-six (57%) patients were diagnosed with neuroblastoma during the course of the disease, and no patients were categorized into the high-risk group. A total of 36 patients (78%) were followed up for≥6 months, and all of them were treated with first-line therapy with glucocorticoids, gammaglobulin and (or) adrenocorticotrophic hormone. Among the 36 patients, 9 patients (25%) were treated with second-line therapy for ≥3 months, including rituximab or cyclophosphamide, and 17 patients (47%) received chemotherapy related to neuroblastoma. At the follow-up time of 4.2 (2.2, 5.5) years, 10 patients (28%) had relapsed of OMAS. The Mitchell and Pike OMS rating scale score at the final follow-up was 0.5 (0, 2.0). Seven patients (19%) were mildly cognitively behind their peers and 6 patients (17%) were severely behind. Only 1 patient had tumor recurrence during follow-up. The history of vaccination or infection before onset was more common in the non-tumor group than in the tumor group (55%(11/20) vs. 23%(6/26), χ² =4.95, P =0.026). Myoclonus occurred more frequently in the non-tumor group (40%(8/20) vs. 4%(1/26), χ² =7.23, P =0.007) as the onset symptom. Univariate Logistic regression analysis showed that the tumor group had less recurrence ( OR= 0.19 (0.04-0.93), P =0.041). The use of second-line therapy or chemotherapy within 6 months of the disease course had a better prognosis ( OR= 11.64 (1.27-106.72), P =0.030). Conclusions: OMAS in children mostly starts in early childhood, and about half are combined with neuroblastoma. Neuroblastoma in combination with OMAS usually has a low risk classification and good prognosis. When comparing patients with OMAS with and without tumors, the latter have a more common infection or vaccination triggers, and myoclonus, as the onset symptom, is more common. Early addition of second-line therapy is associated with better prognosis in OMAS.

Efficient upconversion electroluminescence is highly desirable for a broad range of optoelectronic applications, yet to date, it has been reported only for ensemble systems, while the upconversion electroluminescence efficiency remains very low for single-molecule emitters. Here we report on the observation of anomalously bright single-molecule upconversion electroluminescence, with emission efficiencies improved by more than one order of magnitude over previous studies, and even stronger than normal-bias electroluminescence. Intuitively, the improvement is achieved via engineering the energy-level alignments at the molecule-substrate interface so as to activate an efficient spin-triplet mediated upconversion electroluminescence mechanism that only involves pure carrier injection steps. We further validate the intuitive picture with the construction of delicate electroluminescence diagrams for the excitation of single-molecule electroluminescence, allowing to readily identify the prerequisite conditions for producing efficient upconversion electroluminescence. These findings provide deep insights into the microscopic mechanism of single-molecule upconversion electroluminescence and organic electroluminescence in general., (© 2024. The Author(s).)

The field of synthetic biology and biosystems engineering increasingly acknowledges the need for a holistic design approach that incorporates circuit-host interactions into the design process. Engineered circuits are not isolated entities but inherently entwined with the dynamic host environment. One such circuit-host interaction, 'growth feedback', results when modifications in host growth patterns influence the operation of gene circuits. The growth-mediated effects can range from growth-dependent elevation in protein/mRNA dilution rate to changes in resource reallocation within the cell, which can lead to complete functional collapse in complex circuits. To achieve robust circuit performance, synthetic biologists employ a variety of control mechanisms to stabilize and insulate circuit behavior against growth changes. Here we propose a simple strategy by incorporating one repressive edge in a growth-sensitive bistable circuit. Through both simulation and in vitro experimentation, we demonstrate how this additional repressive node stabilizes protein levels and increases the robustness of a bistable circuit in response to growth feedback. We propose the incorporation of repressive links in gene circuits as a control strategy for desensitizing gene circuits against growth fluctuations., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Surgical removal of the thyroid gland (TG) for treating thyroid disorders leaves the patients on lifelong hormone replacement that partially compensates the physiological needs, but regenerating TG is challenging. Here, an approach is reported to regenerate TG within the spleen for fully restoring the thyroid's functions in mice, by transplanting thyroid tissue blocks to the spleen. Within 48 h, the transplanted tissue efficiently revascularizes, forming thyroid follicles similar to the native gland after 4 weeks. Structurally, the ectopically generated thyroid integrates with the surrounding splenic tissue while maintaining its integrity, separate from the lymphatic tissue. Functionally, it fully restores the native functions of the TG in hormone regulation in response to physiological stimuli, outperforming the established method of oral levothyroxine therapy in maintaining systemic homeostasis. The study demonstrates the full restoration of thyroid functions post-thyroidectomy by intrasplenic TG regeneration, providing fresh insights for designing novel therapies for thyroid-related disorders., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objective: To investigate and analyze the risk factors of massive hemorrhage in patients with renal cell carcinoma and venous tumor thrombus undergoing radical nephrectomy and removal of venous tumor thrombus., Methods: From January 2014 to June 2020, 241 patients with renal cancer and tumor thrombus in a single center of urology at Peking University Third Hospital were retrospectively analyzed. All patients underwent radical nephrectomy and removal of venous tumor thrombus. The relevant preoperative indicators, intraoperative conditions, and postoperative data were statistically analyzed by using statistical software of SPSS 18.0. The main end point of the study was intraoperative bleeding volume greater than 2 000 mL. Logistic regression analysis was used to determine the relevant influencing factors. First, single factor Logistic regression was used for preliminary screening of influencing factors, and variables with single factor Logistic regression analysis P < 0.05 were included in multivariate Logistic regression. In all statistical analyses, P < 0.05 is considered statistically significant., Results: Among the 241 patients included, there were 60 cases of massive hemorrhage, 48 males and 12 females, with a median age of 62 years. The number of non-massive hemorrhage was 181. There were 136 males and 45 females, with a median age of 59 years. Univariate analysis showed that the clinical symptoms (both systemic and local symptoms, OR 2.794, 95% CI 1.087-7.181, P =0.033), surgical approach (open surgery, OR 9.365, 95% CI 4.447-19.72, P < 0.001), Mayo grade (Mayo 3-4, OR 5.257, 95% CI 2.806-10.886, P < 0.001), American Society of Anesthesiologists (ASA) score (ASA level 3, OR 2.842, 95% CI 1.338-6.036, P =0.007), preoperative hemoglobin ( OR 0.978, 95% CI 0.965-0.991, P =0.001), preoperative platelet count ( OR 0.996, 95% CI 0.992-1.000, P =0.037), maximum tumor thrombus width ( OR 1.061, 95% CI 1.033-1.091, P < 0.001), Complicated with bland thrombus ( OR 4.493, 95% CI 2.264-8.915, P < 0.001), adrenalectomy ( OR 3.101, 95% CI 1.614-5.958, P =0.001), segmental resection of the inferior vena cava ( OR 2.857, 95% CI 1.395-5.852, P =0.004). There was a statistically significant difference in these aspects( P < 0.05). Multivariate Logistic regression analysis showed that there was a statistically significant difference in surgical approach (open surgery, OR 6.730, 95% CI 2.947-15.368; P < 0.001), Mayo grade (Mayo 3-4, OR 2.294, 95% CI 1.064-4.948, P =0.034), Complicated with bland thrombus ( OR 3.236, 95% CI 1.492-7.020, P =0.003)., Conclusion: Combining the results of univariate and multivariate Logistic regression analysis, the surgical approach, Mayo grade, and tumor thrombus combined with conventional thrombus were associated risk factors for massive hemorrhage during surgery for renal cell carcinoma with tumor thrombus. Patients who undergo open surgery, high Mayo grade, and tumor thrombus combined with conventional thrombus are at a relatively higher risk of massive hemorrhage.

Objective: To retrospectively analyze clinical data of patients under 40 years old who underwent surgical treatment for renal tumors with tumor thrombus from January 2016 to December 2022 at Peking University Third Hospital, and to evaluate the surgical effect and investigate the relationship between clinicopathological characteristics and prognosis., Methods: The clinical data of 17 young patients with renal tumor thrombus were retrospectively analyzed, and the clinicopathological features and prognosis were summarized. The patients were grouped according to the presence or absence of symptoms, 2017 American Joint Committee on Cancer (AJCC) clinical stage, and postoperative combined adjuvant therapy. Kaplan-Meier method was used to plot the survival curve, and Log-rank test was used to compare the differences in postoperative survival time and progression-free survival time between the different groups. The relationship between clinicopathological features and prognosis was analyzed., Results: All the 17 patients received venous tumor thrombectomy, including 16 patients (94.1%) who underwent radical nephrectomy and 1 patient (5.9%) who underwent partial nephrectomy. Twelve patients (70.6%) had symptoms and 5 (29.4%) had no symptoms before operation. A total of 17 renal tumors were observed, with 2 patients (11.8%) identified as benign and 15 patients (88.2%) classified as malignant. Among the malignant tumors, 1 patient (6.7%) was diagnosed as clear cell carcinoma, while the remaining 14 patients (93.3%) were categorized as non-clear cell carcinoma. In terms of tumor stage, 8 patients (53.3%) were classified as stage Ⅲ according to the AJCC classification, while 7 patients (46.7%) were categorized as stage Ⅳ. Additionally, 6 patients (40%) received multiple adjuvant therapy, while 9 patients (60%) did not undergo such treatment. The follow-up period ranged from 2 to 78 months, with a median follow-up of 41 months. During this time, 3 patients (20%) died. The median survival time after surgery was 39.0 (2.3, 77.8) months, and the progression-free survival time was 16.4 (2.3, 77.8) months. There was no significant difference in postoperative survival time and progression-free survival time among young patients with renal tumor with tumor thrombus, based on the presence of symptoms before surgery ( P =0.307, P =0.302), clinical stage of AJCC ( P =0.340, P =0.492), and postoperative adjuvant therapy ( P =0.459, P =0.253) group., Conclusion: The pathological types of young patients with renal tumor with tumor thrombus are more complex and varied due to symptoms, and the proportion of non-clear cell carcinoma in malignant tumor with tumor thrombus is higher. Symptomatic and non-clear cell carcinoma may be potentially associated with poor prognosis. Surgical operation combined with adjuvant therapy is a relatively safe and effective treatment for young patients with renal tumor and tumor thrombus.

Objective: To investigate the treatment outcome of laparoscopic partial nephrectomy in the patients with renal tumors of moderate to high complexity (R.E.N.A.L. score 7-10)., Methods: In the study, 186 patients with a renal score of 7-10 renal tumors who underwent laparoscopic partial nephrectomy in Peking University Third Hospital from February 2016 to April 2021 were selected. Laparoscopic partial nephrectomy was performed after examination. The patients were followed-up, and their postoperative hemoglobin, creatinine, complications, and length of hospital stay recorded. The data were represented by mean±standard deviation or median (range)., Results: There were 128 males and 58 females in this group, aged (54.6±12.8) years, with body mass index of (25.4 ± 3.4) kg/m 2 ; The tumors were located in 95 cases on the left and 91 cases on the right, with maximum diameter of (3.1±1.2) cm. The patient's preoperative hemoglobin was (142.9±15.8) g/L, and blood creatinine was 78 μmol/L (47-149 μmol/L). According to preoperative CT images, the R.E.N.A.L. score was 7 points for 43 cases, 8 points for 67 cases, 9 points for 53 cases, and 10 points for 23 cases. All the ope-rations were successfully completed, with 12 cases converted to open surgery. The operation time was 150 minutes (69-403 minutes), the warm ischemic time was 25 minutes (3-60 minutes), and the blood loss was 30 mL (5-1 500 mL). There were 9 cases of blood transfusions, with a transfusion volume of 800 mL (200-1 200 mL). Postoperative hemoglobin was (126.2±17.0) g/L. The preoperative crea-tinine was 78 μmol/L (47-149 μmol/L), the postoperative creatinine was 83.5 μmol/L (35-236 μmol/L), the hospital stay was 6 days (3-26 days), and surgical results achieved "the trifecta" in 87 cases (46.8%). In the study, 167 cases were followed up for 12 months (1-62 months), including 1 case with recurrence and metastasis, 4 cases with metastasis, and 2 cases with other tumors (1 case died)., Conclusion: Laparoscopic partial nephrectomy is safe and effective in the treatment of renal tumors with R.E.N.A.L. score of 7-10. Based on the complexity of the tumor, with the increase of difficulty, the warm ischemia time and operation time tend to increase gradually, while "the trifecta" rate gradually decreases. The complications of this operation are less, and the purpose of preserving renal function to the greatest extent is achieved.

Modularity is a key concept in designing synthetic gene circuits, as it allows for constructing complex molecular systems using well-characterized building blocks. One of the major challenges in this field is that these modular components often do not function as expected when assembled into larger circuits. One of the major issues is caused by resource competition, where multiple genes in the circuit compete for the same limited cellular resources, such as transcription factors and ribosomes. In addition, the mutual inhibition between synthetic gene circuits and cell growth results in growth feedback that significantly impacts its host-circuit dynamics. However, the complexity of the gene circuit dynamics under intertwined resource competition and growth feedback is not fully understood. This study developed a theoretical framework to examine the dynamics of synthetic gene circuits by considering both growth feedback and resource competition. Our results suggest a cooperative behavior between resource-competing gene circuits under growth feedback. Cooperation or competition is non-monotonically determined by the metabolic burden threshold. These two diverse effects could lead to the activation or deactivation of one circuit by the other. Lastly, the cooperativity mediated by growth feedback can attenuate the winner-takes-all resource competition. These findings show that coupling growth feedback and resource competition plays a crucial role in the dynamics of the host-circuit system, and understanding its effects helps control unexpected gene expression behaviors., Competing Interests: 5. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Credible diagnostic stratification remains a challenge for coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention. Tongue diagnostic parameters-based diagnostic signatures might predict clopidogrel resistance., Methods: Clinical and tongue diagnostic parameters data were obtained from coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention patients and then analyzed. Tongue diagnostic parameters-based diagnostic signatures were developed through univariate and multivariate logistic regression analysis. The diagnostic prediction was assessed using a receiver operating characteristic curve., Results: A total of 101 patients were consecutively identified. Then, tongue diagnostic parameters were identified as significantly associated with clopidogrel resistance diagnosis and were combined with risk factors to develop a model. The receiver operating characteristic curve analysis showed that tongue diagnostic parameters-based diagnostic signatures performed well in diagnosing clopidogrel resistance with an area under the receiver operating characteristic curve value of 0.819., Conclusions: This study identified a novel tongue diagnostic parameters-based diagnostic signature to reliably distinguish clopidogrel resistance diagnosis in coronary artery disease patients undergoing percutaneous coronary intervention. Further larger, multicenter prospective studies are desired to validate this model., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical features and short-term prognosis of patients with SARS-CoV-2 infection associated acute encephalopathy (AE). Methods: Retrospective cohort study. The clinical data, radiological features and short-term follow-up of 22 cases diagnosed with SARS-CoV-2 infection associated AE in the Department of Neurology, Beijing Children's Hospital from December 2022 to January 2023 were retrospectively analyzed. The patients were divided into cytokine storm group, excitotoxic brain damage group and unclassified encephalopathy group according to the the clinicopathological features and the imaging features. The clinical characteristics of each group were analyzed descriptively. Patients were divided into good prognosis group (≤2 scores) and poor prognosis group (>2 scores) based on the modified Rankin scale (mRS) score of the last follow-up. Fisher exact test or Mann-Whitney U test was used to compare the two groups. Results: A total of 22 cases (12 females, 10 males) were included. The age of onset was 3.3 (1.7, 8.6) years. There were 11 cases (50%) with abnormal medical history, and 4 cases with abnormal family history. All the enrolled patients had fever as the initial clinical symptom, and 21 cases (95%) developed neurological symptoms within 24 hours after fever. The onset of neurological symptoms included convulsions (17 cases) and disturbance of consciousness (5 cases). There were 22 cases of encephalopathy, 20 cases of convulsions, 14 cases of speech disorders, 8 cases of involuntary movements and 3 cases of ataxia during the course of the disease. Clinical classification included 3 cases in the cytokine storm group, all with acute necrotizing encephalopathy (ANE); 9 cases in the excitotoxicity group, 8 cases with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and 1 case with hemiconvulsion-hemiplegia syndrome; and 10 cases of unclassified encephalopathy. Laboratory studies revealed elevated glutathione transaminase in 9 cases, elevated glutamic alanine transaminase in 4 cases, elevated blood glucose in 3 cases, and elevated D-dimer in 3 cases. Serum ferritin was elevated in 3 of 5 cases, serum and cerebrospinal fluid (CSF) neurofilament light chain protein was elevated in 5 of 9 cases, serum cytokines were elevated in 7 of 18 cases, and CSF cytokines were elevated in 7 of 8 cases. Cranial imaging abnormalities were noted in 18 cases, including bilateral symmetric lesions in 3 ANE cases and "bright tree appearance" in 8 AESD cases. All 22 cases received symptomatic treatment and immunotherapy (intravenous immunoglobulin or glucocorticosteroids), and 1 ANE patient received tocilizumab. The follow-up time was 50 (43, 53) d, and 10 patients had a good prognosis and 12 patients had a poor prognosis. No statistically significant differences were found between the two groups in terms of epidemiology, clinical manifestations, biochemical indices, and duration of illness to initiate immunotherapy (all P >0.05). Conclusions: SARS-CoV-2 infection is also a major cause of AE. AESD and ANE are the common AE syndromes. Therefore, it is crucial to identify AE patients with fever, convulsions, and impaired consciousness, and apply aggressive therapy as early as possible.

We report the design and realization of the back focal plane (BFP) imaging for the light emission from a tunnel junction in a low-temperature ultrahigh-vacuum (UHV) scanning tunneling microscope (STM). To achieve the BFP imaging in a UHV environment, a compact "all-in-one" sample holder is designed and fabricated, which allows us to integrate the sample substrate with the photon collection units that include a hemisphere solid immersion lens and an aspherical collecting lens. Such a specially designed holder enables the characterization of light emission both within and beyond the critical angle and also facilitates the optical alignment inside a UHV chamber. To test the performance of the BFP imaging system, we first measure the photoluminescence from dye-doped polystyrene beads on a thin Ag film. A double-ring pattern is observed in the BFP image, arising from two kinds of emission channels: strong surface plasmon coupled emissions around the surface plasmon resonance angle and weak transmitted fluorescence maximized at the critical angle, respectively. Such an observation also helps to determine the emission angle for each image pixel in the BFP image and, more importantly, proves the feasibility of our BFP imaging system. Furthermore, as a proof-of-principle experiment, electrically driven plasmon emissions are used to demonstrate the capability of the constructed BFP imaging system for STM induced electroluminescence measurements. A single-ring pattern is obtained in the BFP image, which reveals the generation and detection of the leakage radiation from the surface plasmon propagating on the Ag surface. Further analyses of the BFP image provide valuable information on the emission angle of the leakage radiation, the orientation of the radiating dipole, and the plasmon wavevector. The UHV-BFP imaging technique demonstrated here opens new routes for future studies on the angular distributed emission and dipole orientation of individual quantum emitters in UHV., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Background: Oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction have a dismal prognosis, and early detection is key to reduce mortality. However, early detection depends on upper gastrointestinal endoscopy, which is not feasible to implement at a population level. We aimed to develop and validate a fully automated machine learning-based prediction tool integrating a minimally invasive sponge cytology test and epidemiological risk factors for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction before endoscopy., Methods: For this multicohort prospective study, we enrolled participants aged 40-75 years undergoing upper gastrointestinal endoscopy screening at 39 tertiary or secondary hospitals in China for model training and testing, and included community-based screening participants for further validation. All participants underwent questionnaire surveys, sponge cytology testing, and endoscopy in a sequential manner. We trained machine learning models to predict a composite outcome of high-grade lesions, defined as histology-confirmed high-grade intraepithelial neoplasia and carcinoma of the oesophagus and oesophagogastric junction. The predictive features included 105 cytological and 15 epidemiological features. Model performance was primarily measured with the area under the receiver operating characteristic curve (AUROC) and average precision. The performance measures for cytologists with AI assistance was also assessed., Findings: Between Jan 1, 2021, and June 30, 2022, 17 498 eligible participants were involved in model training and validation. In the testing set, the AUROC of the final model was 0·960 (95% CI 0·937 to 0·977) and the average precision was 0·482 (0·470 to 0·494). The model achieved similar performance to consensus of cytologists with AI assistance (AUROC 0·955 [95% CI 0·933 to 0·975]; p=0·749; difference 0·005, 95% CI, -0·011 to 0·020). If the model-defined moderate-risk and high-risk groups were referred for endoscopy, the sensitivity was 94·5% (95% CI 88·8 to 97·5), specificity was 91·9% (91·2 to 92·5), and the predictive positive value was 18·4% (15·6 to 21·6), and 90·3% of endoscopies could be avoided. Further validation in community-based screening showed that the AUROC of the model was 0·964 (95% CI 0·920 to 0·990), and 92·8% of endoscopies could be avoided after risk stratification., Interpretation: We developed a prediction tool with favourable performance for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction. This approach could prevent the need for endoscopy screening in many low-risk individuals and ensure resource optimisation by prioritising high-risk individuals., Funding: Science and Technology Commission of Shanghai Municipality., Competing Interests: Declaration of interests L-WW has received research support from the Science and Technology Commission of Shanghai Municipality (grant number 21Y31900100). J-CZ and S-YL are employees of the Harbor Scientific Instrument and received salary support. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Whether to use antibiotics to prevent surgical site infection in elective inguinal tension-free hernia repair has been controversial. To systematically evaluate the effect of prophylactic antibiotic application in elective inguinal tension-free hernia repair, we identified all published randomised controlled trials of the effect of prophylactic antibiotic application on elective inguinal tension-free hernia repair were collected by computer retrieval from the China National Knowledge Infrastructure; VIP Database; Wanfang Database; China Biomedical Literature Database; and PubMed, EMBASE and Cochrane Library databases. Meta-analysis was performed by RevMan 5.3 software. The meta-analysis showed that the total incidence of surgical site infections [P = 0.003] and the incidence of superficial surgical site infections [P = 0.004] in the antibiotic group (AG) were lower than those in the non-antibiotic group (NAG). There was no significant difference in the total incidence of postoperative infections [P = 0.06], deep surgical site infections [P = 0.26] and seroma [P = 0.52] between the AG and the NAG. Based on current evidence, the application of prophylactic antibiotics in elective inguinal tension-free hernia repair can prevent the total incidence of surgical site infections and that of superficial surgical site infections but cannot prevent the total incidence of postoperative infection events, incidence of deep surgical site infections and incidence of seroma., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

The molecular genetic characteristics of a family with rare -88 C>G ( HBB: c.-138 C>G) β-thalassemia gene mutation were studied using cohort study. The cohort study was conducted from June to August 2022 by Prenatal Diagnosis Center of Sanya Women and Children's Hospital Managed by Shanghai Children's Medical Center. The phenotype and genotype were analyzed by hematological cytoanalyzer, automatic electrophoretic analysis system, and next-generation sequencing (NGS). And then, Sanger sequencing was used to verify the rare gene results. The results showed that the proband, her father, her uncle and her younger male cousin had discrete microcytosis (MCV 70.1 fl, 71.9 fl, 73.1 fl and 76.6 fl, respectively) and hypochromia (MCH 21.5 pg,22.0 pg,22.6 pg and 23.5 pg, respectively), elevated hemoglobin A2 level (5.3%, 5.4%, 5.4% and 5.5%, respectively), slightly elevated or normal fetal hemoglobin (Hb F), but no anemia. The proband was identified to have co-inherited ɑ-thalassemia (Hb Westmead gene heterozygous mutation, ɑ ws ɑ/ɑɑ) and β-thalassemia with a rare -88 C>G ( HBB : c.-138 C>G) heterozygous mutation (β -88 C>G /β N ). Her mother had the same α-thalassemia as the proband. Her father, her uncle and her younger male cousin had the same rare -88 C>G heterozygous mutations as the proband. While her grandmother and younger brother were not carrier of thalassemia. In conclusion, 4 cases of rare -88 C>G( HBB:c.-138 C>G ) heterozygous mutation had been detected in a Chinese family. Carriers of this beta-thalassemia are clinically asymptomatic. This study enriches the knowledge of the thalassemia mutation spectrum in Chinese people and provides valuable information for genetic counseling, prenatal diagnosis, and prevention of thalassemia, providing a scientific basis for improving the quality of birth population and preventing birth defects.

To investigate the possible effect of FoxO on coxsackievirus B3 (CVB3) -induced cardiomyocyte inflammation and apoptosis via modulation of the TLR4/NF-κB signaling pathway.Viral myocarditis (VMC) models were establied via CVB3 infection both in vivo and in vitro. Western blotting was adopted to detect FoxO1 and TLR4 expressions in myocardial tissues and cells. Cardiomyocytes of suckling mouse were divided into the control, CVB3, CVB3 + pcDNA, CVB3 + pcDNA-FoxO1, CVB3 + TLR4 siRNA, and CVB3 + pcDNA-FoxO1 + TLR4 siRNA groups. Flow cytometry was employed to evaluate cell apoptosis. The expressions of inflammatory factors including TNF-α, IL-1β, and IL-6 were detected via quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Then, TLR4/NF-κB pathway-related proteins were determined via Western blotting.VMC mice had increased FoxO1 and TLR4 expressions in myocardial tissues. Cardiomyocytes with CVB3 infection also had upregulated protein expressions of p-FoxO1/FoxO1 and TLR4. Compared with those in the control group, the cardiomyocytes in the CVB3 group were increased in LDH and CK-MB levels, cell apoptosis rate and inflammatory factors (TNF-α, IL-1β and IL-6), as well as protein expressions of TLR4 and p-p65/p65. Compared with those in the CVB3 group, the cardiomyocytes in the CVB3 + pcDNA-FoxO1 group were further upregulated whereas those in the CVB3 +TLR4 siRNA group were downregulated in the aforementioned indicators. Furthermore, TLR4 siRNA can reverse the effect of pcDNA-FoxO1 on the aggravation of cardiomyocyte injury induced by CVB3 infection.FoxO1 can upregulate the TLR4/NF-κB signaling pathway to promote cardiomyocyte apoptosis and inflammatory injury in CVB3-induced VMC.

Background: Before the COVID-19 pandemic, the US opioid epidemic triggered a collaborative municipal and academic effort in Tempe, Arizona, which resulted in the world's first open access dashboard featuring neighbourhood-level trends informed by wastewater-based epidemiology (WBE). This study aimed to showcase how wastewater monitoring, once established and accepted by a community, could readily be adapted to respond to newly emerging public health priorities., Methods: In this population-based study in Greater Tempe, Arizona, an existing opioid monitoring WBE network was modified to track SARS-CoV-2 transmission through the analysis of 11 contiguous wastewater catchments. Flow-weighted and time-weighted 24 h composite samples of untreated wastewater were collected at each sampling location within the wastewater collection system for 3 days each week (Tuesday, Thursday, and Saturday) from April 1, 2020, to March 31, 2021 (Area 7 and Tempe St Luke's Hospital were added in July, 2020). Reverse transcription quantitative PCR targeting the E gene of SARS-CoV-2 isolated from the wastewater samples was used to determine the number of genome copies in each catchment. Newly detected clinical cases of COVID-19 by zip code within the City of Tempe, Arizona were reported daily by the Arizona Department of Health Services from May 23, 2020. Maricopa County-level new positive cases, COVID-19-related hospitalisations, deaths, and long-term care facility deaths per day are publicly available and were collected from the Maricopa County Epidemic Curve Dashboard. Viral loads of SARS-CoV-2 (genome copies per day) measured in wastewater from each catchment were aggregated at the zip code level and city level and compared with the clinically reported data using root mean square error to investigate early warning capability of WBE., Findings: Between April 1, 2020, and March 31, 2021, 1556 wastewater samples were analysed. Most locations showed two waves in viral levels peaking in June, 2020, and December, 2020-January, 2021. An additional wave of viral load was seen in catchments close to Arizona State University (Areas 6 and 7) at the beginning of the fall (autumn) semester in late August, 2020. Additionally, an early infection hotspot was detected in the Town of Guadalupe, Arizona, starting the week of May 4, 2020, that was successfully mitigated through targeted interventions. A shift in early warning potential of WBE was seen, from a leading (mean of 8·5 days [SD 2·1], June, 2020) to a lagging (-2·0 days [1·4], January, 2021) indicator compared with newly reported clinical cases., Interpretation: Lessons learned from leveraging an existing neighbourhood-level WBE reporting dashboard include: (1) community buy-in is key, (2) public data sharing is effective, and (3) sub-ZIP-code (postal code) data can help to pinpoint populations at risk, track intervention success in real time, and reveal the effect of local clinical testing capacity on WBE's early warning capability. This successful demonstration of transitioning WBE efforts from opioids to COVID-19 encourages an expansion of WBE to tackle newly emerging and re-emerging threats (eg, mpox and polio)., Funding: National Institutes of Health's RADx-rad initiative, National Science Foundation, Virginia G Piper Charitable Trust, J M Kaplan Fund, and The Flinn Foundation., Competing Interests: Declaration of interests EMD is a managing member of AquaVitas, a company working in the field of wastewater-based epidemiology. RUH is a managing member of AquaVitas and founder of the Arizona State University non-profit project OneWaterOneHealth operating in the same intellectual space. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The effects of host resource limitations on the function of synthetic gene circuits have gained significant attention over the past years. Hosts, having evolved resource capacities optimal for their own genome, have been repeatedly demonstrated to suffer from the added burden of synthetic genetic programs, which may in return pose deleterious effects on the circuit's function. Three resource controller archetypes have been proposed previously to mitigate resource distribution problems in dynamic circuits: the local controller, the global controller, and a "negatively competitive" regulatory (NCR) controller that utilizes synthetic competition to combat resource competition. The dynamics of negative feedback forms of these controllers have been previously investigated, and here we extend the analysis of these resource allocation strategies to the incoherent feedforward loop (iFFL) topology. We demonstrate that the three iFFL controllers can attenuate Winner-Take-All resource competition between two bistable switches. We uncover that the parameters associated with the synthetic competition in the NCR iFFL controller are paramount to its increased efficacy over the local controller type, while the global controllers demonstrate to be relatively ineffectual. Interestingly, unlike the negative feedback counterpart topologies, iFFL controllers exhibit a unique coupling of switch activation thresholds which we term the "coactivation threshold shift" effect. Finally, we demonstrate that a nearly fully orthogonal set of bistable switches could be achieved by pairing an NCR controller with an appropriate level of controller resource consumption.

Background: Increasing evidence have shown that regional lymph node metastasis is a critical prognostic factor in gastric cancer (GC). In addition, lymph node dissection is a key factor in determining the appropriate treatment for GC. However, the association between the number of positive lymph nodes and area of lymph node metastasis in GC remains unclear., Aim: To investigate the clinical value of regional lymph node sorting after radical gastrectomy for GC., Methods: This study included 661 patients with GC who underwent radical gastrectomy at Tianjin Medical University General Hospital between January 2012 and June 2020. The patients were divided into regional sorting and non-sorting groups. Clinicopathological data were collected and retrospectively reviewed to determine the differences in the total number of lymph nodes and number of positive lymph nodes between the groups. Independent sample t -tests were used for intergroup comparisons. Continuous variables that did not conform to a normal distribution were expressed as median (interquartile range), and the Mann-Whitney U test was used for inter-group comparisons., Results: There were no significant differences between the groups in terms of the surgical method, tumor site, immersion depth, and degree of differentiation. The total number of lymph nodes was significantly higher in the regional sorting group ( n = 324) than in the non-sorting group ( n = 337) (32.5 vs 21.2, P < 0.001). There was no significant difference in the number of positive lymph nodes between the two groups. A total of 212 patients with GC had lymph node metastasis in the lymph node regional sorting group, including 89 (41.98%) cases in the first dissection station and 123 (58.02 %) cases in the second dissection station. Binary and multivariate logistic regression results showed that the number of positive lymph nodes ( P < 0.001) was an independent risk factor for lymph node metastases at the second dissection station., Conclusion: Regional sorting of lymph nodes after radical gastrectomy may increase the number of detected lymph nodes, thereby improving the reliability and accuracy of lymph node staging in clinical practice., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

The mutual interactions between the synthetic gene circuits and the host growth could cause unexpected outcomes in the dynamical behaviors of the circuits. However, how the steady states and the stabilities of the gene circuits are affected by host cell growth is not fully understood. Here, we developed a mathematical model for nonlinear growth feedback based on published experimental data. The model analysis predicts that growth feedback could significantly change the qualitative states of the system. Bistability could emerge in a circuit without positive feedback, and high-order multistability (three or more steady states) arises in the self-activation and toggle switch circuits. Our results provide insight into the potential effects of ultrasensitive growth feedback on the emergence of qualitative states in synthetic circuits and the corresponding underlying mechanism., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the treatment and prognosis of multiple primary malignant neoplasms (MPMN) complicated with renal cell carcinoma (RCC), and to make risk stratification., Methods: A retrospective study of 27 cases of MPMN with RCC in two centers, including the different tumors of MPMN, specific treatment methods, and the interval between primary cancers. At the same time, the survival conditions, including recurrence, metastasis and survival, were followed up for statistical analysis. The interval between the two kinds of primary cancer within 6 months was simultaneous MPMNs, and more than 6 months was metachronous MPMNs. For simple risk stratification of cases, as long as one of the MPMNs had a stage Ⅲ or higher malignancy, which was defined as high risk., Results: Among the 27 patients, 20 were male and 7 were female, with age at the time of diagnosis was 42-82 years, with an average age of (61.3±11.7) years. The age at the diagnosis of renal cancer was 43-87 years, with an average age of (66.0±11.3) years. There were 21 cases with duplex primary malignant neoplasms, 4 cases with triple primary malignant neoplasms, and 2 cases with quadruple primary malignant neoplasms. The interval between first cancer and second cancer was 0-360 months, with a median of 18 months. There were 17 cases of metachronous multiple primary malignant neoplasms and 10 cases of simultaneous multiple primary malignant neoplasms. The most common system of MPMN with comorbid RCC involved urologic system, digestive system and respiratory system. The most common locations of MPMN with comorbid RCC were bladder cancer, lung cancer and colon cancer. Follow-up time calcu- lated from the last cancer was 2-156 months, with a median of 32 months. And 14 cases survived and 13 cases died, with 11 cases being tumor related. Tumor stage was the risk factor of prognosis. Any kind of tumor stage in stage Ⅲ or above had a relatively poor prognosis., Conclusion: MPMN complicated with RCC is relatively rare. Standard treatment should be used for each cancer type during the treatment process. The prognosis mainly depends on the highest stage of each tumor. Simple risk stratification shows that the prognosis of the high-risk group is worse. This simple stratification method may be helpful to predict the prognosis.

Quantum-coherent intermolecular energy transfer is believed to play a key role in light harvesting in photosynthesis and photovoltaics. So far, a direct, real-space demonstration of quantum coherence in donor-acceptor systems has been lacking because of the fragile quantum coherence in lossy molecular systems. Here, we precisely control the separations in well-defined donor-acceptor model systems and unveil a transition from incoherent to coherent electronic energy transfer. We monitor the fluorescence from the heterodimers with subnanometre resolution through scanning tunnelling microscopy induced luminescence. With decreasing intermolecular distance, the dipole coupling strength increases and two new emission peaks emerge: a low-intensity peak blueshifted from the donor emission, and an intense peak redshifted from the acceptor emission. Spatially resolved spectroscopic images of the redshifted emission exhibit a σ antibonding-like pattern and thus indicate a delocalized nature of the excitonic state over the whole heterodimer due to the in-phase superposition of molecular excited states. These observations suggest that the exciton can travel coherently through the whole heterodimer as a quantum-mechanical wavepacket. In our model system, the wavelike quantum-coherent transfer channel is three times more efficient than the incoherent channel., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Oxidative stress, apoptosis, and fibrosis have important roles in acute myocardial infarction, which is the main cause of global morbidity and mortality. Guanxin V significantly ameliorates acute myocardial infarction, the underlying mechanism, however, is still unclear., Purpose: In this study, we detected the anti-oxidative, anti-apoptotic, and anti-fibrosis effects of Guanxin V on acute myocardial infarction., Methods: We used left anterior descending coronary artery ligation to construct an acute myocardial infarction model. Cardiac function, heart weight, infarction size, and histopathology were measured. Cardiomyocytes were treated with hydrogen peroxide to build an in vitro model. Cell apoptosis, fibrosis, and reactive oxygen species-related markers were tested. We observed the mitochondrial ultrastructure through transmission electron microscopy. The levels of collagens and TGF-β1 signalling were measured. The lentiviral vector containing the full-length TGF-β1 sequence was administered to investigate the rescue role of Guanxin V., Results: Guanxin V significantly decreased apoptosis and inhibited oxidative stress damage and fibrosis in acute myocardial infarction. Hydrogen peroxide could stimulate cardiomyocytes to produce reactive oxygen species and Guanxin V could significantly reverse hydrogen peroxide-induced cell damage, inhibit oxidative stress damage, apoptosis, and fibrosis, and enhance mitochondrial dynamic balance. Mechanistically, Guanxin V attenuated oxidative stress damage, apoptosis, and fibrosis induced by the TGF-β1 signalling pathway activation., Conclusions: Guanxin V effectively relieved apoptosis, oxidative stress damage, and fibrosis through down-regulating the TGF-β1 signalling pathway, which enhances the knowledge of the cellular and molecular mechanism of Guanxin V in treating acute myocardial infarction., (Copyright © 2022. Published by Elsevier GmbH.)

The high-valence tin-oxo clusters are of great significance because of their structural diversity and potential applications in many fields, e.g., catalysis, extreme ultraviolet (EUV) lithography, and so on. The synthesis of high-nuclearity tin-oxo clusters remains a great challenge currently, since the key inorganic Sn x O y core with Sn 4+ ions could not be obtained only by the in situ Sn-C bond cleavage in organic tin sources. In this context, we synthesize three organic-inorganic hybrid Sn 18 -oxo clusters, [(BuSn) 12 Sn 6 (μ 3 -O) 20 (ba) 12 (PhPO 3 ) 4 ] (Bu = butyl, Hba = benzoic acid), [(BuSn) 12 Sn 6 (μ 3 -O) 20 (pmba) 12 (PhPO 3 ) 4 ]·2CH 3 CN·2H 2 O (Hpmba = p -toluic acid), and [(BuSn) 12 Sn 6 (μ 3 -O) 20 (ptba) 12 (PhPO 3 ) 4 ]·2CH 3 CN·2 i PrOH·2H 2 O (Hptba = p -tert-butyl benzoic acid), as well as one Sn 6 -oxo cluster [(BuSn) 6 (μ 3 -O) 2 (μ 2 -OH) 4 (pnba) 6 (PhPO 3 ) 2 ] (Sn 6 ) (Hpnba = p -nitrobenzoic acid) by combining an inorganic precursor (SnCl 4 ) with an organic one (butyltin hydroxide oxide). It is shown that an inorganic dicyclo-chain-like Sn 6 O 8 core encapsulated in a U-shaped dodecanuclear butyltin-oxo ring plays an important role in the construction of Sn 18 -oxo clusters and that the use of a ligand with an electron-withdrawing group reduces the nuclearity of clusters to Sn 6 . Moreover, electrocatalytic CO 2 reduction studies confirm that the electrocatalytic activities of the Sn 18 clusters are superior to those of the Sn 6 cluster, probably due to the hybrid organotin-inorganotin structures. Our work not only opens a new way for constructing high-nuclearity tin-oxo clusters but also is helpful in deeply revealing the structure-properties relationship of tin-oxo clusters.

Objective: To analyse the clinical and gene characteristics of GRIN2B gene related neurological developmental disorders in children. Methods: The data of 11 children with GRIN2B gene related neurological developmental disorders from November 2016 to February 2021 were collected from Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health and analyzed retrospectively. The clinical features, electroencephalogram (EEG), brain imaging and gene testing results were summarized. Results: Among 11 children 6 were boys and 5 were girls. Two of them were diagnosed with developmental and epileptic encephalopathy. The ages of seizures onset were 3 months and 9 months, respectively. Seizure types included epileptic spasm, tonic seizures, tonic spasm and focal seizures, and 1 patient also had startle attacks. EEG showed interictal multifocal epileptiform discharges. Both of them were added with more than 2 anti-seizure drugs, which were partially effective but could not control. They had moderate to severe mental and motor retardation. The phenotype of 9 cases was developmental delay or intellectual disability without epilepsy, age of visit 1 year to 6 year and 4 months of whom 5 cases had severe developmental delay, 2 cases had moderate and 2 cases had mild delay. Multi-focal epileptiform discharges were observed in 3 cases, no abnormality was found in 3 cases, and the remaining 3 cases did not undergo EEG examination. Ten cases underwent brain magnetic resonance imaging (MRI), 6 cases had nonspecific abnormalities and 4 cases were normal. Nine GRIN2B gene heterozygous variants were detected by next-generation sequencing in these 11 patients, 8 cases had missense variants and 1 case had nonsense variant, all of which were de novo and 3 of which were novel. Missense variants were found in 10 patients, among them 6 cases had severe developmental delay, 3 cases had moderate and 1 case had mild developmental delay, but the patient with nonsense variant showed mild developmental delay without epilepsy. Conclusions: The phenotypes of GRIN2B gene related neurological developmental disorders in children are diverse, ranging from mild intellectual impairment without epilepsy to severe epileptic encephalopathy. Patients with epileptic phenotype usually have an onset age of infancy, and spasm and focal seizures are the most common seizure types. And the epiletice episodes are refractory. Most of the patients with missense variants had severe developmental delay.

Despite extensive investigation demonstrating that resource competition can significantly alter the deterministic behaviors of synthetic gene circuits, it remains unclear how resource competition contributes to the gene expression noise and how this noise can be controlled. Utilizing a two-gene circuit as a prototypical system, we uncover a surprising double-edged role of resource competition in gene expression noise: competition decreases noise through introducing a resource constraint but generates its own type of noise which we name as "resource competitive noise." Utilization of orthogonal resources enables retainment of the noise reduction conferred by resource constraint while removing the added resource competitive noise. The noise reduction effects are studied using three negative feedback types: negatively competitive regulation (NCR), local, and global controllers, each having four placement architectures in the protein biosynthesis pathway (mRNA or protein inhibition on transcription or translation). Our results show that both local and NCR controllers with mRNA-mediated inhibition are efficacious at reducing noise, with NCR controllers demonstrating a superior noise-reduction capability. We also find that combining feedback controllers with orthogonal resources can improve the local controllers. This work provides deep insights into the origin of stochasticity in gene circuits with resource competition and guidance for developing effective noise control strategies., Competing Interests: CONFLICT OF INTEREST The authors declare no competing interests

Object: By retrospectively analyzing the energy spectrum of squamous cell carcinoma, adenocarcinoma, small cell lung cancer (SCLC), and pulmonary metastases that underwent dual-layer detector spectral computed tomography (DLCT) 3-phase scan of the chest, we explored the value of a multiparameter energy spectrum in the assessment of pathological types of lung tumors. Methods: Cases of squamous cell carcinoma ( n  = 20), adenocarcinoma ( n  = 24), SCLC ( n  = 26), and metastases ( n  = 14) were collected. Then the largest cross-sectional area (LCA) of the lesion, computed tomography (CT) values in the plain scan phase, arterial and venous phases (HU, HUa, and HUv), iodine concentration, and effective atomic number in the arterial and venous phases (ICa, ICv, Zeff[a], and Zeff[v]) were measured and compared among the nonsmall cell lung cancer (NSCLC), SCLC and metastases, and other 3 groups of SCLC, squamous cell carcinoma, and adenocarcinoma. Results: Only the LCA is statistically different among SCLC, NSCLC, and metastases ( P  < .05). And the treated subgroup analysis did not show significant differences among the groups. However, the untreated subgroup analysis showed that there was a significant difference between NSCLC and metastases in LCA, SCLC and metastases in ICa, NSCLC and SCLC in HUv, NSCLC and SCLC in Zeff(v) ( P  < .05). Conclusion: The energy spectrum parameters of DLCT have a certain clinical value in distinguishing NSCLC from SCLC in the Zeff(v) and distinguishing SCLC from metastases in the ICa.

Objective: To summarize the clinical characteristics of SYNGAP1-related epilepsy in children. Methods: Data of 13 patients with SYNGAP1 gene variants diagnosed with epilepsy at Department of Neurology, Beijing Children's Hospital were collected retrospectively from March 2017 to October 2020 and the patients were followed up. The clinical features, electroencephalogram(EEG), brain imaging, gene results and treatment were summarized. Results: Twelve patients were followed up successfully among the 13 patients with SYNGAP1 variants. The last follow-up age was 5 years and 7 months (3 years and 1 month to 9 years).The onset age of seizures was 2 years (4 months to 3 years). Seizure types included eyelid myoclonia with or without absence (9 cases), myoclonic seizure (5 cases), atypical absence (4 cases), suspicious atonic seizures(4 cases),unclassified fall attack (6 cases), and the frequency of seizures varied from several times to more than 100 times per day. Four cases had the mimic phenotype of myoclonic astatic epilepsy. The seizures of 10 cases could be triggered by eating (5 cases), emotion (5 cases), fever (3 cases), voice (2 cases), fatigue (2 cases), etc. Electroencephalography (10 cases) showed interictal generalized or focal epileptiform discharges (9 cases), and atypical aphasia (4 cases), myoclonic seizure (2 cases) and eyelid myoclonic seizure (1 case) were monitored. Of the 12 cases, 9 were added with valproate, all of which were effective (the frequency of seizures reduced>50%). Five cases received combined levetiracetam, in 3 the treatments were effective. To last follow-up, 3 cases were seizure free from 6 months to 1 year and 1 month, but the remaining 7 cases still had seizures, one or several times per day. All 13 cases had developmental retardation (speech ability impaired mostly), 2 cases were severe, 10 cases were moderate, 1 case was mild. The SYNGAP1 gene variants of 13 patients were all de novo, including 12 variants. Among them, 4 were frameshift variants, 4 were nonsense variants, 2 were missense variants and 2 were splice site variants. Conclusions: Patients with SYNGAP1-related epilepsy have an early onset age and many seizure types. The main seizure type is eyelid myoclonia with or without absence, and other seizure types include myoclonic seizure, atypical absence, unclassified fall attack, etc. Valproate is effective in most patients, but seizures in some patients might be intractable. Most patients have developmental delay (mainly moderate and severe), speech ability impaired mostly.

Objective: Diabetic kidney disease (DKD) is the most common microvascular complication of type 2 diabetes mellitus (2-DM). Currently, urine and kidney biopsy specimens are the major clinical resources for DKD diagnosis. Our study proposes to evaluate the diagnostic value of blood in monitoring the onset of DKD and distinguishing its status in the clinic., Methods: This study recruited 1,513 participants including healthy adults and patients diagnosed with 2-DM, early-stage DKD (DKD-E), and advanced-stage DKD (DKD-A) from 4 independent medical centers. One discovery and four testing cohorts were established. Sera were collected and subjected to training proteomics and large-scale metabolomics., Results: Deep profiling of serum proteomes and metabolomes revealed several insights. First, the training proteomics revealed that the combination of α 2 -macroglobulin, cathepsin D, and CD324 could serve as a surrogate protein biomarker for monitoring DKD progression. Second, metabolomics demonstrated that galactose metabolism and glycerolipid metabolism are the major disturbed metabolic pathways in DKD, and serum metabolite glycerol-3-galactoside could be used as an independent marker to predict DKD. Third, integrating proteomics and metabolomics increased the diagnostic and predictive stability and accuracy for distinguishing DKD status., Conclusions: Serum integrative omics provide stable and accurate biomarkers for early warning and diagnosis of DKD. Our study provides a rich and open-access data resource for optimizing DKD management., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The Hippo-YAP/TAZ signaling pathway plays a critical role in tissue homeostasis, tumorigenesis, and degeneration disorders. The regulation of YAP/TAZ levels is controlled by a complex regulatory network, where several feedback loops have been identified. However, it remains elusive how these feedback loops contain the YAP/TAZ levels and maintain the system in a healthy physiological state or trap the system in pathological conditions. Here, a mathematical model was developed to represent the YAP/TAZ regulatory network. Through theoretical analyses, three distinct states that designate the one physiological and two pathological outcomes were found. The transition from the physiological state to the two pathological states is mechanistically controlled by coupled bidirectional bistable switches, which are robust to parametric variation and stochastic fluctuations at the molecular level. This work provides a mechanistic understanding of the regulation and dysregulation of YAP/TAZ levels in tissue state transitions., Competing Interests: The authors have declared that no competing interests exist.

Objective: To explore the clinical characteristics, imaging findings, laboratory tests and treatment strategies for Chlamydia psittaci pneumonia. Methods: From January 1, 2019 to January 20, 2021, 48 cases of Psittacosis from 11 hospitals in China were diagnosed via metagenomic next-generation sequencing(mNGS). The data of all patients on occupational history, clinical manifestations, laboratory tests, chest computed tomography(CT)findings, treatment outcomes and prognosis were retrospectively analyzed. Results: Among the 48 patients, there were 29 males and 19 females, with a mean age of (57.1±10.3) years. Thirty patients had a confirmed history of exposure to poultry. The onset to admission interval was (6.5±3.2) days, and hospital stay was (12.4±4.8) days. Clinical manifestations included fever (100%, 48/48), relative bradycardia (71%, 34/48), cough (54.2%, 26/48), sputum (27.1%, 13/48), fatigue (16.7%, 8/48), headache and delirium (20.8%, 9/48), and gastrointestinal symptoms (16.7%, 8/48). Laboratory data showed that white blood cells were (8.0±3.8)×10 9 /L, and the proportion of neutrophils increased in 44 patients. The level of C-reactive protein was (155.3±74.1)mg/L, and that of procalcitonin (PCT)in 59.5% of patients was more than 0.5 μg/L. Percentages of patients with increased lactate dehydrogenase and creatine kinase were 82.9% and 45.2%, respectively. Chest CT scans showed unilateral lung involvement in 34 cases(70.8%) and single lobe involvement in 27 cases(56.3%).The most common imaging change was consolidation, with 38 cases (79.2%) showing lobar consolidation. In terms of treatment, 25 patients were treated with fluoroquinolones alone, 6 patients with doxycycline alone, and 13 patients with combined treatment. The combined-treatment group and the doxycycline alone group were similar in the course of defervescence. The combined treatment group and the doxycycline alone group were both superior to the fluoroquinolones alone group. However, 11 patients were admitted to ICU, all of them received artificial ventilation, and 5 cases developed shock, and one died. Conclusions: Chlamydia psittaci pneumonia is an animal-derived infectious disease with unique features in clinical symptoms, laboratory tests and chest imaging. Appropriate treatment is able to significantly shorten the course of disease and improve the prognosis.

The kidney local microenvironment (KLM) plays a critical role in the pathogenesis of kidney fibrosis. However, the composition and regulation of a fibrotic KLM remain unclear. Through a multidisciplinary approach, we investigated the roles of the hepatocyte growth factor/c-met signaling pathway in regulating KLM formation in various chronic kidney disease (CKD) models. We performed a retrospective analysis of single-cell RNA sequencing data and determined that tubular epithelial cells and macrophages are two major cell populations in a fibrotic kidney. We then created a mathematical model that predicted loss of c-met in tubular cells would cause greater responses to injury than loss of c-met in macrophages. By generating c-met conditional knockout mice, we validated that loss of c-met influences epithelial plasticity, myofibroblast activation, and extracellular matrix synthesis/degradation, which ultimately determined the characteristics of the fibrotic KLM. Our findings open the possibility of designing effective therapeutic strategies to retard CKD., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors.)

With the continuous development of kidney transplantation technique, the survival time after kidney transplantation is gradually prolonged. Thus, the malignant tumor has been the important influencing factor on the long-term survival for kidney transplantation patients. Renal cell carcinoma is a relatively common tumor after kidney transplantation. Besides, clear cell renal cell carcinoma and papillary renal cell carcinoma are the relatively common pathological types for renal cell carcinoma following kidney transplantation. However, bilateral renal cell carcinoma following kidney transplantation is comparatively rare. In this article, we presented a case of bilateral papillary renal cell carcinoma, which occurred after kidney transplantation. And the diagnosis and treatment were introduced in detail. The patient was 37 years old, and he underwent kidney transplantation 13 years ago in our hospital, because of kidney failure. After kidney transplantation, he had regular medical check-up every year. In this year, his urological ultrasound results indicated bilateral renal tumors. And then, he received abdominal and pelvic computed tomography, and the result also showed bilateral renal tumors, which were likely to be malignant tumors. After adequate consultation, the patient chose surgical treatment. The patient received long-term immunosuppressive therapy, because of kidney transplantation. Considering this, the surgeon decided to choose a staging surgical treatment, in order to reduce the bad influence of one-stage surgery. Then, the patient first underwent retroperitoneal laparoscopic radical nephrectomy for right renal tumor in our hospital, and he had no complications after operation. The pathological results showed papillary renal cell carcinoma. He was discharged successfully. He underwent retroperitoneal laparoscopic radical nephrectomy for left renal tumor in our hospital one month later, and he had no complications after operation. The pathological results also showed papillary renal cell carcinoma. He was discharged successfully two days after surgery. In the 3-month follow-up, the patient was recovering well. To sum up, the incidence of bilateral renal cell carcinoma following kidney transplantation is relatively rare, and bilateral radical nephrectomy is effective and safe treatment. Above all, it is the patient's condition that determines the choice of staging surgery or simultaneous surgery.

Background: Some prevalent but rarely studied causes of hospital admissions, such as sepsis is still unknown whether affected by air pollution., Methods: We used time-series regression within generalized additive models to estimate the effect of air pollutant level on the sepsis-related hospital admissions, for the years 2017-18, using data from six cities in Sichuan, China. Potential effect modifications by age and sex were also explored. The effects of air pollutant on hospital stays for sepsis were also quantified., Results: Positive associations between short-term exposure to NO 2 and O 3 and risk of sepsis-related hospital admissions and stays were found. Each 10 μg/m 3 increase in short-term NO 2 at lag 03 and O 3 at lag 4 was associated with an increase of 2.76% (95% CI: 0.67, 4.84%) and 0.64% (95% CI: 0.14, 1.14%) hospital admissions, respectively. An increase of 0.72% (95% CI: 0.05, 1.40%) hospital stay was associated with 10 μg/m 3 increase in O 3 concentration at lag 4. Besides, the adverse effect of exposure to NO 2 was more significant in males and population aged less than 14 years; while more significant in females and population aged 14 ~ 65 and over 65 years for exposure to O 3 . These associations remained stable after the adjustment of other air pollutants.8., Conclusion: Exposure to ambient NO 2 and O 3 may cause substantial sepsis hospitalizations, and hospital stays in Sichuan, China. These associations were different in subgroup by age and sex.

Aim: Platinum-based chemotherapy is the standard treatment for ovarian cancer. However, tumor cells' resistance to platinum drugs often occurs. This paper provides a review of Forkhead box O (FOXO) protein's role in platinum resistance of ovarian cancer which hopefully may provide some further guidance for the treatment of platinum-resistant ovarian cancer., Methods: We reviewed a 128 published papers from authoritative and professional journals on FOXO and platinum-resistant ovarian cancer, and adopts qualitative analyses and interpretation based on the literature., Results: Ovarian cancer often has abnormal activation of cellular pathways, the most important of which is the PI3K/AKT pathway. FOXOs act as crucial downstream factor of the PI3K/Akt pathway and are negatively regulated by it. DNA damage response and apoptosis including the relationship between FOXOs and ATM-Chk2-p53 are essential for platinum resistance of ovarian cancer. Through gene expression analysis in platinum-resistant ovarian cancer cell model, it was found that FoxO-1 is decreased in platinum-resistant ovarian cancer, so studying the role of FOXO in the pathway on platinum-induced apoptosis may further guide the treatment of platinum-resistant ovarian cancer., Conclusions: There are many drug resistance mechanisms in ovarian cancer, wherein the decrease in cancer cells apoptosis is one of the important causes. Constituted by a series of transcription factors evolving conservatively and mainly working in inhibiting cancer, FOXO proteins play various roles in cells' antitumor response. More and more evidence suggests that we need to re-understand the role that FOXOs have played in cancer development and treatment., (© 2021 Japan Society of Obstetrics and Gynecology.)

Growth feedback, the inherent coupling between the synthetic gene circuit and the host cell growth, could significantly change the circuit behaviors. Previously, a diverse array of emergent behaviors, such as growth bistability, enhanced ultrasensitivity, and topology-dependent memory loss, were reported to be induced by growth feedback. However, the influence of the growth feedback on the circuit functions remains underexplored. Here, we reported an unexpected damped oscillatory behavior of a self-activation gene circuit induced by nutrient-modulating growth feedback. Specifically, after dilution of the activated self-activation switch into the fresh medium with moderate nutrients, its gene expression first decreases as the cell grows and then shows a significant overshoot before it reaches the steady state, leading to damped oscillation dynamics. Fitting the data with a coarse-grained model suggests a nonmonotonic growth-rate regulation on gene production rate. The underlying mechanism of the oscillation was demonstrated by a molecular mathematical model, which includes the ribosome allocation toward gene production, cell growth, and cell maintenance. Interestingly, the model predicted a counterintuitive dependence of oscillation amplitude on the nutrition level, where the highest peak was found in the medium with moderate nutrients, but was not observed in rich nutrients. We experimentally verified this prediction by tuning the nutrient level in the culture medium. We did not observe significant oscillatory behavior for the toggle switch, suggesting that the emergence of damped oscillatory behavior depends on circuit network topology. Our results demonstrated a new nonlinear emergent behavior mediated by growth feedback, which depends on the ribosome allocation between gene circuit and cell growth.

Objective: To investigate the etiology of epilepsy onset before 6 months old and improve clinical understanding. Methods: The medical history, electroencephalogram, brain imaging, genetic examination and other clinical data of 340 patients who were diagnosed with epilepsy with onset under 6 months of age and were hospitalized in the Department of Neurology, Beijing Children's Hospital, Capital Medical University between January 2017 and December 2018 were retrospectively analyzed. Rank sum test was used to compare the ages of onset of different etiologic groups. Results: Of the 340 patients, 196 were males and 144 were females. The age of onset was 90.5 (48.0, 135.5) days. In the 250 (73.5%) underwent genetic test, 103 (41.2%) had pathogenic or likely pathogenic variants, involving 43 single gene variants and 2 chromosomal abnormalities. Seventy-nine patients (23.2%) had genetic etiology, 66 (19.4%) had structural etiology, 19 (5.6%) had metabolic etiology, 13 (3.8%) had multiple etiologies, and 163 (47.9%) had unknown etiology. In the 79 cases with genetic etiology, 30 single gene variants were detected, including 19 cases of PRRT2, 10 cases of KCNQ2, 7 cases of SCN1A, 6 cases of SCN2A, 6 cases of STXBP1, 5 cases of CDKL5, 2 cases of ARX, and 1 case of each of 23 gene variants. Two cases had chromosomal abnormalities which were 21-trisomy and 16p11.2 microdeletion syndrome respectively. Among the 66 cases with structural etiologies, 37 cases had acquired factors such as perinatal brain injury, 28 cases had congenital factors such as cortical malformation and 1 case was perinatal brain injury combined megalencephaly. The onset age of genetic etiology was 95 (26, 128) days, that of structural etiology was 90 (58, 30) days, and that of metabolic etiology was 57 (30, 90) days. The onset age of metabolic etiology was earlier than that of structural etiology ( U =436.500, P =0.044). Conclusions: Genetic etiology is the most common defined etiology of infants with early-onset epilepsy aged 0-6 months, and there are certain differences in the age of onset between different etiologies. Proper application of genetic test is helpful to identify the etiology and guide treatment.

Three new diarylpropanes ( 1 - 3 ), including two diarylpropane glycosides, and three known ones, were isolated from 70% aqueous acetone extract of the twigs and leaves of Horsfieldia kingii . Their structures were elucidated by spectroscopic analysis. Bioactive evaluation of inhibition on DDC enzyme assay showed that the new compounds were inactive.