Longitudinal imaging of vitreal hyperreflective foci in mice with acute optic nerve damage using visible-light optical coherence tomography.

Hyperreflective foci (HRFs) appear in optical coherence tomography (OCT) images of the retina and vitreous of patients with various ocular diseases. HRFs are hypothesized to be immune cells that appear in response to ischemia or tissue damage. To accurately identify HRFs and establish their clinical significance, it is necessary to replicate the detection of similar patterns in vivo in a small animal model. We combined visible-light OCT with temporal speckle averaging (TSA) to visualize and track vitreal HRFs (VHRFs) densities for three days after an optic nerve crush (ONC) injury. Resulting vis-OCT images revealed that VHRF density significantly increased approximately 10-fold at 12 h after ONC and returned to baseline three days after ONC. Additional immunohistochemistry results confirmed these VHRFs as inflammatory cells induced from optic nerve damage.

Giant Magnon-Polaron Anomalies in Spin Seebeck Effect in Double Umbrella-Structured Tb_{3}Fe_{5}O_{12} Films.

We report a giant hysteretic spin Seebeck effect (SSE) anomaly with a sign reversal at magnetic fields much stronger than the coercive field in a (001)-oriented Tb_{3}Fe_{5}O_{12} film. The high-field SSE enhancement reaches 4200% at approximately 105 K over its weak-field value and presents a nonmonotonic dependence on temperature. The unexpected high-field hysteresis of SSE is found to be associated with a magnetic transition of double-umbrella spin texture in TbIG. Nearly parallel dispersion curves of magnons and acoustic phonons around this neoteric transition are supported by theoretical calculations, leading to a high density of field-tuned magnon polarons and consequently an extraordinarily large SSE. Our study provides insight into the evolution of magnon dispersions of double-umbrella TbIG and could potentially boost the efficiency of magnon-polarons SSE devices.

Neutrophil Extracellular Traps Regulate Surgical Brain Injury by Activating the cGAS-STING Pathway.

Surgical brain injury (SBI), induced by neurosurgical procedures or instruments, has not attracted adequate attention. The pathophysiological process of SBI remains sparse compared to that of other central nervous system diseases thus far. Therefore, novel and effective therapies for SBI are urgently needed. In this study, we found that neutrophil extracellular traps (NETs) were present in the circulation and brain tissues of rats after SBI, which promoted neuroinflammation, cerebral edema, neuronal cell death, and aggravated neurological dysfunction. Inhibition of NETs formation by peptidylarginine deiminase (PAD) inhibitor or disruption of NETs with deoxyribonuclease I (DNase I) attenuated SBI-induced damages and improved the recovery of neurological function. We show that SBI triggered the activation of cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING), and that inhibition of the cGAS-STING pathway could be beneficial. It is worth noting that DNase I markedly suppressed the activation of cGAS-STING, which was reversed by the cGAS product cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP, cGAMP). Furthermore, the neuroprotective effect of DNase I in SBI was also abolished by cGAMP. NETs may participate in the pathophysiological regulation of SBI by acting through the cGAS-STING pathway. We also found that high-dose vitamin C administration could effectively inhibit the formation of NETs post-SBI. Thus, targeting NETs may provide a novel therapeutic strategy for SBI treatment, and high-dose vitamin C intervention may be a promising translational therapy with an excellent safety profile and low cost.

Gut colonization with multidrug resistant organisms in the intensive care unit: a systematic review and meta-analysis.

BACKGROUND: Gut colonization with multidrug-resistant organisms (MDRO) frequently precedes infection among patients in the intensive care unit (ICU), although the dynamics of colonization are not completely understood. We performed a systematic review and meta-analysis of ICU studies which described the cumulative incidence and rates of MDRO gut acquisition. METHODS: We systematically searched PubMed, Embase, and Web of Science for studies published from 2010 to 2023 reporting on gut acquisition of MDRO in the ICU. MDRO were defined as multidrug resistant non-Pseudomonas Gram-negative bacteria (NP-GN), Pseudomonas spp., and vancomycin-resistant Enterococcus (VRE). We included observational studies which obtained perianal or rectal swabs at ICU admission (within 48 h) and at one or more subsequent timepoints. Our primary outcome was the incidence rate of gut acquisition of MDRO, defined as any MDRO newly detected after ICU admission (i.e., not present at baseline) for all patient-time at risk. The study was registered with PROSPERO, CRD42023481569. RESULTS: Of 482 studies initially identified, 14 studies with 37,305 patients met criteria for inclusion. The pooled incidence of gut acquisition of MDRO during ICU hospitalization was 5% (range: 1-43%) with a pooled incidence rate of 12.2 (95% CI 8.1-18.6) per 1000 patient-days. Median time to acquisition ranged from 4 to 26 days after ICU admission. Results were similar for NP-GN and Pseudomonas spp., with insufficient data to assess VRE. Among six studies which provided sufficient data to perform curve fitting, there was a quasi-linear increase in gut MDRO colonization of 1.41% per day which was stable through 30 days of ICU hospitalization (R2 = 0.50, p < 0.01). CONCLUSIONS: Acquisition of gut MDRO was common in the ICU and increases with days spent in ICU through 30 days of follow-up. These data may guide future interventions seeking to prevent gut acquisition of MDRO in the ICU.

The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure.

Aggregation of α-synuclein is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson's disease and Lewy body dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy body dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5-Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly rearranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which form the E46-K80 salt bridge in the wild-type fibril structure. We hypothesize that, under our conditions, the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap-a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.

3D-Printed Cardiac Models for Fetal Counseling: A Pilot Study and Novel Approach to Improve Communication.

A fetal cardiology consultation involves using two-dimensional drawings to explain the cardiac anatomy which can result in inherent variation in how the congenital heart disease (CHD) is conveyed. In this pilot study, we incorporated three-dimensional printed (3DP) models into fetal counseling to demonstrate feasibility and evaluate the impact on parental knowledge, understanding, and anxiety. Parents with a prenatal diagnosis of a muscular ventricular septal defect (VSD) and/or coarctation of aorta were enrolled. Providers were randomized into a Model or Drawing Group and crossed after six months. Parents completed a survey after the consultation which evaluated knowledge of the CHD lesion, expectant surgical management, self-rated understanding, attitude towards the visualization tool, and anxiety. Twenty-nine patients enrolled over a 12 month period. Twelve consultations were done for coarctation of aorta, 13 for VSD, and four for coarctation with a VSD. Both Model and Drawing groups scored similarly in self-reported understanding and confidence, helpfulness of and improvement in communication with the visualization tool. The Model group had higher scores on questions related to the CHD anatomy and surgical intervention [5 [4-5] versus 4 [3.5-5]], p = 0.23 although this didn't reach statistical significance. For the majority (83%) of consultations, the cardiologist agreed that the 3D model improved communication. In this pilot study, we demonstrate the use of 3DP cardiac models during prenatal CHD counseling is feasible and produces results related to parental understanding and knowledge that are equal to and possibly better than the current standard of care.

TMT-based proteomics analysis of the cerebral cortex of TauT knockout rats.

BACKGROUND: Taurine serves a variety of nutritional and physiological roles, and it is mostly transported in cells via taurine transporter (TauT). The effect of taurine transporter in cerebral cortex is still unknown. We employed TMT label-based proteomics to find differences in proteins in the cerebral cortex of TauT knockout rats in this investigation. The goal of this research was to see how TauT deletion affected protein alterations in brain tissue and to see if there was a new research area for TauT. METHODS: The cerebral cortex of TauT knockout rats and wild-type control rats were analyzed using TMT-based proteomics, and differentially expressed proteins were analyzed by bioinformatics analysis means such as GO and KEGG, the association between the proteins was found by PPI, and biologically significant and interesting proteins were selected for verification by WB and immunohistochemistry. RESULTS: There were total of 8275 proteins found, but only 35 differentially expressed proteins were identified (27 up-regulated and 8 down-regulated), and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the biological pathways and functional classification of the proteins. The results show that these differentially expressed proteins are mainly enriched in lysine degradation, cell cycle, chronic myeloid leukemia, and longevity regulating pathways-multiple species, renal cell carcinoma, pathways in cancer, etc. To verify the proteomic data, we analyzed the expression of Annexin6 and Pik3r2 by western blotting and immunofluorescence. The results are consistent with proteomics, which proves the reliability of our proteomics data. CONCLUSION: Through TMT-based proteomics, we have a comprehensive understanding of the effect of TauT knockout on the changes of other proteins in the cerebral cortex, providing new evidence for further understanding the function of TauT.

High-Frequency Positive Pressure Ventilation as Primary Rescue Strategy for Patients with Congenital Diaphragmatic Hernia: A Comparison to High-Frequency Oscillatory Ventilation.

OBJECTIVE: The aim of this article was to evaluate high-frequency positive pressure ventilation (HFPPV) compared with high-frequency oscillatory ventilation (HFOV) as a rescue ventilation strategy for patients with congenital diaphragmatic hernia (CDH). HFPPV is a pressure-controlled conventional ventilation method utilizing high respiratory rate and low positive end-expiratory pressure. STUDY DESIGN: Seventy-seven patients diagnosed with CDH from January 2005 to September 2019 who were treated with stepwise progression from HFPPV to HFOV versus only HFOV were included. Fisher's exact test and the Kruskal-Wallis test were used to compare outcomes. RESULTS: Patients treated with HFPPV + HFOV had higher survival to discharge (80 vs. 50%, p = 0.007) and to surgical intervention (95.6 vs. 68.8%, p = 0.003), with average age at repair 2 days earlier (p = 0.004). Need for extracorporeal membrane oxygenation (p = 0.490), inhaled nitric oxide (p = 0.585), supplemental oxygen (p = 0.341), and pulmonary hypertension medications (p = 0.381) were similar. CONCLUSION: In CDH patients who fail respiratory support with conventional ventilation, HFPPV may be used as an intermediary mode of rescue ventilation prior to HFOV without adverse effects. KEY POINTS: · HFPPV may be used as an intermediary mode of rescue ventilation prior to HFOV without adverse effect.. · HFPPV is more widely available and can mitigate the limitations faced when using HFOV.. · HFPPV allows for intra- or interhospital transfer of neonates with CDH..

Downregulation of α-l-fucosidase 1 suppresses glioma progression by enhancing autophagy and inhibiting macrophage infiltration.

α-l-Fucosidase 1 (FUCA1), a lysosomal enzyme that catalyses the hydrolytic cleavage of the terminal fucose residue, has been reported to be involved in tumorigenesis. However, the clinical significance and biological roles of FUCA1 in glioma remain largely unknown. We analyzed FUCA1 expression according to data in Oncomine, The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases and further verified FUCA1 expression with immunohistochemistry and real-time PCR analysis in glioma tissues. The results showed that FUCA1 overexpression was significantly associated with high-grade glioma as well as high mortality rates in the survival analysis. Data analyzed in cBioPortal showed that alterations in FUCA1 (1.4%) were correlated with worse survival in glioblastoma multiforme patients. Functional experiments showed that downregulation of FUCA1 suppressed glioma growth in vitro and in vivo. Conversely, overexpression of FUCA1 had the opposite effects on glioma. Mechanistically, transient inhibition of FUCA1 promoted the formation of large acidic vacuoles, as revealed by staining with acridine orange, increased the ratio of LC3-B/LC3-A, and modified the expression of Beclin-1 and Atg12, which are autophagic markers. Upregulation of FUCA1 attenuated starvation-induced autophagy in glioma. In addition, lower levels of tumor-infiltrating macrophages, including CD68+ (-30%), F4/80+ (-50%), and CD11c+ macrophages (-50%), were identified in FUCA1-downregulated glioma tissues, and CCL2/CCL5 neutralizing Abs blocked this effect. These results show that FUCA1 could serve as a potential therapeutic target for the treatment of patients with glioma by enhancing autophagy and inhibiting macrophage infiltration.

Immune checkpoint inhibitor therapy in solid organ transplant recipients: A patient-centered systematic review.

BACKGROUND: The use of immunotherapies in the treatment of metastatic cancers has significantly advanced oncology. However, due to safety concerns, solid organ transplant recipients (SOTRs) are routinely excluded from immunotherapy trials; thus, there is limited data for these agents in this population. METHODS: A systematic review was performed to evaluate the safety and efficacy of immunotherapies in SOTRs with metastatic cancers. Fisher's exact test and Kruskal-Wallis test were used for analysis. RESULTS: In total, 37% of patients experienced organ rejection, and 14% died as a result of graft rejection. Nivolumab was associated with the highest rejection rate (52.2%), followed by pembrolizumab (26.7%) and ipilimumab (25%; P = .1774). The highest rejection rate was seen in patients with kidney transplants (40.1%), then liver (35%) and heart (20%) transplants (P = .775), and 64% of patients succumbed to the progression of malignancy. For all cases, rates of progression or death secondary to disease were highest for ipilimumab (75%), followed by nivolumab (43%) and pembrolizumab (40%; P = .1892). The overall response rate was highest for pembrolizumab (40%), followed by nivolumab (30%) and ipilimumab (25%; P = .7929). LIMITATIONS: The small sample size. CONCLUSION: Physicians must be cautious when administering immunotherapy to SOTRs. However, rejection is not the most common cause for death in this population.

Immediate versus delayed temporization at posterior single implant sites: A randomized controlled trial.

AIMS: We conducted a randomized controlled trial to assess the clinical outcomes of two loading protocols involving either immediate or delayed prosthetic temporization of single implants placed at posterior, healed sites. MATERIALS AND METHODS: Forty-nine patients in need of single implants at premolar or molar sites were randomized to receive a temporary crown either immediately after implant placement or 3 months later. Randomization was stratified by sex, implant location (premolar/molar) and arch (maxilla/mandible). Final implant screw-retained zirconia crowns with angulated screw channels were delivered at 5 months after surgery. Radiographic bone levels (primary outcome), peri-implant mucosal margin levels and peri-implant probing depths were recorded at baseline, 6 and 12 months after surgery. RESULTS: Both treatment arms showed similar patterns of soft tissue and bone re-modelling from the implant platform over 12 months [mean bone level change 1.6 mm (SD 1.0 mm) in the delayed, and 1.2 mm (SD 1.3 mm) in the immediate temporization group], with the majority of changes occurring within the first 6 months. CONCLUSIONS: Immediate or delayed temporization of single implants placed at posterior healed sites resulted in largely similar 1-year outcomes with respect to peri-implant bone levels and soft tissue changes.

Multicenter investigation of the reliability and validity of the live donor assessment tool as an enhancement to the psychosocial evaluation of living donors.

The live donor assessment tool (LDAT) is the first psychosocial assessment tool developed to standardize live donor psychosocial evaluations. A multicenter study was conducted to explore reliability and validity of the LDAT and determine its ability to enhance the psychosocial evaluation beyond its center of origin. Four transplant programs participated, each with their own team of evaluators and unique demographics. Liver and kidney living donors (LDs) undergoing both standard psychosocial evaluation and LDAT from June 2015 to September 2016 were studied. LDAT interrater reliability, associations between LDAT scores and psychosocial evaluation outcome, and psychosocial outcomes postdonation were tested. 386 LD evaluations were compared and had a mean LDAT score of 67.34 ± 7.57. In 140 LDs with two LDATs by different observers, the interrater scores correlated (r = 0.63). LDAT scores at each center and overall stratified to the conventional grouping of psychosocial risk level. LDAT scores of 131 subjects who proceeded with donation were expectedly lower in LDs requiring postdonation counseling (t = -2.78, P = .01). The LDAT had good reliability between raters and predicted outcome of the psychosocial evaluation across centers. It can be used to standardize language among clinicians to communicate psychosocial risk of LD candidates and assist teams when anticipating postdonation psychosocial needs.

Enhanced Expression of PD-L1 on Microglia After Surgical Brain Injury Exerts Self-Protection from Inflammation and Promotes Neurological Repair.

Neuroinflammation and brain edema are major complications in the pathophysiology of surgical brain injury (SBI). Programmed death-ligand 1 (PD-L1), an immune inhibitory receptor ligand, has been increasingly investigated for inhibition of T cell-mediated immunity and braking inflammatory response. However, the negative immunomodulatory capacity of PD-L1 and their possible mechanism in SBI is not yet clear. This study aimed to evaluate the expression and the role of PD-L1 in a mouse model of SBI induced inflammation and to further study the potential therapeutic effects of PD-L1 on SBI. Here we showed that PD-L1 expression was markedly elevated in the surrounding peri-resection brain tissue post-SBI in vivo. PD-L1 was up-regulated through ERK signal pathway in LPS-treated BV-2 cells in vitro. Furthermore, blockade of the PD-L1 checkpoint using PD-L1 antibody significantly enhanced brain edema, exacerbated apoptosis and increased neurodeficits post-SBI. Moreover, activated PD-1/PD-L1 with PD-L1 protein significantly attenuated the inflammation responses and brain edema post-SBI. These results suggest that enhanced expression of PD-L1 post-SBI exerts self-protection from inflammation and promotes neurological repair. PD-L1 signal may have therapeutic potential for neurodegenerative disorders.

Synthesis of Poly(N-vinylamide)s and Poly(vinylamine)s and Their Block Copolymers by Organotellurium-Mediated Radical Polymerization.

Controlled polymerization of acyclic N-vinylamides, that is, N-methyl-N-vinylacetamide (NMVA), N-vinylacetamide (NVA), and N-vinylformamide (NVF), by organotellurium-mediated radical polymerization (TERP) is reported. The corresponding poly(N-vinylamide)s with controlled molecular weight and low dispersity (Ð<1.25) were obtained with high monomer conversion in all cases. This is the first report on the controlled polymerization of NVF. Hydrolysis of the polymers, in particular PNVF, occurred quantitatively under mild reaction conditions, giving structurally controlled poly(vinylamine)s. Block copolymers containing poly(N-vinylamide) and poly(vinylamine) segments were also synthesized in a controlled manner.

MicroRNA-124-3p represses cell growth and cell motility by targeting EphA2 in glioma.

MiR-124-3p and EphA2 are aberrantly expressed in glioma tissue specimens. In the present study, we firstly investigated that miR-124-3p inhibits EphA2 expression mediated by binding its 3'-UTR to regulate the progression of human glioma. The U87MG and LN229 cells were transfected with miR-124-3p mimics and/or siRNA-EphA2, and then the role of miR-124-3p and EphA2 in the colony-formation, cell-cycle, migration and invasion of glioma cells in vitro were examined. Proteins involved in the epithelial-mesenchymal transition were examined using western blot. The results showed that miR-124-3p was significantly downregulated in glioma tissues, whereas a marked upregulation of EphA2 expression was found. Colony-formation and flow cytometry assays demonstrated that EphA2 downregulation or miR-124-3p mimics caused growth and cell-cycle inhibition in glioma. Transwell migration and invasion assays demonstrated that EphA2 downregulation or miR-124-3p mimics suppressed the migration and invasion of glioma cells. EphA2 downregulation or miR-124-3p mimics reduced the level of vimentin in U87MG and LN229 cells. In conclusion, miR-124-3p was found to suppress the growth, migration and invasion of glioma cells in vitro via EphA2. Furthermore, we validated miR-124-3p enforced its biological modulation via targeting EphA2 through the rescue experiment. Conclusively, our study proclaimed that miR-124-3p can counteract the malignant phenotypes of glioma cells by the inhibitory effect of the EphA2.

Aß inhibits mesenchymal stem cell-pericyte transition through MAPK pathway.

Multiple independent reports have demonstrated pericyte loss in both the hippocampus and cortex in human Alzheimer's disease (AD). The differentiation and recruitment of pericytes are the essential steps in vasculature development. However, the role of amyloid beta (Aß) in pericyte differentiation has not yet been fully elucidated. In this study, we investigated the interaction between Aß and differentiation of mesenchymal stem cells (MSCs) toward pericytes in culture. Our results showed that mice overexpressing Aß-precursor protein (APP/PS1) exhibited the loss of pericytes compared with the control group mice, evidenced by the lack of desmin expression in the cortex of 12-month-old mice. Interestingly, we further found that both Aß40 and Aß42 inhibited the expressions of pericyte markers (α-SMA, desmin, and PDGFRß) in cultured MSCs which can be differentiated into mature pericytes. Mechanistically, the inhibitory effects of Aßs on MSC-pericyte transition is mediated by the activation of the ERK1/2 MAPK signal pathway. These new insights into the roles of Aß in pericyte differentiation may help to develop more effective strategies for the treatment of AD.

Differential expression of the PAL gene family in rice seedlings exposed to chromium by microarray analysis.

Phenylalanine ammonia-lyase (PAL) is one of the principle enzymes involved in plant's secondary metabolism. Expression of individual isogene from the PAL gene family is variable with species of plants in responses to different stresses. In this study, transcriptome analysis of the PAL gene family in rice seedlings exposed to potassium chromate Cr(VI) or chromium nitrate Cr(III) was conducted using Agilent 44K rice microarray and real-time quantitative RT-PCR. Uptake and accumulation of both Cr species by rice seedlings and their effect on PAL activity were also determined. Three days of Cr exposure led to significant accumulation of Cr in plant tissues, but majority being in roots rather than shoots. Changes of PAL activities in rice tissues were evident from both Cr treatments. Individual isogene from the rice PAL gene family was expressed differentially in response to both Cr variants. Comparing gene expression between two Cr treatments, only osPAL2 and osPAL4 genes were expressed in similar patterns. Also, gene expression pattern was inconsistent in both plant tissues. Results indicated that expression of individual isoform from the rice PAL gene family is tissue, and stimulus specific under different Cr exposure, suggesting their different detoxification strategies for decreasing or eliminating Cr stresses.

Living Ab Initio Emulsion Polymerization of Methyl Methacrylate in Water Using a Water-Soluble Organotellurium Chain Transfer Agent under Thermal and Photochemical Conditions.

Ab initio emulsion polymerization of methyl methacrylate (MMA) using a water-soluble organotellurium chain transfer agent in the presence of the surfactant Brij 98 in water is reported. Polymerization proceeded under both thermal and visible light-irradiation conditions, giving poly(methyl methacrylate) (PMMA) with controlled molecular weight and low dispersity (D<1.5). Despite the formation of an opaque latex, the photoactivation of the organotellurium dormant species took place efficiently, as demonstrated by the quantitative monomer conversion and temporal control. Control of polymer particle size (PDI<0.030) was also achieved using a semi-batch monomer addition process. The PMMA polymer in the particles retained high end-group fidelity and was successfully used for the synthesis of block copolymers.