Fate mapping of Spp1 expression reveals age-dependent plasticity of disease-associated microglia-like cells after brain injury.

Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1（Spp1） to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1+ microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions.

PGE2 -EP3 axis promotes brown adipose tissue formation through stabilization of WTAP RNA methyltransferase.

Brown adipose tissue (BAT) functions as a thermogenic organ and is negatively associated with cardiometabolic diseases. N6 -methyladenosine (m6 A) modulation regulates the fate of stem cells. Here, we show that the prostaglandin E2 (PGE2 )-E-prostanoid receptor 3 (EP3) axis was activated during mouse interscapular BAT development. Disruption of EP3 impaired the browning process during adipocyte differentiation from pre-adipocytes. Brown adipocyte-specific depletion of EP3 compromised interscapular BAT formation and aggravated high-fat diet-induced obesity and insulin resistance in vivo. Mechanistically, activation of EP3 stabilized the Zfp410 mRNA via WTAP-mediated m6 A modification, while knockdown of Zfp410 abolished the EP3-induced enhancement of brown adipogenesis. EP3 prevented ubiquitin-mediated degradation of WTAP by eliminating PKA-mediated ERK1/2 inhibition during brown adipocyte differentiation. Ablation of WTAP in brown adipocytes abrogated the protective effect of EP3 overexpression in high-fat diet-fed mice. Inhibition of EP3 also retarded human embryonic stem cell differentiation into mature brown adipocytes by reducing the WTAP levels. Thus, a conserved PGE2 -EP3 axis promotes BAT development by stabilizing WTAP/Zfp410 signaling in a PKA/ERK1/2-dependent manner.

Cancer-associated fibroblast-associated gene IGFBP2 promotes glioma progression through induction of M2 macrophage polarization.

We elucidated the molecular mechanism of cancer-associated fibroblast (CAF)-associated gene insulin-like growth factor binding protein-2 (IGFBP2)-induced M2 macrophage polarization in the tumor microenvironment involved in glioma progression. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) provided bulk RNA-sequencing datasets, ESTIMATE scores for glioma stromal cells, and overall survival-clinicopathological correlation analyses. TIMER provided CAF abundance in the TCGA glioma-related dataset, differential gene analysis was performed for high- and low-CAF groups, and weighted gene coexpression network analysis identified CAF-related genes. Univariate and multifactorial cyclooxygenase (COX) regression analyses created the CAF risk models single sample gene set enrichment analysis, CIBERSORT, and GSE84465. Mice were implanted with gliomas, and Western blot and RT-quantitative PCR showed IGFBP2 in tumor tissues. Adeno-associated virus (AAV) decreased IGFBP2, flow cytometry measured M1 and M2 macrophage ratios, and immunohistochemistry detected markers. TCGA and CGGA transcriptome data showed malignant gliomas had higher stromal cell scores and worse prognoses. Low- and high-CAF TCGA gliomas were detected, and differential expression, WGCNA, and multifactorial COX identified 132 CAF-related genes and seven high-risk genes (CPQ, EFEMP2, IGFBP2, RAB42, TNFRSF12A, and VASN). Neither CAF risk score, grade, nor 1p/19q affected glioma prognosis. CAF only enriched EFEMP2 and IGFBP2. Gene Expression Profiling Interactive Analysis compared EFEMP2 and IGFBP2 expression in normal brain tissue and gliomas. Low-grade glioma and malignant glioblastoma highly expressed IGFBP2 and EFEMP2. GSEA raised IGFBP2. CIBERSORT linked M2 macrophage infiltration to TCGA glioma immune cell subpopulation IGFBP2 expression. IGFBP2 knockdown stopped mouse glioma and M2 macrophage polarization. CAF plays a procarcinogenic role in glioma, and the CAF-related gene IGFBP2 could promote glioma progression by inducing M2 macrophage polarization.NEW & NOTEWORTHY The cancer-associated fibroblast (CAF)-related gene insulin-like growth factor binding protein-2 (IGFBP2) is highly expressed in gliomas and is associated with poor prognosis. CAF-related gene IGFBP2 promotes glioma progression by inducing polarization of M2 macrophages. This study provides a new basis for an in-depth investigation of the functional mechanisms of the glioma tumor microenvironment and the search for key genes involved in immune regulation in CAF.

Development of a Decafluorobiphenyl Cyclized Peptide Targeting the NEMO-IKKα/ß Interaction that Enhances Cell Penetration and Attenuates Lipopolysaccharide-Induced Acute Lung Injury.

Aberrant canonical NF-κB signaling has been implicated in diseases, such as autoimmune disorders and cancer. Direct disruption of the interaction of NEMO and IKKα/ß has been developed as a novel way to inhibit the overactivation of NF-κB. Peptides are a potential solution for disrupting protein-protein interactions (PPIs); however, they typically suffer from poor stability in vivo and limited tissue penetration permeability, hampering their widespread use as new chemical biology tools and potential therapeutics. In this work, decafluorobiphenyl-cysteine SNAr chemistry, molecular modeling, and biological validation allowed the development of peptide PPI inhibitors. The resulting cyclic peptide specifically inhibited canonical NF-κB signaling in vitro and in vivo, and presented positive metabolic stability, anti-inflammatory effects, and low cytotoxicity. Importantly, our results also revealed that cyclic peptides had huge potential in acute lung injury (ALI) treatment, and confirmed the role of the decafluorobiphenyl-based cyclization strategy in enhancing the biological activity of peptide NEMO-IKKα/ß inhibitors. Moreover, it provided a promising method for the development of peptide-PPI inhibitors.

Ultrahigh extinction ratio and a low power silicon thermo-optic switch.

The silicon thermo-optic switch (TOS) is one of the most fundamental and crucial blocks in large-scale silicon photonic integrated circuits (PICs). An energy-efficient silicon TOS with ultrahigh extinction ratio can effectively mitigate cross talk and reduce power consumption in optical systems. In this Letter, we demonstrate a silicon TOS based on cascading Mach-Zehnder interferometers (MZIs) with spiral thermo-optic phase shifters. The experimental results show that an ultrahigh extinction ratio of 58.8 dB is obtained, and the switching power consumption is as low as 2.32 mW/π without silicon air trench. The rise time and fall time of the silicon TOS are about 10.8 and 11.2 µs, respectively. Particularly, the figure of merit (FOM) has been improved compared with previously reported silicon TOS. The proposed silicon TOS may find potential applications in optical switch arrays, on-chip optical delay lines, etc.

Assessment of right ventricular diastolic function in pediatric patients with repaired tetralogy of Fallot by cardiovascular magnetic resonance and echocardiography.

OBJECTIVES: Cardiovascular magnetic resonance (CMR) imaging is routinely performed for assessing right ventricular (RV) systolic but not diastolic function. We aimed to investigate CMR-based assessment of RV diastolic function in pediatric patients with repaired tetralogy of Fallot (rTOF), compared to transthoracic echocardiography (TTE) measurements. METHODS: A total of 130 consecutive pediatric patients with rTOF who underwent clinically indicated CMR and same-day TTE were included. Forty-three controls were recruited. Phase-contrast images were used to measure trans-tricuspid valve flow velocities during early (E) and late diastolic (A) phases (measured in cm/s). Feature tracking of the tricuspid annulus was performed to derive early (e') and late diastolic (a') myocardial velocities (measured in cm/s). RV diastolic function was evaluated by E/A ratio, E/e' ratio, and E-wave deceleration time (measured in milliseconds). Regression analyses were utilized to identify potential variables associated with RV diastolic dysfunction (DD). The performance of CMR-derived parameters in diagnosing RV DD was assessed using receiver-operating characteristic analyses. RESULTS: Good agreement was found between CMR and TTE measurements (ICC 0.70-0.89). Patients with RV DD (n = 67) showed significantly different CMR-derived parameters including E and e' velocities, and E/A and E/e' ratio, compared to patients without DD (n = 63) (all p < 0.05). CMR-derived E and e' velocities and E/e' ratio were independent predictors of RV DD. E/e' of 5.8 demonstrated the highest discrimination of RV DD (AUC 0.76, sensitivity 70%, specificity 86%). CONCLUSIONS: CMR-derived parameters showed good agreement with TTE parameters in determining RV DD. CMR-derived E/e' was proved to be the most effective in identifying RV DD. CLINICAL RELEVANCE STATEMENT: This study demonstrated the feasibility and efficacy of CMR in assessing diastolic function in pediatric patients. RV DD was presented in over half of patients according to current TTE guidelines, highlighting the need for assessing RV diastolic function during follow-up. KEY POINTS: • Routinely acquired cine and phase-contrast cardiovascular magnetic resonance (CMR) images yielded right ventricular (RV) diastolic parameters which demonstrated good agreement with transthoracic echocardiography (TTE) measurements. • There was a high prevalence of RV diastolic function impairment in pediatric patients with repaired tetralogy of Fallot (rTOF). • CMR is a reliable complementary modality of TTE for RV diastolic function evaluation.

C-H Bond Sulfonylation from Thianthrenium Salts and DABCO·(SO2)2: Synthesis of 2-Sulfonylindoles.

A three-component reaction of 1-(1H-indol-1-yl)isoquinolines or 1-(pyridin-2-yl)-1H-indoles, DABCO·(SO2)2, and thianthrenium salts under synergistic photoredox and palladium catalysis is accomplished. This direct C-H bond sulfonylation of indoles with the insertion of sulfur dioxide under mild conditions works efficiently, giving rise to a wide range of 2-sulfonated indoles in moderate to good yields under mild conditions. In this protocol, the generality of aryl/alkyl thianthrenium salts is demonstrated as well. A photoredox radical process combined with palladium catalysis is proposed.

The important role of whole-process computed tomography guidance for percutaneous gastrostomy in esophageal cancer patients who are unsuitable for or have had unsuccessful attempts with endoscopic and fluoroscopic gastrostomy.

PURPOSE: To explore the value of clinical application with the whole process computed tomography (CT) guided percutaneous gastrostomy in esophageal tumor patients. MATERIALS AND METHODS: A consecutive series of 32 esophageal tumor patients in whom endoscopic gastrostomy or fluoroscopy guided gastrostomy were considered too dangerous or impossible due to the esophagus complete obstruction, complicate esophageal mediastinal fistula, esophageal trachea fistula or severe heart disease. All of the 32 patients were included in this study from 2 medical center and underwent the gastrostomy under whole process CT guided. RESULTS: All of the gastrostomy procedure was finished successfully under whole process CT guided and the technical success rate was 100%. The average time for each operation was 27 min. No serious complications occurred and the minor complications occurred in 3 patients, including local infection, severe hyperplasia of granulation tissue and tube dislodgment. There were no procedure related deaths. CONCLUSION: The technical success rate of whole process CT guided percutaneous gastrostomy is high and the complication is low. This technique can be used feasible and effectively in some special patients.

Greatly isolated heterogeneous circulating tumor cells using hybrid engineered cell membrane-camouflaged magnetic nanoparticles.

BACKGROUND: Circulating tumor cells (CTCs) are considered as a useful biomarker for early cancer diagnosis, which play a crucial role in metastatic process. Unfortunately, the tumor heterogeneity and extremely rare occurrence rate of CTCs among billions of interfering leukocytes seriously hamper the sensitivity and purity of CTCs isolation. METHODS: To address these, we firstly used microfluidic chips to detect the broad-spectrum of triple target combination biomarkers in CTCs of 10 types of cancer patients, including EpCAM, EGFR and Her2. Then, we constructed hybrid engineered cell membrane-camouflaged magnetic nanoparticles (HE-CM-MNs) for efficient capture of heterogeneous CTCs with high-purity, which was enabled by inheriting the recognition ability of HE-CM for various CTCs and reducing homologous cell interaction with leukocytes. Compared with single E-CM-MNs, HE-CM-MNs showed a significant improvement in the capture efficiency for a cell mixture, with an efficiency of 90%. And the capture efficiency of HE-CM-MNs toward 12 subpopulations of tumor cells was ranged from 70 to 85%. Furthermore, by using HE-CM-MNs, we successfully isolated heterogeneous CTCs with high purity from clinical blood samples. Finally, the captured CTCs by HE-CM-MNs could be used for gene mutation analysis. CONCLUSIONS: This study demonstrated the promising potential of HE-CM-MNs for heterogeneous CTCs detection and downstream analysis.

Adjacent segment degeneration after single- and double-level cervical total disc replacement: a cohort with an over 12-year follow-up.

PURPOSE: To characterize the change of adjacent segment degeneration (ASD) after cervical total disc replacement (CTDR) with more than 12-year follow-up, and identify the risk factors for ASD. METHOD: This process included 75 patients underwent CTDR from February 2004 to December 2012, with the follow-up of 151.9 ± 36.0 (m). The artificial disc included ProDisc-C, Prestige-LP and Mobi-C. ASD was followed up at 1 week, 6 months, 1 year, 2 years, 5 years, 10 years after CTDR and at the endpoint of June 2022. The radiographic measurements were cervical mobility, intervertebral disc height (IDH), cervical lordosis and balance status. The complications were implant migration, subsidence and heterotopic ossification (HO). RESULTS: Cervical mobility in adjacent segments, IDH and lordosis showed no statistical differences between ASD and NASD group. Balance status, subsidence and migration showed no relationship with ASD. Postoperative ASD increased at 6 m and especially between 6 m to 2y. There was no difference between the incidence of upper ASD and lower ASD all the time and few ASD-related reoperation. The majority of adjacent segments were C4/5 (33.6%) and C6/7 (34.2%), and ASD of C5/6 had the highest incidence (61.5%). Cox regression showed ASD was not related to the types of prosthesis or operated numbers. Generalized estimating equations (GEE) analysis showed severe HO had a higher (2.68 times) probability to suffer from ASD. CONCLUSIONS: After over 12-year follow-up of CTDR, the occurrence of ASD and HO had temporal synchronization. ASD was not merely a natural progression but with the pathological process such as HO.

A novel classification that defines the normal cervical spine: an analysis based on 632 asymptomatic Chinese volunteers.

PURPOSE: The "normal" cervical spine may be non-lordotic shapes and the cervical spine alignment targets are less well established. So, the study was to propose novel classification for cervical spine morphologies with Chinese asymptomatic subjects, and to address cervical balance status based on the classification. METHOD: An overall 632 asymptomatic individuals on cervical spine were selected from January 2020 to December 2022, with six age groups from 20-30 year to 70 plus group. Cervical alignment contained C2-7 cervical lordosis (C2-7 CL) and T1 slope (T1S), together with C1-2 CL, C2-4 CL, C5-7 CL, C2S, cervical sagittal vertical axis (CSVA), thoracic inlet angle (TIA) and neck tilt (NT). C2-7 cervical lordosis was regarded as primary outcomes. To identify groups with similar cervical alignment parameters, a 2-step cluster analysis was performed. RESULTS: C2-7 CL, T1S, CSVA, TIA and NT increased by age and mean value of them were larger in male than female group. Four unique clusters of female lordotic cluster, female kyphotic cluster, male lordotic cluster and male kyphotic cluster were classified mainly based on gender and C2-C7 CL. T1S was the independent influencing factor for C2-7 CL in all individuals and C2-7 CL = -28.65 + 0.57 × TIA, which varied from clusters. Although interactions among cervical parameters, it showed the alignment was more coordinated in lordotic groups. CONCLUSIONS: The cervical sagittal profile varied with age and gender. Four clusters were naturally classified based on C2-7 CL and gender. The cervical balance status was addressed by C2-7 CL = - 28.65 + 0.57 × TIA.

Structural basis for ligand binding modes of CTP synthase.

Cytidine triphosphate synthase (CTPS), which comprises an ammonia ligase domain and a glutamine amidotransferase domain, catalyzes the final step of de novo CTP biosynthesis. The activity of CTPS is regulated by the binding of four nucleotides and glutamine. While glutamine serves as an ammonia donor for the ATP-dependent conversion of UTP to CTP, the fourth nucleotide GTP acts as an allosteric activator. Models have been proposed to explain the mechanisms of action at the active site of the ammonia ligase domain and the conformational changes derived by GTP binding. However, actual GTP/ATP/UTP binding modes and relevant conformational changes have not been revealed fully. Here, we report the discovery of binding modes of four nucleotides and a glutamine analog 6-diazo-5-oxo-L-norleucine in Drosophila CTPS by cryo-electron microscopy with near-atomic resolution. Interactions between GTP and surrounding residues indicate that GTP acts to coordinate reactions at both domains by directly blocking ammonia leakage and stabilizing the ammonia tunnel. Additionally, we observe the ATP-dependent UTP phosphorylation intermediate and determine interacting residues at the ammonia ligase. A noncanonical CTP binding at the ATP binding site suggests another layer of feedback inhibition. Our findings not only delineate the structure of CTPS in the presence of all substrates but also complete our understanding of the underlying mechanisms of the allosteric regulation and CTP synthesis.

Iprodione induces hepatotoxicity in zebrafish by mediating ROS generation and upregulating p53 signalling pathway.

Iprodione is an effective and broad-spectrum fungicide commonly used for early disease control in fruit trees and vegetables. Due to rainfall, iprodione often finds its way into water bodies, posing toxicity risks to non-target organisms and potentially entering the human food chain. However, there is limited information available regarding the developmental toxicity of iprodione specifically on the liver in existing literature. In this study, we employed larval and adult zebrafish as models to investigate the toxicity of iprodione. Our findings revealed that iprodione exposure led to yolk sac edema and increased mortality in zebrafish. Notably, iprodione exhibited specific effects on zebrafish liver development. Additionally, zebrafish exposed to iprodione experienced an overload of reactive oxygen species, resulting in the upregulation of p53 gene expression. This, in turn, triggered hepatocyte apoptosis and disrupted carbohydrate/lipid metabolism as well as energy demand systems. These results demonstrated the substantial impact of iprodione on zebrafish liver development and function. Furthermore, the application of astaxanthin (an antioxidant) and p53 morpholino partially mitigated the liver toxicity caused by iprodione. To summarize, iprodione induces apoptosis through the upregulation of p53 mediated by oxidative stress signals, leading to liver toxicity in zebrafish. Our study highlights that exposure to iprodione can result in hepatotoxicity in zebrafish, and it may potentially pose toxicity risks to other aquatic organisms and even humans.

Short-term postoperative bacteriobilia or fungibilia in liver transplantation patients with donation after circulatory death allografts associated with a longer hospital stay: A single-center retrospective observational study in China.

BACKGROUND: Normal bile is sterile. Studies have shown that cholangitis after liver transplantation (LT) was associated with a relatively poor prognosis. It remains unclear whether the bacteriobilia or fungibilia impact the patient outcomes in LT recipients, especially with donation after circulatory death (DCD) allografts, which was correlated with a higher risk of allograft failure. METHODS: This retrospective study included 139 LT recipients of DCD grafts from 2019 to 2021. All patients were divided into two groups according to the presence or absence of bacteriobilia or fungibilia. The prevalence and microbial spectrum of postoperative bacteriobilia or fungibilia and its possible association with outcomes, especially hospital stay were analyzed. RESULTS: Totally 135 and 171 organisms were isolated at weeks 1 and 2, respectively. Among all patients included in this analysis, 83 (59.7%) developed bacteriobilia or fungibilia within 2 weeks post-transplantation. The occurrence of bacteriobilia or fungibilia (ß = 7.43, 95% CI: 0.02 to 14.82, P = 0.049), particularly the detection of Pseudomonas (ß = 18.84, 95% CI: 6.51 to 31.07, P = 0.003) within 2 weeks post-transplantation was associated with a longer hospital stay. However, it did not affect the graft and patient survival. CONCLUSIONS: The occurrence of bacteriobilia or fungibilia, particularly Pseudomonas within 2 weeks post-transplantation, could influence the recovery of liver function and was associated with prolonged hospital stay but not the graft and patient survival.

Compound electrolyte intraocular irrigating solution produces better effects on vision recovery of cataract patients after surgery than Ringer lactate solution.

PURPOSE: Intraocular irrigating solution is extensively applied in cataract surgery. This paper explored the difference and relationship between optical coherence tomography (OCT) and optical quality analysis system (OQAS) parameters induced by compound electrolyte intraocular irrigating solution (CEIIS) or Ringer lactate (RL) solution during uncomplicated cataract surgery. METHODS: Totally 200 senior cataract patients were randomly divided into the CEIIS and RL groups (N = 100 patients/group). The anterior chamber was irrigated by CEIIS or RL during phacoemulsification. Patients were subdivided into diabetes mellitus (DM)+ and DM- groups. The central macular thickness (CMT), hyper reflective foci (HF), modulation transfer function cutoff frequency (MTF cutoff), Strehl ratio (SR), objective scatter index (OSI), and OQAS values (OVs) at 100%, 20%, and 9% contrast levels were measured preoperatively and 1 day and 1 week after operation using spectral-domain optical coherence tomography and OQAS II, respectively. Best-corrected visual acuity (BCVA) was assessed using the Snellen scale, followed by statistical analysis of its logarithm of the minimal angle of resolution. RESULTS: There were no significant differences in clinical characteristics between the CEIIS and RL groups. Both groups exhibited notably increased postoperative CMT, MTF cutoff, SR, OV at 100%, 20%, and 9% contrast levels, and reduced OSI, indicating CEIIS and RL improved postoperative visual quality. CEIIS surpassed RL solution in improving postoperative visual quality, decelerating the increase of macular HF numbers and CMT in DM+ patients and postoperative BCVA. There was no difference between CEIIS and RL in long-term vision improvement. CONCLUSION: CEIIS surpasses RL in postoperative visual recovery and retards increases of macular HF numbers and CMT in senior DM+ cataract patients.

Mismatch-Guided Deoxyribonucleic Acid Assembly Enables Ultrasensitive and Multiplex Detection of Low-Allele-Fraction Variants in Clinical Samples.

Somatic mutations are important signatures in clinical cancer treatment. However, accurate detection of rare somatic mutations with low variant-allele frequencies (VAFs) in clinical samples is challenging because of the interference caused by high concentrations of wild-type (WT) sequences. Here, we report a post amplification SNV-specific DNA assembly (PANDA) technology that eliminates the high concentration pressure caused by WT through a mismatch-guided DNA assembly and enables the ultrasensitive detection of cancer mutations with VAFs as low as 0.1%. Because it generates an assembly product that only exposes a single-stranded domain with the minimal length for signal readout and thus eliminates possible interferences from secondary structures and cross-interactions among sequences, PANDA is highly versatile and expandable for multiplex testing. With ultrahigh sensitivity, PANDA enabled the quantitative analysis of EGFR mutations in cell-free DNA of 68 clinical plasma samples and four pleuroperitoneal fluid samples, with test results highly consistent with NGS deep sequencing. Compared to digital PCR, PANDA returned fewer false negatives and ambiguous cases of clinical tests. Meanwhile, it also offers much lower upfront instrumental and operational costs. The multiplexity was demonstrated by developing a 3-plex PANDA for the simultaneous analysis of three EGFR mutations in 54 pairs of tumor and the adjacent noncancerous tissue samples collected from lung cancer patients. Because of the ultrahigh sensitivity, multiplexity, and simplicity, we anticipate that PANDA will find wide applications for analyzing clinically important rare mutations in diverse devastating diseases.

Orthogonally Engineered Albumin with Attenuated Macrophage Phagocytosis for the Targeted Visualization and Phototherapy of Liver Cancer.

The five-year survival rate of hepatocellular carcinoma (HCC) remains unsatisfactory. This reflects, in part, the paucity of effective methods that allow the target-specific diagnosis and therapy of HCC. Here, we report a strategy based on engineered human serum albumin (HSA) that permits the HCC-targeted delivery of diagnostic and therapeutic agents. Covalent cysteine conjugation combined with the exploitation of host-guest chemistry was used to effect the orthogonal functionalization of HSA with two functionally independent peptides. One of these peptides targets glypican-3 (GPC-3), an HCC-specific biomarker, while the second reduces macrophage phagocytosis through immune-checkpoint stimulation. This orthogonally engineered HSA proved effective for the GPC-3-targeted delivery of near-infrared fluorescent and phototherapeutic agents, thus permitting target-specific optical visualization and photodynamic ablation of HCC in vivo. This study thus offers new insights into specificity-enhanced fluorescence-guided surgery and phototherapy of HCC through the orthogonal engineering of biocompatible proteins.

White matter changes in young and middle-aged males with chronic prostatitis/chronic pelvic pain syndrome: Tract-based spatial statistics analysis.

The supraspinal mechanism plays a key role in developing and maintaining chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, it is not clear how white matter changes in young and middle-aged males with CP/CPPS. In this cross-sectional study, 23 CP/CPPS patients and 22 healthy controls (HCs) were recruited. Tract-based spatial statistics was applied to investigate the differences in diffusion tensor imaging metrics, including fractional anisotropy (FA), mean diffusion (MD), radial diffusion (RD) and axial diffusion (AD), between CP/CPPS patients and HCs. The study also examined the association between white matter alterations and clinical variables in patients using correlation analysis. Compared with HCs, patients showed decreased FA, MD, RD and AD in the body and genu of the corpus callosum and right anterior corona radiata. In addition, they showed increased FA along with decreased MD, RD and AD in the left posterior limb of the internal capsule (PLIC-L), left external capsule and left cerebral peduncle. The FA of PLIC-L was negatively correlated with disease duration (r = -.54, corrected p = .017), while MD and RD were positively correlated (r = .45, corrected p = .042; r = .57, corrected p = .017). These results suggest that CP/CPPS is associated with extensive changes in white matter tracts, which are involved in pain processing. In particular, the FA, MD and RD values in the PLIC-L were correlated with the disease duration, indicating that the long-term course of CP/CPPS may have effects on the white matter microstructure of the pain perception pathways.

Kindlin-2 promotes rear focal adhesion disassembly and directional persistence during cell migration.

Cell migration involves front-to-rear asymmetric focal adhesion (FA) dynamics, which facilitates trailing edge detachment and directional persistence. Here, we show that kindlin-2 is crucial for FA sliding and disassembly in migrating cells. Loss of kindlin-2 markedly reduced FA number and selectively impaired rear FA sliding and disassembly, resulting in defective rear retraction and reduced directional persistence during cell migration. Kindlin-2-deficient cells failed to develop serum-induced actomyosin-dependent tension at FAs. At the molecular level, kindlin-2 directly interacted with myosin light chain kinase (MYLK, hereafter referred to as MLCK), which was enhanced in response to serum stimulation. Serum deprivation inhibited rear FA disassembly, which was released in response to serum stimulation. Overexpression of the MLCK-binding kindlin-2 F0F1 fragment (amino acid residues 1-167), which inhibits the interaction of endogenous kindlin-2 with MLCK, phenocopied kindlin-2 deficiency-induced migration defects. Inhibition of MLCK, like loss of kindlin-2, also impaired trailing-edge detachment, rear FA disassembly and directional persistence. These results suggest a role of kindlin-2 in promoting actomyosin contractility at FAs, leading to increased rear FA sliding and disassembly, and directional persistence during cell migration.

Dual Stealth Functional Immuno-magnetic Nanoparticles for High-Performance Isolation of Circulating Tumor Cells.

As a biomarker of hepatocellular carcinoma (HCC) biopsy, circulating tumor cells (CTCs) are often used in the diagnosis of cancer and treatment guidance. For CTCs detection, immuno-magnetic nanoparticles (IMNs) are one of the most commonly used platforms. However, the nonspecific adsorption of proteins and non-tumor cells weakens the performance of IMNs to capture CTCs. In this work, we developed an IMNs platform which was constructed by a biomimetic protein corona precoating and a polyethylene glycol (PEG) spacer to form the PEG and corona-coated IMNs (IP-CMNs). Due to the dual stealth effect of protein corona precoating and PEG spacer, the nonspecific protein adsorption and cell binding of P-CMNs could reduce by ∼5.5- and ∼5.4-fold, respectively, compared with those of unmodified particles. Furthermore, the PEG spacer could not only reduce the interaction between IP-CMNs and leukocytes but also enhance the capture performance toward tumor cells. By using artificial blood samples, the capture efficiency of IP-CMNs toward rare CTCs was found to be 88.3%, while it was 70.5% by using commercial IMNs. Finally, CTCs were successfully isolated in all HCC patient blood samples (7/7) using IP-CMNs. These results provide insight into the use of the multifunctional nanoplatform as a useful tool for CTCs detection.