P. aeruginosa CtpA protease adopts a novel activation mechanism to initiate the proteolytic process.

During bacterial cell growth, hydrolases cleave peptide cross-links between strands of the peptidoglycan sacculus to allow new strand insertion. The Pseudomonas aeruginosa carboxyl-terminal processing protease (CTP) CtpA regulates some of these hydrolases by degrading them. CtpA assembles as an inactive hexamer composed of a trimer-of-dimers, but its lipoprotein binding partner LbcA activates CtpA by an unknown mechanism. Here, we report the cryo-EM structures of the CtpA-LbcA complex. LbcA has an N-terminal adaptor domain that binds to CtpA, and a C-terminal superhelical tetratricopeptide repeat domain. One LbcA molecule attaches to each of the three vertices of a CtpA hexamer. LbcA triggers relocation of the CtpA PDZ domain, remodeling of the substrate binding pocket, and realignment of the catalytic residues. Surprisingly, only one CtpA molecule in a CtpA dimer is activated upon LbcA binding. Also, a long loop from one CtpA dimer inserts into a neighboring dimer to facilitate the proteolytic activity. This work has revealed an activation mechanism for a bacterial CTP that is strikingly different from other CTPs that have been characterized structurally.

Ηigh-resolution structure of mammalian PI31-20S proteasome complex reveals mechanism of proteasome inhibition.

Proteasome-catalyzed protein degradation mediates and regulates critical aspects of many cellular functions and is an important element of proteostasis in health and disease. Proteasome function is determined in part by the types of proteasome holoenzymes formed between the 20S core particle that catalyzes peptide bond hydrolysis and any of multiple regulatory proteins to which it binds. One of these regulators, PI31, was previously identified as an in vitro 20S proteasome inhibitor, but neither the molecular mechanism nor the possible physiologic significance of PI31-mediated proteasome inhibition has been clear. Here we report a high-resolution cryo-EM structure of the mammalian 20S proteasome in complex with PI31. The structure shows that two copies of the intrinsically disordered carboxyl terminus of PI31 are present in the central cavity of the closed-gate conformation of the proteasome and interact with proteasome catalytic sites in a manner that blocks proteolysis of substrates but resists their own degradation. The two inhibitory polypeptide chains appear to originate from PI31 monomers that enter the catalytic chamber from opposite ends of the 20S cylinder. We present evidence that PI31 can inhibit proteasome activity in mammalian cells and may serve regulatory functions for the control of cellular proteostasis.

Lung nodule malignancy classification with associated pulmonary fibrosis using 3D attention-gated convolutional network with CT scans.

BACKGROUND: Chest Computed tomography (CT) scans detect lung nodules and assess pulmonary fibrosis. While pulmonary fibrosis indicates increased lung cancer risk, current clinical practice characterizes nodule risk of malignancy based on nodule size and smoking history; little consideration is given to the fibrotic microenvironment. PURPOSE: To evaluate the effect of incorporating fibrotic microenvironment into classifying malignancy of lung nodules in chest CT images using deep learning techniques. MATERIALS AND METHODS: We developed a visualizable 3D classification model trained with in-house CT dataset for the nodule malignancy classification task. Three slightly-modified datasets were created: (1) nodule alone (microenvironment removed); (2) nodule with surrounding lung microenvironment; and (3) nodule in microenvironment with semantic fibrosis metadata. For each of the models, tenfold cross-validation was performed. Results were evaluated using quantitative measures, such as accuracy, sensitivity, specificity, and area-under-curve (AUC), as well as qualitative assessments, such as attention maps and class activation maps (CAM). RESULTS: The classification model trained with nodule alone achieved 75.61% accuracy, 50.00% sensitivity, 88.46% specificity, and 0.78 AUC; the model trained with nodule and microenvironment achieved 79.03% accuracy, 65.46% sensitivity, 85.86% specificity, and 0.84 AUC. The model trained with additional semantic fibrosis metadata achieved 80.84% accuracy, 74.67% sensitivity, 84.95% specificity, and 0.89 AUC. Our visual evaluation of attention maps and CAM suggested that both the nodules and the microenvironment contributed to the task. CONCLUSION: The nodule malignancy classification performance was found to be improving with microenvironment data. Further improvement was found when incorporating semantic fibrosis information.

Comparison of lung cancer occurring in fibrotic versus non-fibrotic lung on chest CT.

PURPOSE: Evaluate the behavior of lung nodules occurring in areas of pulmonary fibrosis and compare them to pulmonary nodules occurring in the non-fibrotic lung parenchyma. METHODS: This retrospective review of chest CT scans and electronic medical records received expedited IRB approval and a waiver of informed consent. 4500 consecutive patients with a chest CT scan report containing the word fibrosis or a specific type of fibrosis were identified using the system M*Model Catalyst (Maplewood, Minnesota, U.S.). The largest nodule was measured in the longest dimension and re-evaluated, in the same way, on the follow-up exam if multiple time points were available. The nodule doubling time was calculated. If the patient developed cancer, the histologic diagnosis was documented. RESULTS: Six hundred and nine patients were found to have at least one pulmonary nodule on either the first or the second CT scan. 274 of the largest pulmonary nodules were in the fibrotic tissue and 335 were in the non-fibrotic lung parenchyma. Pathology proven cancer was more common in nodules occurring in areas of pulmonary fibrosis compared to nodules occurring in areas of non-fibrotic lung (34% vs 15%, p < 0.01). Adenocarcinoma was the most common cell type in both groups but more frequent in cancers occurring in non-fibrotic tissue. In the non-fibrotic lung, 1 of 126 (0.8%) of nodules measuring 1 to 6 mm were cancer. In contrast, 5 of 49 (10.2%) of nodules in fibrosis measuring 1 to 6 mm represented biopsy-proven cancer (p < 0.01). The doubling time for squamous cell cancer was shorter in the fibrotic lung compared to non-fibrotic lung, however, the difference was not statistically significant (p = 0.24). 15 incident lung nodules on second CT obtained ≤ 18 months after first CT scan was found in fibrotic lung and eight (53%) were diagnosed as cancer. CONCLUSIONS: Nodules occurring in fibrotic lung tissue are more likely to be cancer than nodules in the nonfibrotic lung. Incident pulmonary nodules in pulmonary fibrosis have a high likelihood of being cancer.

Caenorhabditis elegans Flamingo FMI-1 controls dendrite self-avoidance through F-actin assembly.

Self-avoidance is a conserved mechanism that prevents crossover between sister dendrites from the same neuron, ensuring proper functioning of the neuronal circuits. Several adhesion molecules are known to be important for dendrite self-avoidance, but the underlying molecular mechanisms are incompletely defined. Here, we show that FMI-1/Flamingo, an atypical cadherin, is required autonomously for self-avoidance in the multidendritic PVD neuron of Caenorhabditis elegans The fmi-1 mutant shows increased crossover between sister PVD dendrites. Our genetic analysis suggests that FMI-1 promotes transient F-actin assembly at the tips of contacting sister dendrites to facilitate their efficient retraction during self-avoidance events, probably by interacting with WSP-1/N-WASP. Mutations of vang-1, which encodes the planar cell polarity protein Vangl2 previously shown to inhibit F-actin assembly, suppress self-avoidance defects of the fmi-1 mutant. FMI-1 downregulates VANG-1 levels probably through forming protein complexes. Our study identifies molecular links between Flamingo and the F-actin cytoskeleton that facilitate efficient dendrite self-avoidance.

Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans.

BACKGROUND: Hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease, is a rare skin disease presenting with asymptomatic small hyperkeratotic papules. The lesions often appear on the dorsal feet and lower legs, and typically develop after the fourth decade of life. A genetic basis for HLP is suspected; however, so far no gene defect linked to the development of HLP has been identified. OBJECTIVES: We aimed to identify the genetic cause of HLP. METHODS: For mutational analysis we studied a cohort of five patients with HLP using next-generation sequencing (NGS). We used DNA -extracted from fresh skin biopsies alongside ethylenediamine tetraacetic acid (EDTA) blood samples from two patients, and formalin-fixed -paraffin-embedded skin biopsy material from three patients. In addition, immunofluorescence staining of HLP lesions from four patients was investigated. RESULTS: In all samples from the five patients with HLP we identified by NGS rare variants in the SPTLC1 gene. In four patients we detected small deletions/frameshift variants and in one patient a splicing variant, predicted to disturb the splicing process. In blood samples the detected variants were heterozygous with an allele frequency of 49% and 50%, respectively. In skin biopsies the allele frequency was within the range of 46-62%. Immunofluorescence staining revealed reduced SPTLC1 protein levels in skin of patients. CONCLUSIONS: Our findings suggest that pathogenic variants in the SPTLC1 gene are the underlying genetic cause of HLP. Of note, the identified variants were either frameshift- or splicing variants probably leading to nonsense-mediated mRNA decay and thus reduced SPTLC1 protein levels. We conclude that diminished SPTLC1, the key enzyme in sphingolipid biosynthesis, leads to the development of HLP, which highlights the sphingolipid pathway as a new therapeutic target.

Outcomes of surgery and subsequent therapy for central nervous system oligoprogression in EGFR-mutated NSCLC patients.

BACKGROUND: Oligoprogression is an emerging issue in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, the surgical treatment for central nervous system (CNS) oligoprogression is not widely discussed. We investigated the outcomes of craniotomy with adjuvant whole-brain radiotherapy (WBRT) and subsequent therapies for CNS oligoprogression in patients with EGFR-mutated NSCLC. METHODS: NSCLC patients with CNS oligoprogression were identified from a tertiary medical center. The outcomes of surgery with adjuvant WBRT or WBRT alone were analyzed, along with other variables. Overall survival and progression-free survival were analyzed using the log-rank test as the primary and secondary endpoints. A COX regression model was used to identify the possible prognostic factors. RESULTS: Thirty-seven patients with CNS oligoprogression who underwent surgery or WBRT were included in the study after reviewing 728 patients. Twenty-one patients underwent surgery with adjuvant WBRT, and 16 received WBRT alone. The median overall survival for surgery and WBRT alone groups was 43 (95% CI 17-69) and 22 (95% CI 15-29) months, respectively. Female sex was a positive prognostic factor for overall survival (OR 0.19, 95% CI 0.06-0.57). Patients who continued previous tyrosine kinase inhibitors (OR 3.48, 95% CI 1.06-11.4) and induced oligoprogression (OR 3.35, 95% CI 1.18-9.52) were associated with worse overall survival. Smoking history (OR 4.27, 95% CI 1.54-11.8) and induced oligoprogression (OR 5.53, 95% CI 2.1-14.7) were associated with worse progression-free survival. CONCLUSIONS: Surgery combined with adjuvant WBRT is a feasible treatment modality for CNS oligoprogression in patients with EGFR-mutated NSCLC. Changing the systemic-targeted therapy after local treatments may be associated with improved overall survival.

Using multivariate nonlinear mixed-effects model to investigate factors influencing symptom improvement after high tibial osteotomy in combination with bone marrow concentrate injection for medial compartment knee osteoarthritis: a prospective, open-label study.

PURPOSE: To investigate the effects of various demographic, structural, radiographic, and clinical factors on the prognosis of patients with medial compartmental knee osteoarthritis with varus deformity undergoing medial opening wedge high tibial osteotomy (HTO) in combination with bone marrow concentrate (BMC) injection. METHODS: In this prospective study, 20 patients underwent medial opening wedge HTO in combination with BMC injection with 12 months of follow-up. The structural and radiographic outcomes were evaluated by femorotibial angle and posterior tibial slope angle. The clinical outcomes were evaluated by visual analogue scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), and The Knee injury and Osteoarthritis Outcome Score (KOOS). Multivariate nonlinear mixed-effects models with asymptotic regressions were used to model the trajectory of symptom improvement. RESULTS: Medial opening wedge HTO in combination with BMC corrected the malalignment of the knee and led to significant symptom relief. The improvement of clinical symptoms reached a plateau 6 months after the surgery. Greater symptom severity at baseline and lower Kellgren-Lawrance (KL) grades were correlated with better post-operative clinical outcomes. Body-Mass-Index (BMI), femorotibial angle, age, and sex may also play a role in influencing the extent of symptom relief. CONCLUSION: Symptom severity at baseline is important for prognosis prediction. In clinical practice, we suggest that the evaluation of clinical features and functional status of the patients be more emphasised.

Evaluation of the safety, radiographic and resident training results of thoracic pedicle screws placement using resection of the transverse process.

OBJECTIVE: This study aimed at the evaluation and assessment of a simple method, the transverse process resection (TPR) technique, for freehand thoracic pedicle screw placement and the learning curve for trainee surgeons. METHODS: In the TPR technique, the tip of the thoracic transverse process (TP) is removed to create an entry point in the cancellous bone of the TP, and the thoracic pedicle is cannulated from the TP. We retrospectively evaluated the safety and radiographic results of the TPR technique and compared with that of conventional pedicle screws. The training performance of seven neurosurgical residents with TPR techniques were evaluated. RESULTS: Among 46 patients, a total of 322 thoracic screws were analyzed, including 178 screws placed using the TPR technique and 144 screws using the conventional straight-forward (SF) technique. TPR screws had greater medial angulations in all levels from T2 to T12 compared to SF screws (p < 0.001). The incidence of pedicle breach was lower in the TPR screws compared to SF screws (6.2% vs. 21.5%, p < 0.001), especially for screws placed by residents (6.7% vs. 29.6%, p < 0.001). Residents had improved performance following a cadaveric training course on the TPR technique (p = 0.001). CONCLUSION: This study demonstrated the safety of the TPR technique for thoracic pedicle screw placement and its short learning curve for trainee surgeons.

Therapeutic Peptide RF16 Derived from CXCL8 Inhibits MDA-MB-231 Cell Invasion and Metastasis.

Interleukin (IL)-8 plays a vital role in regulating inflammation and breast cancer formation by activating CXCR1/2. We previously designed an antagonist peptide, (RF16), to inhibits the activation of downstream signaling pathways by competing with IL-8 in binding to CXCR1/2, thereby inhibiting IL-8-induced chemoattractant monocyte binding. To evaluate the effect of the RF16 peptide on breast cancer progression, triple-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells were used to investigate whether RF16 can inhibit the IL-8-induced breast cancer metastasis. Using growth, proliferation, and invasiveness assays, the results revealed that RF16 reduced cell proliferation, migration, and invasiveness in MDA-MB-231 cells. The RF16 peptide also regulated the protein and mRNA expressions of epithelial-mesenchymal transition (EMT) markers in IL-8-stimulated MDA-MB-231 cells. It also inhibited downstream IL-8 signaling and the IL-8-induced inflammatory response via the mitogen-activated protein kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) pathways. In the xenograft tumor mouse model, RF16 synergistically reinforces the antitumor efficacy of docetaxel by improving mouse survival and retarding tumor growth. Our results indicate that RF16 significantly inhibited IL-8-stimulated cell growth, migration, and invasion in MDA-MB-231 breast cancer cells by blocking the activation of p38 and AKT cascades. It indicated that the RF16 peptide may serve as a new supplementary drug for breast cancer.

The mycobacterial proteasomal ATPase Mpa forms a gapped ring to engage the 20S proteasome.

Although many bacterial species do not possess proteasome systems, the actinobacteria, including the human pathogen Mycobacterium tuberculosis, use proteasome systems for targeted protein removal. Previous structural analyses of the mycobacterial proteasome ATPase Mpa revealed a general structural conservation with the archaeal proteasome-activating nucleotidase and eukaryotic proteasomal Rpt1-6 ATPases, such as the N-terminal coiled-coil domain, oligosaccharide-/oligonucleotide-binding domain, and ATPase domain. However, Mpa has a unique ß-grasp domain that in the ADP-bound crystal structure appears to interfere with the docking to the 20S proteasome core particle (CP). Thus, it is unclear how Mpa binds to proteasome CPs. In this report, we show by cryo-EM that the Mpa hexamer in the presence of a degradation substrate and ATP forms a gapped ring, with two of its six ATPase domains being highly flexible. We found that the linkers between the oligonucleotide-binding and ATPase domains undergo conformational changes that are important for function, revealing a previously unappreciated role of the linker region in ATP hydrolysis-driven protein unfolding. We propose that this gapped ring configuration is an intermediate state that helps rearrange its ß-grasp domains and activating C termini to facilitate engagement with proteasome CPs. This work provides new insights into the crucial process of how an ATPase interacts with a bacterial proteasome protease.

Quantum fidelity of electromagnetically induced transparency: the full quantum theory.

We present a full quantum model to study the fidelity of single photons with different quantum states propagating in a medium exhibiting electromagnetically induced transparency (EIT). By using the general reservoir theory, we can calculate the quantum state of the transmitted probe photons that reveal the EIT phenomenon predicted by semiclassical theory while reflecting the influence of the quantum fluctuations of the strong coupling field. Our study shows that the coupling field fluctuations not only change the quantum state of the probe photons, but also slightly affect its transmittance. Moreover, we demonstrate that the squeezed coupling field can enhance the influence of its fluctuations on the quantum state of the probe photons, which means that the EIT effect can be manipulated by controlling the quantum state properties of the coupling field. The full quantum theory in this paper is suitable for studying quantum systems related to the EIT mechanism that would allow us to examine various quantum effects in EIT-based systems from a full quantum perspective.

Effects of electron transport layer thickness on light extraction in corrugated OLEDs.

This study reported the effects of electron transport layer (ETL) thickness on light extraction in corrugated organic light-emitting diodes (OLEDs) and each layer in OLEDs exhibited a periodical corrugated structure, which was determined by depositing thin films on a glass substrate with a nanoimprinted blazed grating structure. The insight is that light extraction in corrugated OLEDs significantly depends on the ETL thickness. Varying the ETL thickness changed the distribution of carrier recombination and led to exciton formation and optical interference, thereby resulting in different attribution of optical loss modes in OLEDs, which increased or even decreased light extraction and device efficiency. Trapped light extraction from the surface plasmon polariton (SPP) and waveguide (WG) modes was identified by splitting the light into transverse electric and transverse magnetic emissions. Thus, the contributions from the individual SPP and WG modes to the external quantum efficiency (EQE) were distinctly clarified by comparing the experimental results with the theoretical calculations. At the ETL thickness of 115 nm, the corrugated OLED exhibited a significantly enhanced (1.83-fold) EQE compared to the planar one due to the effective extraction of trapped light from the SPP and WG modes. The EQE was enhanced by 0.5%, wherein 0.39% came from the WG mode and 0.11% came from the SPP mode.

State-of-the-Art Capability of Convolutional Neural Networks to Distinguish the Signal in the Ionosphere.

Recovering and distinguishing different ionospheric layers and signals usually requires slow and complicated procedures. In this work, we construct and train five convolutional neural network (CNN) models: DeepLab, fully convolutional DenseNet24 (FC-DenseNet24), deep watershed transform (DWT), Mask R-CNN, and spatial attention-UNet (SA-UNet) for the recovery of ionograms. The performance of the models is evaluated by intersection over union (IoU). We collect and manually label 6131 ionograms, which are acquired from a low-latitude ionosonde in Taiwan. These ionograms are contaminated by strong quasi-static noise, with an average signal-to-noise ratio (SNR) equal to 1.4. Applying the five models to these noisy ionograms, we show that the models can recover useful signals with IoU > 0.6. The highest accuracy is achieved by SA-UNet. For signals with less than 15% of samples in the data set, they can be recovered by Mask R-CNN to some degree (IoU > 0.2). In addition to the number of samples, we identify and examine the effects of three factors: (1) SNR, (2) shape of signal, (3) overlapping of signals on the recovery accuracy of different models. Our results indicate that FC-DenseNet24, DWT, Mask R-CNN and SA-UNet are capable of identifying signals from very noisy ionograms (SNR < 1.4), overlapping signals can be well identified by DWT, Mask R-CNN and SA-UNet, and that more elongated signals are better identified by all models.

Constructing a Carbon-Encapsulated Carbon Composite Material with Hierarchically Porous Architectures for Efficient Capacitive Storage in Organic Supercapacitors.

Hierarchical porous activated carbon (HPAC) materials with fascinating porous features are favored for their function as active materials for supercapacitors. However, achieving high mass-loading of the HPAC electrodes remains challenging. Inspired by the concepts of carbon/carbon (C/C) composites and hydrogels, a novel hydrogel-derived HPAC (H-HPAC) encapsulated H-HPAC (H@H) composite material was successfully synthesized in this study. In comparison with the original H-HPAC, it is noticed that the specific surface area and pore parameters of the resulting H@H are observably decreased, while the proportions of nitrogen species are dramatically enhanced. The free-standing and flexible H@H electrodes with a mass-loading of 7.5 mg/cm2 are further prepared for electrochemical measurements. The experiments revealed remarkable reversible capacitance (118.6 F/g at 1 mA/cm2), rate capability (73.9 F/g at 10 mA/cm2), and cycling stability (76.6% of retention after 30,000 cycles at 5 mA) are delivered by the coin-type symmetric cells. The cycling stability is even better than that of the H-HPAC electrode. Consequently, the findings of the present study suggest that the nature of the HPAC surface is a significant factor affecting the corresponding capacitive performances.

The Citrus Flavonoid Nobiletin Downregulates Angiopoietin-like Protein 3 (ANGPTL3) Expression and Exhibits Lipid-Modulating Effects in Hepatic Cells and Adult Zebrafish Models.

Nobiletin, a dietary citrus flavonoid, exerts biological activities against hyperlipidemia, obesity, and atherosclerotic cardiovascular diseases (ASCVDs). The aim of this study was to explore the lipid-lowering effects of nobiletin and the underlying molecular mechanisms in vitro in hepatic cells and in vivo in zebrafish models. Transcriptome and gene ontology (GO) analyses of differentially expressed genes (DEGs) by gene set enrichment analysis (GSEA) showed that a set of twenty-eight core enrichment DEGs associated with "GO BP regulation of lipid metabolic process" (GO: 0019216) were significantly downregulated in nobiletin-treated cells. Among these genes, angiopoietin-like 3 (ANGPTL3), an inhibitor of lipoprotein lipase (LPL) activity that regulates TG-rich lipoprotein (TGRL) metabolism in circulation, was the protein most markedly downregulated by nobiletin. Nobiletin (20 and 40 µM) significantly reduced the levels of ANGPTL3 mRNA and intracellular and secreted ANGPTL3 proteins in hepatic cell lines. Furthermore, alleviation of secreted ANGPTL3 production by nobiletin was found to reinstate LPL catalytic activity. Nobiletin significantly inhibited ANGPTL3 promoter activity and attenuated the transcription factor liver X receptor-α (LXRα)-mediated ANGPTL3 transcription. Molecular docking analysis predicted that nobiletin could bind to the ligand-binding domain of LXRα, thereby counteracting LXRα activation. In animal studies, orally administered nobiletin significantly alleviated the levels of plasma triglycerides (TGs) and cholesterol in zebrafish fed a high-fat diet. Moreover, nobiletin significantly reduced the amounts of hepatic ANGPTL3 protein in zebrafish. Our findings suggest that nobiletin may regulate the LXRα-ANGPTL3-LPL axis and exhibit lipid-modulating effects in vitro and in vivo. Thus, nobiletin is a potential ANGPTL3 inhibitor for the regulation of lipid metabolism to ameliorate dyslipidemia and ASCVDs.

Transcriptomic Analysis Suggests Auxin Regulation in Dorsal-Ventral Petal Asymmetry of Wild Progenitor Sinningia speciosa.

The establishment of dorsal-ventral (DV) petal asymmetry is accompanied by differential growth of DV petal size, shape, and color differences, which enhance ornamental values. Genes involved in flower symmetry in Sinningia speciosa have been identified as CYCLOIDEA (SsCYC), but which gene regulatory network (GRN) is associated with SsCYC to establish DV petal asymmetry is still unknown. To uncover the GRN of DV petal asymmetry, we identified 630 DV differentially expressed genes (DV-DEGs) from the RNA-Seq of dorsal and ventral petals in the wild progenitor, S. speciosa 'ES'. Validated by qRT-PCR, genes in the auxin signaling transduction pathway, SsCYC, and a major regulator of anthocyanin biosynthesis were upregulated in dorsal petals. These genes correlated with a higher endogenous auxin level in dorsal petals, with longer tube length growth through cell expansion and a purple dorsal color. Over-expression of SsCYC in Nicotiana reduced petal size by regulating cell growth, suggesting that SsCYC also controls cell expansion. This suggests that auxin and SsCYC both regulate DV petal asymmetry. Transiently over-expressed SsCYC, however, could not activate most major auxin signaling genes, suggesting that SsCYC may not trigger auxin regulation. Whether auxin can activate SsCYC or whether they act independently to regulate DV petal asymmetry remains to be explored in the future.

Response Surface Methodology Optimization in High-Performance Solid-State Supercapattery Cells Using NiCo2S4-Graphene Hybrids.

In this work, NiCo2S4-graphene hybrids (NCS@G) with high electrochemical performance were prepared using a hydrothermal method. The response surface methodology (RSM), along with a central composite design (CCD), was used to investigate the effect of independent variables (G/NCS, hydrothermal time, and S/Ni) on the specific capacitances of the NCS@G/Ni composite electrodes. RSM analysis revealed that the developed quadratic model with regression coefficient values of more than 0.95 could be well adapted to represent experimental results. Optimized preparation conditions for NCS@G were G/NCS = 6.0%, hydrothermal time = 10.0, and S/Ni = 6.0 of NCS@G (111) sample. The maximum specific capacitance of NCS@G (111)/Ni fabricated at the optimal condition is about 216% higher than the best result obtained using the conventional experimental method. The enhanced capacitive performance of the NCS@G (111) sample can be attributed to the synergistic effect between NCS nanoparticles and graphene, which has the meso/macropores conductive network and low diffusion resistance. Notably, the NCS@G (111) could not only provide numerous reaction sites but also prevent the restacking of graphene layers. Furthermore, a supercapattery cell was fabricated with an (G + AC)/Ni anode, a NCS@G (111)/Ni cathode, and a carboxymethyl cellulose-potassium hydroxide (CMC-KOH) gel electrolyte. The NCS@G (111)//(G + AC) demonstrates an outstanding energy density of 80 Wh kg-1 at a power density of 4 kW kg-1, and a good cycling performance of 75% after 5000 cycles at 2 A g-1. Applying the synthesis strategy of RSM endows remarkable capacitive performance of the hybrid materials, providing an economical pathway to design promising composite electrode material and fabricate high-performance energy storage devices.

Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis.

Peritoneal fibrosis remains a problem in kidney failure patients treated with peritoneal dialysis. Severe peritoneal fibrosis with encapsulation or encapsulating peritoneal sclerosis is devastating and life-threatening. Although submesothelial fibroblasts as the major precursor of scar-producing myofibroblasts in animal models and M2 macrophage (Mϕ)-derived chemokines in peritoneal effluents of patients before diagnosis of encapsulating peritoneal sclerosis have been identified, attenuation of peritoneal fibrosis is an unmet medical need partly because the mechanism for cross talk between Mϕs and fibroblasts remains unclear. We use a sodium hypochlorite-induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal Mϕs activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11bhigh F4/80high resident Mϕs but accumulation of CD11bint F4/80int inflammatory Mϕs (InfMϕs) through recruiting blood monocytes and activating local cell proliferation. InfMϕs switch to express chemokine (C-C motif) ligand 17 (CCL17), CCL22, and arginase-1 from day 2 after hypochlorite injury. More than 75% of InfMϕs undergo genetic recombination by Csf1r-driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin-induced Mϕ ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce Mϕs, myofibroblasts, fibrosis, and improve peritoneal function after injury. Mechanistically, CCL17 stimulates migration and collagen production of submesothelial fibroblasts in culture. By breeding mice that are induced to express red fluorescent protein in Mϕs and green fluorescence protein (GFP) in Col1a1-expressing cells, we confirmed that Mϕs do not produce collagen in peritoneum before and after injury. However, small numbers of fibrocytes are found in fibrotic peritoneum of chimeric mice with bone marrow from Col1a1-GFP reporter mice, but they do not contribute to myofibroblasts. These data demonstrate that InfMϕs switch to pro-fibrotic phenotype and activate peritoneal fibroblasts through CCL17 after injury. CCL17 blockade in patients with peritoneal fibrosis may provide a novel therapy. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Computer-Aided Three-Dimensional Virtual Surgical Planning in Complex Skull Base Reconstruction for Sphenoid Wing Dysplasia in Neurofibromatosis Type 1.

ABSTRACT: Unilateral sphenoid dysplasia is a rare but distinctive manifestation of neurofibromatosis type 1, causing pulsatile exophthalmos, decreased vision, and facial deformity. Surgical intervention is required to prevent visual deterioration. However, the reconstruction of a complex cranial base defect while fulfilling cosmetic needs is challenging. The asymmetric anatomy impedes identification and preservation of vital structures, and the use of bone grafts is often unsustainable due to resorption. Here we demonstrate a multimodal technique combining mirror-image-based virtual surgical planning, stereolithography, and neuronavigation to achieve skull base reconstruction and restore facial symmetry in an neurofibromatosis type 1 patient with sphenoid dysplasia. Preoperative surgical planning involved mirror-image simulation based on the unaffected contralateral counterpart and a stereolithographic skull-base model fabricated to design a patient-specific titanium mesh. Surgical reconstruction via the transcranial approach under intraoperative neuronavigation was performed. Immediate resolution of pulsatile proptosis was observed postoperatively. With the help of virtual surgical planning, stereolithography, and neuronavigation, precise and sustainable reconstruction with patient-specific implants can be tailored for a complex skull base defect.