CT-based radiomics for predicting success of shock wave lithotripsy in ureteral stones larger than 1 cm.

PURPOSE: This study aims to investigate the predictive value of CT-based radiomics in determining the success of extracorporeal shock wave lithotripsy (SWL) treatment for ureteral stones larger than 10mm in adult patients. MATERIALS AND METHODS: A total of 301 eligible patients (165/136 successful/unsuccessful) who underwent SWL were retrospectively evaluated and divided into a training cohort (n = 241) and a test cohort (n = 60) following an 8:2 ratio. Univariate analysis was performed to assess clinical characteristics for constructing a nomogram. Radiomics and conventional radiological characteristics of stones were evaluated. Following feature selection, radiomics and radiological models were constructed using logistic regression (LR), support vector machine (SVM), random forest (RF), K nearest neighbor (KNN), and XGBoost. The models' performance was compared using metrics such as the area under the receiver operating characteristic curve (AUC), precision, recall, accuracy, and F1 score. Finally, a nomogram was created incorporating the best image model signature and clinical predictors. RESULTS: The SVM-based radiomics model showed superior predictive performance in both training and test cohorts (AUC: 0.956, 0.891, respectively). The nomogram, which combined SVM-based radiomics signature with proximal ureter diameter (PUD), demonstrated further improved predictive performance in the test cohort (AUC: 0.891 vs. 0.939, P = 0.166). CONCLUSIONS: Integration of CT-derived radiomics and PUD showed excellent ability to predict SWL treatment success in patients with ureteral stones larger than 10mm, providing a promising approach for clinical decision-making.

Socio-ecological model as a framework to understand the low participation of Earth Hour among Chinese college students: conflict between belief and practice.

Earth Hour, a global mass effort coordinated to show concern for green urban construction and sustainable development, was first organized by the World Wildlife Fund in Australia in 2007 with a growing trend of participation worldwide. However, analysis of participation in Earth Hour based on a large population are sparse, with only a few studies reporting details in positive results without a clear pattern that explains the potential low participation. This study focuses on the non-participants and analyzed the reasons for low participation in Earth Hour using a questionnaire with 401 college students based on the socio-ecological model. Two aspects are explored: (1) social-demographic features; (2) psychosocial traits (environmental awareness, acceptance for law, social support from family and friends and knowledge about the event). Barriers toward participation are included as mediators to explain how these basic features change students' decision on joining large-scale environmental campaign. A participation analysis method using binary logistic regression and one-way MANOVA is applied in data analysis. This study highlights that the irrelevance between students' belief and practice on environmental protection should not be overlooked, and that college students are inclined to join in groups in relevant activities-conversely, herd effect could greatly reduce their willingness to participation. The findings of this study have wider implications for school educators, practitioners and organizations involved in pro-environmental career. This paper highlights that, from an international perspective, the essence of collective action with a similar nature to Earth Hour and contributes to a global dialogue on fostering sustainable behaviors.

Antibodies expand the scope of angiotensin receptor pharmacology.

G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue and cellular levels. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays and structural studies, we develop maternally selective heavy-chain-only antibody ('nanobody') antagonists against the angiotensin II type I receptor and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to angiotensin II type I receptor with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.

SCO-spondin knockout mice exhibit small brain ventricles and mild spine deformation.

Reissner's fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo, an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.

Threshold effect of technological innovation on carbon emission intensity based on multi-source heterogeneous data.

It is of much importance to clarify the impact of technological innovation on carbon emission intensity for the low-carbon transformation of China's economy. This study, based on the panel data of 30 Chinese provinces and municipalities from 2010 to 2020, measures and analyzes the carbon emission intensity and the level of technological innovation, establishing a spatial econometric model to study the spatial spillover effect and a panel threshold model to analyze the nonlinear influence of technological innovation level on carbon emission intensity. The findings are as follows: First, the overall carbon emission intensity in China shows a decreasing trend from 2010 to 2020, with the average dropping from 3.09 in 2010 to 1.98 in 2020; Second, the spatial autocorrelation results reveal that the level of technological innovation and carbon emission intensity in China are obviously aggregated in the global spatial distribution pattern. Third, the regression results of the spatial econometric model show that the direct effect of technological innovation on carbon emission intensity is significantly negative at the level of 1%, that is, the improvement of the technological innovation in a certain area has a significant inhibitory effect on carbon emission intensity. Fourth, based on the level of economic development, there is a significant three-threshold effect of the level of technological innovation on carbon emission intensity in China, and the influence of the level of technological innovation on carbon emission intensity varies in the direction of existence and coefficient values within different threshold intervals. As economic development reaches the third interval, the technological innovation level has the most significant inhibition on carbon emission intensity. These findings enriches the research of the nonlinear relationship between technological innovation and carbon emission intensity, clarifies the spatial spillover effect and threshold effect between among them, and provides inspiration for better promote the low-carbon transformation of economy.

Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.

G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue, and cellular level. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays, and structural studies, we develop maternally selective heavy chain-only antibody ("nanobody") antagonists against the angiotensin II type I receptor (AT1R) and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to AT1R with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.

A collaboration between immune cells and the choroid plexus epithelium in brain inflammation.

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use chronic two-photon imaging in awake mice and single-cell transcriptomics to demonstrate that in addition to these roles, the ChP is a complex immune organ that regulates brain inflammation. In a mouse meningitis model, neutrophils and monocytes accumulated in ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process, including the discovery of epithelial cells that transiently specialized to nurture immune cells, coordinate their recruitment, survival, and differentiation, and ultimately, control the opening/closing of the ChP brain barrier. Collectively, we provide a new conceptual understanding and comprehensive roadmap of neuroinflammation at the ChP brain barrier.

SCO-spondin knockout mice exhibit small brain ventricles and mild spine deformation.

Reissner's fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo , an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.

Age-appropriate potassium clearance from perinatal cerebrospinal fluid depends on choroid plexus NKCC1.

Regulation of the volume and electrolyte composition of the cerebrospinal fluid (CSF) is vital for brain development and function. The Na-K-Cl co-transporter NKCC1 in the choroid plexus (ChP) plays key roles in regulating CSF volume by co-transporting ions and mediating same-direction water movements. Our previous study showed ChP NKCC1 is highly phosphorylated in neonatal mice as the CSF K+ level drastically decreases and that overexpression of NKCC1 in the ChP accelerates CSF K+ clearance and reduces ventricle size [1]. These data suggest that NKCC1 mediates CSF K+ clearance following birth in mice. In this current study, we used CRISPR technology to create a conditional NKCC1 knockout mouse line and evaluated CSF K+ by Inductively Coupled Plasma Optical Emission spectroscopy (ICP-OES). We demonstrated ChP-specific reduction of total and phosphorylated NKCC1 in neonatal mice following embryonic intraventricular delivery of Cre recombinase using AAV2/5. ChP-NKCC1 knockdown was accompanied by a delayed perinatal clearance of CSF K+. No gross morphological disruptions were observed in the cerebral cortex. We extended our previous results by showing embryonic and perinatal rats shared key characteristics with mice, including decreased ChP NKCC1 expression level, increased ChP NKCC1 phosphorylation state, and increased CSF K+ levels compared to adult. Collectively, these follow up data support ChP NKCC1's role in age-appropriate CSF K+ clearance during neonatal development.

Design, synthesis and anti-tumor evaluation of plinabulin derivatives as potential agents targeting ß-tubulin.

Plinabulin is a promising microtubule destabilizing agent in phase 3 clinical stage for treating non-small cell lung cancer. However, the high toxicity and the poor water solubility of plinabulin limited its use and more plinabulin derivatives need to be explored. Here, two series of 29 plinabulin derivatives were designed, synthesized and evaluated for their anti-tumor effect against three types of cancer cell lines. Most of derivatives exerted obvious inhibition to the proliferation of the cell lines tested. Among them, compound 11c exerted stronger efficiency than plinabulin, and the reason might be the additional hydrogen bond between the nitrogen atom of the indole ring in compound 11c and Gln134 of ß-tubulin. Immunofluorescence assay showed that compound 11c at 10 nM significantly disrupted tubulin structure. Compound 11c also significantly induced G2/M cell cycle arrest and apoptosis in dose dependent manner. These results suggest that compound 11c might be a potential candidate for cancer treatment as antimicrotubule agent.

Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution.

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake TtrmNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.

Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus.

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

Bombyx mori Flap endonuclease 1 correlates with the repair of ultraviolet-induced DNA damage.

Solar ultraviolet radiation (UV) can cause DNA damage in microorganisms. Flap endonuclease 1 (FEN1) is a structure-specific nuclease and plays important roles in DNA replication and repair. At present, the properties and functions of FEN1 have not been characterized in detail in invertebrates such as Bombyx mori. In this study, Bombyx mori FEN1 (BmFEN1) was expressed in E. coli, and was shown to have nuclease activity that nonspecifically cleaved DNA in vitro. However, inside the cell, BmFEN1 did not cleave DNA randomly. Truncated BmFEN1 missing the nuclear localization signal (346-380 aa) still had the nuclease activity, but was no longer precisely localized to the sites of UV-induced DNA damage. It was further found that BmFEN1 favored the faster repair of UV-damaged DNA. The present study will provide a reference for further understanding the functions of BmFEN1 and UV-induced DNA damage repair mechanisms in insects.

Bioconversion of Methanol by Synthetic Methylotrophy.

As an important building block in the chemical industry, methanol has become an attractive substrate in biorefinery owing to its abundance and low cost. With the development of synthetic biology, metabolic engineering of non-methylotrophy to construct synthetic methylotrophy has drawn increased attention. As for the metabolic construction of methanol assimilation pathway in some industrial hosts, several artificial methanol assimilation pathways have recently been designed and constructed based on the computer-aided design. Particularly, these artificial methanol assimilation pathways possess advantages of shorter reaction steps, stronger driving forces, and independence on oxygen. Accordingly, this chapter reviewed strategies of constructing synthetic methylotrophs, including introducing methanol metabolic modules derived from natural methylotrophs and designing artificial methanol assimilation pathways. Future challenges and prospects were also discussed.

A newly-recorded species of the genus Rhodotritoma Arrow, 1925 (Coleoptera, Erotylidae) from China.

Background: The genus Rhodotritoma Arrow, 1925 (Coleoptera, Erotylidae, Erotylinae, Tritomini) includes 12 known species worldwide, including three species distributed in China. In the last four decades, no work was conducted on Rhodotritoma in China. In this paper, we review the taxonomy of this genus for Chinese fauna and redescribe a newly-recorded species in China. New information: Rhodotritomamanipurica Arrow, 1925 is recorded from China for the first time. The morphological characters of the adult are redescribed in detail and illustrated. A key to species of the genus Rhodotritoma Arrow, 1925 in China is provided. Chinese specimens were collected from Tibet Autonomous Region and Yunnan Province, which were then deposited in the Museum of Hebei University. The holotype examined is kept in the Natural History Museum.

A Meta-Analysis of the Efficacy of Albumin Paclitaxel versus Docetaxel in the Treatment of Breast Cancer.

Objective: To use meta-analysis to systematically compare the efficacy and adverse reaction rates of albumin paclitaxel and docetaxel in the treatment of breast cancer. Methods: This study included Chinese and English literature studies on clinical controlled studies of albumin paclitaxel and docetaxel in the treatment of breast cancer by searching CNKI, Weipu, Wanfang, PubMed, Embase, and Cochrane Library. Two researchers participated in the screening of the literature, used the inclusion and exclusion criteria as reference indicators, extracted relevant data, and used the software RevMan5.3 to conduct quality evaluation and meta-analysis of the literature. Results: 4 literature stuides were retrieved that met the inclusion criteria, with 243 study subjects. The included literature had a lower risk of bias. Meta-analysis results showed that compared with the docetaxel group, the protein paclitaxel group had significant differences in objective effective rate (ORR) (OR = 1.56, 95% CI (0.80, 3.03), P=0.19), complete remission (CR) (OR = 1.79, 95% CI (0.96, 3.35), P=0.07), partial remission (PR) (OR = 0.88, 95% CI (0.53, 1.47), P=0.62), nausea (OR = 0.87, 95% CI (0.51, 1.74), P=0.84), and vomiting (OR = 0.62, 95% CI (0.45, 1.78) P=0.76). The reason may be that the number of literatures included in this study is small or the sample size is insufficient. However, it had an advantage in the incidence of neutropenia (OR = 0.38, 95% CI (0.16, 0.88), P=0.02), and the difference between the two groups was statistically significant. Conclusion: Albumin paclitaxel treatment can better reduce the incidence of neutropenia in breast cancer patients and is of great significance to the safety of breast cancer patients.

Macrophages on the margin: choroid plexus immune responses.

The choroid plexus (ChP), an epithelial bilayer containing a network of mesenchymal, immune, and neuronal cells, forms the blood-cerebrospinal fluid (CSF) barrier (BCSFB). While best recognized for secreting CSF, the ChP is also a hotbed of immune cell activity and can provide circulating peripheral immune cells with passage into the central nervous system (CNS). Here, we review recent studies on ChP immune cells, with a focus on the ontogeny, development, and behaviors of ChP macrophages, the principal resident immune cells of the ChP. We highlight the implications of immune cells for ChP barrier function, CSF cytokines and volume regulation, and their contribution to neurodevelopmental disorders, with possible age-specific features to be elucidated in the future.

Deep sequencing of 1320 genes reveals the landscape of protein-truncating variants and their contribution to psoriasis in 19,973 Chinese individuals.

Protein-truncating variants (PTVs) have important impacts on phenotype diversity and disease. However, their population genetics characteristics in more globally diverse populations are not well defined. Here, we describe patterns of PTVs in 1320 genes sequenced in 10,539 healthy controls and 9434 patients with psoriasis, all of Han Chinese ancestry. We identify 8720 PTVs, of which 77% are novel, and estimate 88% of all PTVs are deleterious and subject to purifying selection. Furthermore, we show that individuals with psoriasis have a significantly higher burden of PTVs compared to controls (P = 0.02). Finally, we identified 18 PTVs in 14 genes with unusually high levels of population differentiation, consistent with the action of local adaptation. Our study provides insights into patterns and consequences of PTVs.

Structures and absolute configurations of phomalones from the coral-associated fungus Parengyodontium album sp. SCSIO 40430.

Coral-associated microorganisms are likely to play an important role in host defense by the production of antimicrobials. Six new chromanones, namely, phomalichenones H-M (5, 6, and 8-11), and ten known analogues (1-4, 7, and 12-16) were isolated from the coral-associated fungus Parengyodontium album sp. SCSIO 40430. Their structures were elucidated by comprehensive spectroscopic analyses. In addition, the structure of 8 was confirmed by X-ray crystallographic analysis. Resolution using a chiral column showed that each of the compounds 1-8 was an enantiomeric mixture with variable enantiomeric excess (ee) values. Their absolute configurations were determined by a comparison of the experimental and calculated ECD data and by a modified Mosher's method. A plausible biosynthetic scheme was proposed for the production of 1-16. Compounds 2, 3, 13, and 14 were found to be active against Mycobacterium tuberculosis H37Ra with MIC values of 16-64 µg mL-1.