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Prion diseases are caused by the misfolding of prion protein (PrP). Misfolded PrP forms protease-resistant aggregates in vivo (PrPSc) that are able to template the conversion of the native form of the protein (PrPC), a property shared by in vitro–produced PrP fibrils. Here we produced amyloid fibrils in vitro from recombinant, full-length human PrPC (residues 23–231) and determined their structure using cryo-EM, building a model for the fibril core comprising residues 170−229. The PrP fibril consists of two protofibrils intertwined in a left-handed helix. Lys194 and Glu196 from opposing subunits form salt bridges, creating a hydrophilic cavity at the interface of the two protofibrils. By comparison with the structure of PrPC, we propose that two α-helices in the C-terminal domain of PrPC are converted into β-strands stabilized by a disulfide bond in the PrP fibril. Our data suggest that different PrP mutations may play distinct roles in modulating the conformational conversion.A cryo-EM structure of amyloid fibrils formed in vitro with recombinant human PrP provides insights into fibril architecture and the potential role of disease mutations.

Cardiac patch is considered a promising strategy for enhancing stem cell therapy of myocardial infarction (MI). However, the underlying mechanisms for cardiac patch repairing infarcted myocardium remain unclear. In this study, we investigated the mechanisms of PCL/gelatin patch loaded with MSCs on activating endogenous cardiac repair. PCL/gelatin patch was fabricated by electrospun. The patch enhanced the survival of the seeded MSCs and their HIF‐1α, Tβ4, VEGF and SDF‐1 expression and decreased CXCL14 expression in hypoxic and serum‐deprived conditions. In murine MI models, the survival and distribution of the engrafted MSCs and the activation of the epicardium were examined, respectively. At 4 weeks after transplantation of the cell patch, the cardiac functions were significantly improved. The engrafted MSCs migrated across the epicardium and into the myocardium. Tendency of HIF‐1α, Tβ4, VEGF, SDF‐1 and CXCL14 expression in the infarcted myocardium was similar with expression in vitro. The epicardium was activated and epicardial‐derived cells (EPDCs) migrated into deep tissue. The EPDCs differentiated into endothelial cells and smooth muscle cells, and some of EPDCs showed to have differentiated into cardiomyocytes. Density of blood and lymphatic capillaries increased significantly. More c‐kit+ cells were recruited into the infarcted myocardium after transplantation of the cell patch. The results suggest that epicardial transplantation of the cell patch promotes repair of the infarcted myocardium and improves cardiac functions by enhancing the survival of the transplanted cells, accelerating locality paracrine, and then activating the epicardium and recruiting endogenous c‐kit+ cells. Epicardial transplantation of the cell patch may be applied as a novel effective MI therapy.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. Misfolded Cu, Zn-superoxide dismutase (SOD1) has been linked to both familial and sporadic ALS. SOD1 fibrils formed in vitro share toxic properties with ALS inclusions. Here we produced cytotoxic amyloid fibrils from full-length apo human SOD1 under reducing conditions and determined the atomic structure using cryo-EM. The SOD1 fibril consists of a single protofilament with a left-handed helix. The fibril core exhibits a serpentine fold comprising N-terminal segment (residues 3–55) and C-terminal segment (residues 86–153) with an intrinsic disordered segment. The two segments are zipped up by three salt bridge pairs. By comparison with the structure of apo SOD1 dimer, we propose that eight β-strands (to form a β-barrel) and one α-helix in the subunit of apo SOD1 convert into thirteen β-strands stabilized by five hydrophobic cavities in the SOD1 fibril. Our data provide insights into how SOD1 converts between structurally and functionally distinct states. Misfolded SOD1 has been linked to both familial and sporadic ALS. Here the authors have determined the cryo-EM structure of SOD1 fibrils, providing insights into the conversion of SOD1 from its immature form into an aggregated form during pathogenesis of ALS.

Objective NUT midline carcinoma (NMC), a rare type of squamous cell carcinoma, is genetically characterised by NUT midline carcinoma family member 1 (NUTM1) gene rearrangement. NMC can arise from the lungs; however, there is no standard for the management of primary pulmonary NMC. This study aimed to confirm the clinical features and report the treatments, especially with immune checkpoint inhibitors (ICIs), and outcomes of patients with primary pulmonary NMC. Methods A retrospective review of patients with primary pulmonary NMC was performed in the First Affiliated Hospital of Guangzhou Medical University between January 2015 and December 2018. Clinical manifestations as well as radiographic and pathological findings were recorded. Whole-exome sequencing (WES), a predictor for ICI response, was used to determine the tumour mutational burden (TMB). Treatments, especially by immune checkpoint blockade, and patient survival were analysed. Results Seven patients with primary pulmonary mass (four men and three women) with a mean age of 42 years (range, 23–74) who were diagnosed with NMC according to NUT immunohistochemistry staining were included for analysis. One patient had a rare fusion of CHRM5-NUTM1 by tumour sequencing. A wide range of TMB (1.75–73.81 mutations/Mbp) was observed. The initial treatments included chemotherapy (5/7, 71.4%), surgery (1/7, 14.3%), and radiotherapy (1/7, 14.3%). Five patients (5/7, 71.4%) received ICIs (programmed cell death protein 1 [PD1]/programmed cell death ligand 1 [PDL1] monoclonal antibody) as second- or higher-line treatments. The median overall survival (OS) was 4.1 months (range, 1.5–26.7 months). Conclusions Patients with primary pulmonary NMC have a poor prognosis and chemotherapy is often preferred. Checkpoint immunotherapy is a good option as the second- or higher-line treatment. TMB seems to be not associated with OS.

The epicardium plays an important role in cardiomyogenesis during development, while it becomes quiescent in adult heart during homeostasis. This study investigates the efficiency of thymosin β4 (Tβ4) release with RPRHQGVM conjugated to the C-terminus of RADA16-I (RADA-RPR), the functionalized self-assembling peptide (SAP), to activate the epicardium and repairing the infarcted myocardium. The functionalized SAP was constituted with self-assembling motif, Tβ4-binding site, and cell adhesive ligand. Myocardial infarction (MI) models of the transgenic mice were established by ligation of the left anterior descending coronary artery. At one week after intramyocardial injection of Tβ4-conjugated SAP, the activation of the epicardium was assessed. At four weeks after implantation, the migration and differentiation of epicardium-derived cells (EPDCs) as well as angiogenesis, lymphangiogenesis and myocardial regeneration were examined. We found that the designer RADA-RPR bound Tβ4 and adhered to EPDCs and that Tβ4 released from the functionalized SAP could effectively activate the epicardium and induce EPDCs to differentiate towards cardiovascular cells as well as lymphatic endothelial cells. Moreover, SAP-released Tβ4 (SAP-Tβ4) promoted proliferation of cardiomyocytes. Furthermore, angiogenesis, lymphangiogenesis and myocardial regeneration were enhanced in the MI models at 4 weeks after delivery of SAP-Tβ4 along with attenuation of adverse myocardial remodeling and significantly improved cardiac function. These results demonstrate that sustained release of Tβ4 from the functionalized SAP can activate the epicardium and effectively enhance the repair of infarcted myocardium. We believe the delivery of SAP-Tβ4 may be a promising strategy for MI therapy.

Numerous studies have yielded inconsistent results regarding the relationship between p53 status and the response to neoadjuvant radiation-based therapy in patients with rectal cancer. We conducted a meta-analysis to clarify the relationship between p53 status and response to radiation-based therapy in rectal cancer. A total of 30 previously published eligible studies including 1,830 cases were identified and included in this meta-analysis. Wild-type form of p53 status (low expression of p53 protein and/or wild-type p53 gene) was associated with pathologic response in rectal cancer patients who received neoadjuvant radiation-based therapy (good response: risk ratio [RR] =1.30; 95% confidence intervals [CI] =1.14-1.49; p<0.001; complete response RR=1.65; 95% CI=1.19-2.30; p=0.003; poor response RR=0.85; 95% CI=0.75-0.96; p=0.007). In further stratified analyses, this association remained for sub-groups of good and poor response in neoadjuvant radiotherapy (RT) setting, good and complete response in chemoradiotherapy (CRT) setting. And the association between response and the presence of p53 gene mutations was stronger than that between response and protein positivity. The results of the present meta-analysis indicate that P53 status is a predictive factor for response in rectal cancer patient undergoing neoadjuvant radiation-based therapy.

Human induced pluripotent stem cells (hiPSCs) offer significant potential for differentiation and research applications in cardiovascular diseases. When induced differentiated hiPSC-derived cardiomyocytes (hiPSC-CMs) are transplanted into the infarcted myocardial region, they exhibit extremely low survival rates and unsatisfactory therapeutic effects due to ischemia, hypoxia, and immune inflammation in the surrounding environment. To address this issue, we used Panax notoginseng saponin R1 (NGR1), which has demonstrated significant protective effects in prior research, to pretreat hiPSC-CMs before transplantation. Utilizing an in vitro H2O2 oxidative stress model and a nude mouse myocardial infarction (MI) model, we investigated the mechanism through which NGR1 pretreatment enhances the therapeutic efficacy of hiPSC-CM transplantation. The results revealed that the hiPSC-CMs expressed cTnT. NGR1 did not promote the proliferation of hiPSC-CMs but instead induced elevated levels of p-Akt protein in these cells. Compared to hiPSC-CM transplantation alone, transplantation of hiPSC-CMs pretreated with NGR1 exhibited higher ejection fraction (EF) and fractional shortening (FS) values, along with reduced infarct size and collagen deposition. Additionally, there were more HNA-positive cardiomyocytes in the cardiac tissue, fewer TUNEL-positive signals, and increased VWF-positive and Lyve1-positive signals. Furthermore, the gene expression levels of VEGFC, IGF-1, and SDF-1 were higher. Therefore, NGR1 pretreatment improves the survival of transplanted hiPSC-CMs in tissues, reduces myocardial apoptosis, enhances cardiac function, decreases infarct size and collagen deposition, promotes angiogenesis and lymphangiogenesis, and stimulates paracrine secretion.

Purpose To compare the morphological and biomechanical properties of normal cornea and keratoconus at different stages. Methods A total of 408 patients (517 eyes) with keratoconus were included in this study. According to the Topographic Keratoconus (TKC) grading method, keratoconus was divided into stage I (TKC = 1, 130 eyes), stage II (TKC = 1–2, 2, 164 eyes), stage III (TKC = 2–3, 3, 125 eyes) and stage IV (TKC = 3–4, 4, 98 eyes). A total of 158 normal subjects (158 eyes) were recruited as the normal group. The corneal morphological parameters and biomechanical parameters were obtained with Scheimpflug tomography (Pentacam) and corneal visualization Scheimpflug technology (Corvis ST), and the receiver operating characteristic (ROC) curves were drawn. Results Each corneal morphological and most biomechanical parameters of the keratoconic eyes were significantly different from those of the normal eyes in this study ( p  < 0.001). ROC curve demonstrated that most parameters in this study showed high efficiency in diagnosing keratoconus (the area under the ROC (AUC) was > 0.9), with the Belin-Ambrósio deviation (BAD-D) and Tomographic and Biomechanical Index (TBI) showing higher efficiency. The efficiency of BAD-D and TBI was high in differentiating keratoconus at different stages (AUC > 0.963). The comparison of ROC curves of keratoconus at different stages did not reveal statistically significant differences for TBI. Conclusion BAD-D and TBI can effectively diagnose stage I keratoconus. Moreover, the efficiency of TBI is the same in diagnosing keratoconus at all stages, while the diagnostic efficiency of other parameters increases with the increase in keratoconus stages.

PurposeTo report the long-term outcomes of Boston keratoprosthesis type I (B-KPro type I) implantation in the management of severe ocular surface disorders.MethodsRetrospective case series. Patients who underwent B-KPro type I implantation at the People’s Liberation Army General Hospital were enrolled between March 2011 and September 2019. Data regarding visual acuity (VA), B-KPro type I retention and postoperative complications were recorded and analysed.ResultsA total of 103 eyes of 100 patients who underwent B-KPro type I implantation were included. The main indications were chemical burn (59.2%), ocular trauma (25.2%), herpetic keratitis (11.7%) and autoimmune diseases (3.9%). The percentage of eyes with postoperative VA of 10/200 or better was 82.7% at 6 months, 82.8% at 12 months, 77.9% at 2 years, 72.4% at 3 years, 71.1% at 4 years, 69.4% at 5 years, 58.9% at 6 years, 56.8% at 7 years and 42.9% at 8 years. Preoperatively, 8.7% eyes were diagnosed with new-onset glaucoma. Retroprosthetic membrane formation occurred in 19.4% eye. Corneal melting occurred in 18.4% eyes. Sterile vitritis was diagnosed in 4.9% eyes and infectious endophthalmitis in 2.9% eyes. Retinal detachment occurred in 0.9% eyes.ConclusionsIn a Chinese patient group, B-KPro type I is a viable option for treating severe ocular surface disorders in eyes where conventional keratoplasty would have a poor prognosis, especially in patients with chemical and thermal burns. Improved visual outcomes and high retention rate can be achieved and maintained in most cases.

Polycrystalline diamond compact (PDC) bits experience a serious wear problem in drilling tight gravel layers. To achieve efficient drilling and prolong the bit service life, a simplified model of a PDC bit with double cutting teeth was established by using finite-element numerical simulation technology, and the rock-breaking process of PDC bit cutting teeth was simulated using the Archard wear principle. The numerical simulation results of the wear loss of the PDC bit cutting teeth, such as the caster angle, temperature, linear velocity, and bit pressure, as well as previous experimental research results, were combined into a training dataset. Then, machine learning methods for equal-probability gene expression programming (EP-GEP) were used. Based on the accuracy of the training set, the effectiveness of this method in predicting the wear of PDC bits was demonstrated by verifying the dataset. Finally, a prediction dataset was established by a Latin hypercube experiment and finite-element numerical simulation. Through comparison with the EP-GEP prediction results, it was verified that the prediction accuracy of this method meets actual engineering needs. The results of the sensitivity analysis method for the gray correlation degree show that the degree of influence of bit wear is in the order of temperature, back dip angle of the PDC cutter, linear speed, and bit pressure. These results demonstrate that when an actual PDC bit is drilling hard strata such as a conglomerate layer, after the local high temperature is generated in the formation cut by the bit, appropriate cooling measures should be taken to increase the bit pressure and reduce the rotating speed appropriately. Doing so can effectively reduce the wear of the bit and prolong its service life. This study provides guidance for predicting the wear of a PDC bit when drilling in conglomerate, adjusting drilling parameters reasonably, and prolonging the service life of the bit.