Deciphering the Dysregulating IGF-1-SP1-CD248 Pathway in Fibroblast Functionality during Diabetic Wound Healing.

Reduced fibroblast activity is a critical factor in the progression of diabetic ulcers. CD248, a transmembrane glycoprotein prominently expressed in activated fibroblasts, plays a pivotal role in wound healing. However, the role of CD248 in diabetic wound healing and the CD248 regulatory pathway remains largely unexplored. Our study shows that CD248 expression is significantly reduced in skin wounds from both diabetic patients and mice. Single-cell transcriptome data analyses reveal a marked reduction of CD248-enriched secretory-reticular fibroblasts in diabetic wounds. We identify insulin-like growth factor-1 (IGF-1) as a key regulator of CD248 expression through the Akt/mTOR signaling pathway and the Sp1 transcription factor. Overexpression of CD248 enhances fibroblast motility, elucidating the underrepresentation of CD248-enriched fibroblasts in diabetic wounds. Immunohistochemical staining of diabetic wound samples further confirm low SP1 expression and fewer CD248-positive secretory-reticular fibroblasts. Further investigation reveals that elevated tumor necrosis factor α (TNFα) levels in diabetic environment promotes IGF-1 resistance, and inhibiting IGF-1-induced CD248 expression. In summary, our findings underscore the critical role of the IGF1-SP1-CD248 axis in activating reticular fibroblasts during wound-healing processes. Targeting this axis in fibroblasts could help develop a therapeutic regimen for diabetic ulcers.

A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity.

Deep learning-based methods for generating functional proteins address the growing need for novel biocatalysts, allowing for precise tailoring of functionalities to meet specific requirements. This advancement leads to the development of highly efficient and specialized proteins with diverse applications across scientific, technological, and biomedical fields. This study establishes a pipeline for protein sequence generation with a conditional protein diffusion model, namely CPDiffusion, to create diverse sequences of proteins with enhanced functions. CPDiffusion accommodates protein-specific conditions, such as secondary structures and highly conserved amino acids. Without relying on extensive training data, CPDiffusion effectively captures highly conserved residues and sequence features for specific protein families. We applied CPDiffusion to generate artificial sequences of Argonaute (Ago) proteins based on the backbone structures of wild-type (WT) Kurthia massiliensis Ago (KmAgo) and Pyrococcus furiosus Ago (PfAgo), which are complex multi-domain programmable endonucleases. The generated sequences deviate by up to nearly 400 amino acids from their WT templates. Experimental tests demonstrated that the majority of the generated proteins for both KmAgo and PfAgo show unambiguous activity in DNA cleavage, with many of them exhibiting superior activity as compared to the WT. These findings underscore CPDiffusion's remarkable success rate in generating novel sequences for proteins with complex structures and functions in a single step, leading to enhanced activity. This approach facilitates the design of enzymes with multi-domain molecular structures and intricate functions through in silico generation and screening, all accomplished without the need for supervision from labeled data.

Strong Electronic Metal-Support Interactions Enable the Increased Spin State of Co-N4 Active Sites and Performance for Acidic Oxygen Reduction Reaction.

Nonprecious metal catalysts, particularly M-N-C catalysts, are widely recognized as promising contenders for the oxygen reduction reaction (ORR). However, a notable performance gap persists between M-N-C catalysts and Pt-based catalysts under acidic conditions. In this study, hybrid catalysts comprising single Co atoms and ultralow concentrations of Pt3Co intermetallic nanoparticles (NPs) are introduced to enhance ORR performance. Under acidic conditions, these hybrid catalysts demonstrate ORR efficiency with a half-wave potential of 0.895 V, negligible decay even after 80 000 cycles, and a high maximum power density of 1.34 W cm-2 in fuel cells. This performance surpasses those of Co-N-C and Pt/Co-N-C catalysts. Both experimental findings and theoretical computations suggest that the heightened ORR activity stems from an increase in the spin density of Co sites induced by noble metal NPs, facilitating the activation of O-O bonds via side-on overlapping and enabling a transition in the reaction pathway from associative to dissociative processes. This research offers a promising avenue for the systematic design of M-N-C cathodes with an enhanced performance for acidic fuel cells.

Growth pattern of de novo small clusters of colorectal cancer is regulated by Notch signaling at detachment.

Cancer cell clusters have a higher capacity for metastasis than single cells, suggesting cancer cell clusters have biological properties different from those of single cells. The nature of de novo cancer cell clusters that are newly formed from tumor masses is largely unknown. Herein, we generated small cell clusters from colorectal cancer organoids and tracked the growth patterns of the clusters up to four cells. Growth patterns were classified into actively growing and poorly growing spheroids (PG). Notch signaling was robustly activated in small clusters immediately after dissociation, and Notch signaling inhibition markedly increased the proportion of PG spheroids. Only a limited number of PG spheroids grew under growth-permissive conditions in vitro, but xenograft tumors derived from Notch inhibited clusters showed growth rates comparable to those of untreated spheroids. Thus, de novo clusters are composed of cells with interchangeable growth fates, which are regulated in a context-dependent manner by Notch signaling.

Trimodal Multiplexed Lateral Flow Test Strips Assisted with a Portable Microfluidic Centrifugation Device.

During the COVID-19 pandemic, the use of lateral flow assays (LFAs) expanded significantly, offering testing beyond traditional health care. Their appeal lies in the ease of use, affordability, and quick results. However, LFAs often have lower sensitivity and specificity compared with ELISA and PCR tests. Efforts to improve LFAs have increased detection times and complexity, limiting their use in large-scale point-of-care settings. To address this, we propose a novel approach using probes that generate multiple signals to enhance the sensitivity and selectivity. This concept also allows multiplexed LFAs to detect multiple analytes concurrently. We developed a trimodal probe that integrates fluorescence, color, and magnetism into a single nanohybrid. The strong plasmonic absorption and high fluorescence of Au nanoparticles and polymer dots enable qualitative and semiquantitative diagnosis, while the magnetic signal facilitates accurate quantitative measurements. As proof-of-concept targets, we selected CYFRA 21-1 and CA15-3, biomarkers for lung and breast cancer, respectively. This trimodal LFA demonstrated a remarkable detection limit of 0.26 ng/mL for CYFRA 21-1 and 2.8 U/mL for CA15-3. To the best of our knowledge, this is the first platform of a trimodal LFA with multiplexing ability. The platform's accuracy and reliability were validated using clinical serum samples, showing excellent consistency with electrochemiluminescence immunoassay results. This universal concept can be applied to other targets, paving the way for the next-generation LFAs.

Biological and genomic characterization of a polyvalent phage PSH-1 against multidrug-resistant Salmonella Enteritidis.

BACKGROUND: Bacteriophage has been renewed attention as a new antibacterial agent due to the limitations of antibiotic treatment. Bacteriophages are generally thought to be highly host specific and even strain specific, but a small number of polyvalent bacteriophages have been found to infect bacteria of different genera. RESULTS: In this study, a virulent lytic bacteriophage (named Salmonella phage PSH-1) of Salmonella Enteritidis was isolated from the sewage samples of a large-scale pig farm, PSH-1 demonstrated lytic activity against four multidrug-resistant Salmonella Enteritidis isolates and Escherichia coli, and then its biological characteristics, genome and bacteriostatic ability were investigated. The results showed that the initial titer of PSH-1 was 1.15 × 1010 PFU/mL and the optimal multiplicity of infection (MOI) was 0.01, PSH-1 has stable activity in the range of pH 3.0-11.0. One-step growth curve showed that its latent period was 20 min, burst time was 80 min, and the burst was 495 particles. The whole-genome sequencing results revealed phage PSH-1 had a linear dsDNA with 48,466 bp length. The G/C content was 45.33%. Non-coding RNA genes and virulence factors were not found. Eighty- five open reading frames (ORFs) were identified after online annotation. By tests, the use of phage could succeed in controlling the artificial Salmonella contamination in milk at a range of temperatures. CONCLUSIONS: This study reports a novel Salmonella Enteritidis phage PSH-1, which has a robust lytic ability, no virulence factors, and good stability. The characterization and genomic analysis of PSH-1 will develop our understanding of phage biology and diversity and provide a potential arsenal for controlling of salmonellosis.

Potential plausible role of Wharton's jelly mesenchymal stem cells for diabetic bone regeneration.

This letter addresses the review titled "Wharton's jelly mesenchymal stem cells: Future regenerative medicine for clinical applications in mitigation of radiation injury". The review highlights the regenerative potential of Wharton's jelly mesenchymal stem cells (WJ-MSCs) and describes why WJ-MSCs will become one of the most probable stem cells for future regenerative medicine. The potential plausible role of WJ-MSCs for diabetic bone regeneration should be noticeable, which will provide a new strategy for improving bone regeneration under diabetic conditions.

Effectiveness of chest pain center accreditation on the hospital outcome of acute aortic dissection: a nationwide study in China.

BACKGROUND: The National Chest Pain Center Program (NCPCP) is a nationwide, quality enhancement program aimed at raising the standard of care for patients experiencing acute chest pain in China. The benefits of chest pain center (CPC) accreditation on acute coronary syndrome have been demonstrated. However, there is no evidence to indicate whether CPC accreditation improves outcomes for patients with acute aortic dissection (AAD). METHODS: We conducted a retrospective observational study of patients with AAD from 1671 hospitals in China, using data from the NCPCP spanning the period from January 1, 2016 to December 31, 2022. The patients were divided into 2 groups: pre-accreditation and post-accreditation admissions. The outcomes examined included in-hospital mortality, misdiagnosis, and Stanford type A AAD surgery. Multivariate logistic regression was employed to explore the relationship between CPC accreditation and in-hospital outcomes. Furthermore, we stratified the hospitals based on their geographical location (Eastern/Central/Western regions) or administrative status (provincial/non-provincial capital areas) to assess the impact of CPC accreditation on AAD patients across various regions. RESULTS: The analysis encompassed a total of 40,848 patients diagnosed with AAD. The post-accreditation group exhibited significantly lower rates of in-hospital mortality and misdiagnosis (12.1% vs. 16.3%, P < 0.001 and 2.9% vs. 5.4%, P < 0.001, respectively) as well as a notably higher rate of Stanford type A AAD surgery (61.1% vs. 42.1%, P < 0.001) compared with the pre-accreditation group. After adjusting for potential covariates, CPC accreditation was associated with substantially reduced risks of in-hospital mortality (adjusted OR 0.644, 95% CI 0.599-0.693) and misdiagnosis (adjusted OR 0.554, 95% CI 0.493-0.624), along with an increase in the proportion of patients undergoing Stanford type A AAD surgery (adjusted OR 1.973, 95% CI 1.797-2.165). Following CPC accreditation, there were significant reductions in in-hospital mortality across various regions, particularly in Western regions (from 21.5 to 14.1%). Moreover, CPC accreditation demonstrated a more pronounced impact on in-hospital mortality in non-provincial cities compared to provincial cities (adjusted OR 0.607 vs. 0.713). CONCLUSION: CPC accreditation is correlated with improved management and in-hospital outcomes for patients with AAD.

Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway.

In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway.

Novel glucomannan-like polysaccharide from Lycium barbarum L. ameliorates renal fibrosis via blocking macrophage-to-myofibroblasts transition.

The macrophage to myofibroblasts transition (MMT) has been reported as a newly key target in renal fibrosis. Lycium barbarum L. is a traditional Chinese medicine for improving renal function, in which its polysaccharides (LBPs) are the mainly active components. However, whether the role of LBPs in treating renal fibrosis is related to MMT process remain unclear. The purpose of this study was to explore the relationship between the regulating effect on MMT process and the anti-fibrotic effect of LBPs. Initially, small molecular weight LBPs fractions (LBP-S) were firstly isolated via Sephadex G-100 column. Then, the potent inhibitory effect of LBP-S on MMT process was revealed on bone marrow-derived macrophages (BMDM) model induced by TGF-ß. Subsequently, the chemical structure of LBP-S was elucidated through monosaccharide, methylation and NMR spectrum analysis. In vivo biodistribution characteristics studies demonstrated that LBP-S exhibited effectively accumulation in kidney via intraperitoneal administration. Finally, LBP-S showed a satisfactory anti-renal fibrotic effect on unilateral ureteral obstruction operation (UUO) mice, which was significantly reduced following macrophage depletion. Overall, our findings indicated that LPB-S could alleviate renal fibrosis through regulating MMT process and providing new candidate agents for chronic kidney disease (CKD) related fibrosis treatment.

Schisandra chinensis (Turcz.) Baill neutral polysaccharides alleviate Parkinson's disease via effectively activating MCL-1 expression regulation of autophagy signaling.

The purified neutral polysaccharide fraction, namely SBP-1, was isolated and characterized from Schisandra chinensis (Turcz.) Baill crude polysaccharides, which have anti-Parkinson's disease activity were investigated in vivo and in vitro. Experiments have shown that the main chain of SBP-1 was Glcp-(1→, →4)-Glcp-(1→ and →4,6)-Glcp-(1→. We also revealed the effect of SBP-1 on the PD mice model and the potential underlying molecular mechanism. The results showed that SBP-1 administration improved behavioral deficits, increased tyrosine hydroxylase-positive cells, attenuated loss of dopaminergic neurons in MPTP-exposed mice, and reduced cell death induced by MPP+. The MCL-1 was identified as the target of SBP-1 by the combination of docking-SPR-ITC, WB, and IF experiments. Subsequently, the study showed that SBP-1 could target MCL-1 to enhance autophagy with a change in the apoptotic response, which was further demonstrated by a change in LC3/P62, PI3K/AKT/mTOR, and possesses a change in the expression of BCL2/BAX/Caspase3. These results demonstrate that SBP-1 may protect neurons against MPP+ or MPTP-induced damage in vitro and in vivo through enhancing autophagy. In summary, these findings indicate that SBP-1 and S. chinensis show potential as effective candidates for further investigation in the prevention and treatment of PD or associated illnesses, specifically through autophagy apoptotic-based mechanisms.

Giant retroperitoneal hemolymphangioma: A case report and review of literature.

BACKGROUND: Hemolymphangioma is a very rare benign tumor in clinical practice caused by abnormalities of the vasculature. Its clinical features are often atypical, and it is easy to miss and misdiagnose. When the time of nuclear magnetic T1 is significantly reduced, the diagnosis of hemangioma should be considered. Therefore, we report this case in the hope of raising clinicians' awareness of the disease. CASE SUMMARY: A 37-year-old man presented with a giant retroperitoneal hemolymphangioma. Computed tomography and magnetic resonance imaging indicated the possibility of a large perirenal lymphatic cyst. The postoperative pathological diagnosis is retroperitoneal hemolymphangioma. The patient underwent surgical excision after adequate drainage. The postoperative recovery was smooth and there were no complications. There was no recurrence during half a year of follow-up. CONCLUSION: This case reiterates that large retroperitoneal cystic masses with significantly shortened nuclear T1 time should be considered hemolymphangioma. Specific clinical basis and experience for the diagnosis and treatment of these diseases is necessary.

Compliance with evidence-based radiographic imaging guidelines by chiropractic interns at a chiropractic training program.

OBJECTIVE: Evidence-based radiographic guidelines are used to justify the need for radiographs and prevent their overuse. This study aimed to assess whether 4th-year chiropractic interns at the International Medical University plan to use x-ray imaging in their future private practice in line with the principles taught throughout their chiropractic program and the evidence-based imaging guidelines. METHODS: A survey questionnaire was distributed to 74 final year chiropractic interns, with 62 completed responses. The questionnaire consisted of 8 case scenarios representing potential chiropractic patients. The interns were asked to decide whether to x-ray the patient or not, and which x-ray views to request if they chose to x-ray the patient. RESULTS: Results were compared with the gold standard using percentage agreement. The findings revealed that the chiropractic students adhered to the gold standard answers for 6 out of 8 cases. However, they did not perform well in selecting the correct x-ray views for the 3 cases where radiography was indicated by the gold standard. CONCLUSION: Results suggest that while the interns have a good understanding of when radiography is necessary, they may need additional training in selecting the appropriate x-ray views for each case.

A Self-Supervised Few-Shot Semantic Segmentation Method Based on Multi-Task Learning and Dense Attention Computation.

Nowadays, autonomous driving technology has become widely prevalent. The intelligent vehicles have been equipped with various sensors (e.g., vision sensors, LiDAR, depth cameras etc.). Among them, the vision systems with tailored semantic segmentation and perception algorithms play critical roles in scene understanding. However, the traditional supervised semantic segmentation needs a large number of pixel-level manual annotations to complete model training. Although few-shot methods reduce the annotation work to some extent, they are still labor intensive. In this paper, a self-supervised few-shot semantic segmentation method based on Multi-task Learning and Dense Attention Computation (dubbed MLDAC) is proposed. The salient part of an image is split into two parts; one of them serves as the support mask for few-shot segmentation, while cross-entropy losses are calculated between the other part and the entire region with the predicted results separately as multi-task learning so as to improve the model's generalization ability. Swin Transformer is used as our backbone to extract feature maps at different scales. These feature maps are then input to multiple levels of dense attention computation blocks to enhance pixel-level correspondence. The final prediction results are obtained through inter-scale mixing and feature skip connection. The experimental results indicate that MLDAC obtains 55.1% and 26.8% one-shot mIoU self-supervised few-shot segmentation on the PASCAL-5i and COCO-20i datasets, respectively. In addition, it achieves 78.1% on the FSS-1000 few-shot dataset, proving its efficacy.

Synthesis of C(3) SCF3-Substituted Pyrrolidinoindoline by PIII/PV Redox Catalysis Using CF3SO2Cl as Electrophilic CF3S Reagent.

This work reports a method for the catalytic synthesis of C(3) SCF3-substituted pyrrolidinindoline using a small-ring organophosphorus-based catalyst and a hydrosilane reductant, with trifluoromethanesulfonyl chloride as the electrophilic SCF3 reagent. This method can drive the conversion of tryptamine to the C(3) SCF3-substituted pyrrolidine indoline. The readily available, inexpensive trifluoromethanesulfonyl chloride could be activated as an electrophilic SCF3 source by PIII/PV redox catalysis and could efficiently participate in the reaction of tryptamines, thus providing various substituted C(3) SCF3-substituted pyrrolidinoindoline in moderate to excellent yields. This presented strategy features a broad substrate scope, and the structure has value for in-depth research.

Regulation of matrix reloading by tumor endothelial marker 1 protects against abdominal aortic aneurysm.

Tumor endothelial marker 1 (TEM1), an activated mesenchymal cell marker, is implicated in tissue remodeling and repair. Herein, we investigated the role and therapeutic implications of TEM1 in abdominal aortic aneurysm (AAA), a potentially life-threatening aortic disease characterized by vascular inflammation and matrix turnover. Characterization of human AAA revealed increased TEM1 expression derived mainly from medial vascular smooth muscle cells (VSMCs) and adventitial fibroblasts. Bioinformatics analysis demonstrated the association between TEM1-expressing VSMCs and fibroblasts and collagen gene expression. Consistently, collagen content and TEM1 expressed by VSMCs and fibroblasts were increased during CaCl2-induced AAA formation in mice. TEM1 silencing in VSMCs and fibroblasts inhibited transforming growth factor-ß1-induced phenotypic change, SMAD2 phosphorylation, and COL1A1 gene expression. Also, Tem1 deficiency reduced collagen synthesis and exacerbated CaCl2-induced AAA formation in mice without disturbing elastin destruction and inflammatory responses. In contrast, rTEM1 promoted phenotypic change and COL1A1 gene expression through SMAD2 phosphorylation in VSMCs and fibroblasts. Treatment with rTEM1 enhanced collagen synthesis, attenuated elastin fragmentation, and inhibited CaCl2-induced and angiotensin II-infused AAA formation. In summary, TEM1 in resident stromal cells regulates collagen synthesis to counteract aortic wall failure during AAA formation. Matrix integrity restored by rTEM1 treatment may hold therapeutic potential against AAA.

Unleashing the Power of Evolution in Xylanase Engineering: Investigating the Role of Distal Mutation Regulation.

The drive to enhance enzyme performance in industrial applications frequently clashes with the practical limitations of exhaustive experimental screening, underscoring the urgency for more refined and strategic methodologies in enzyme engineering. In this study, xylanase Xyl-1 was used as the model, coupling evolutionary insights with energy functions to obtain theoretical potential mutants, which were subsequently validated experimentally. We observed that mutations in the nonloop region primarily aimed at enhancing stability and also encountered selective pressure for activity. Notably, mutations in this region simultaneously boosted the Xyl-1 stability and activity, achieving a 65% success rate. Using a greedy strategy, mutant M4 was developed, achieving a 12 °C higher melting temperature and doubled activity. By integration of spectroscopy, crystallography, and quantum mechanics/molecular mechanics molecular dynamics, the mechanism behind the enhanced thermal stability of M4 was elucidated. It was determined that the activity differences between M4 and the wild type were primarily driven by dynamic factors influenced by distal mutations. In conclusion, the study emphasizes the pivotal role of evolution-based approaches in augmenting the stability and activity of the enzymes. It sheds light on the unique adaptive mechanisms employed by various structural regions of proteins and expands our understanding of the intricate relationship between distant mutations and enzyme dynamics.

Broadband and fabrication-tolerant 3-dB couplers with topological valley edge modes.

3-dB couplers, which are commonly used in photonic integrated circuits for on-chip information processing, precision measurement, and quantum computing, face challenges in achieving robust performance due to their limited 3-dB bandwidths and sensitivity to fabrication errors. To address this, we introduce topological physics to nanophotonics, developing a framework for topological 3-dB couplers. These couplers exhibit broad working wavelength range and robustness against fabrication dimensional errors. By leveraging valley-Hall topology and mirror symmetry, the photonic-crystal-slab couplers achieve ideal 3-dB splitting characterized by a wavelength-insensitive scattering matrix. Tolerance analysis confirms the superiority on broad bandwidth of 48 nm and robust splitting against dimensional errors of 20 nm. We further propose a topological interferometer for on-chip distance measurement, which also exhibits robustness against dimensional errors. This extension of topological principles to the fields of interferometers, may open up new possibilities for constructing robust wavelength division multiplexing, temperature-drift-insensitive sensing, and optical coherence tomography applications.

Erratum: Lower Bounds on Quantum Annealing Times [Phys. Rev. Lett. 130, 140601 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.140601.