Sanguineous cardiopulmonary bypass prime accelerates the inflammatory response during pediatric cardiac surgery.

BACKGROUND: The inflammatory response to cardiopulmonary bypass (CPB) in pediatric patients remains an unresolved challenge. Sanguineous CPB prime, composed of allogenic blood products, is one potentially important stimulus. This study aims to identify specific inflammatory mediators active in sanguineous CPB prime and their impact on the inflammatory response at CPB initiation. METHODS: In a post-hoc analysis of a prospective observational cohort study (NCT05154864), where pediatric patients undergoing cardiac surgery with CPB were enrolled after informed consent, patients were grouped by CPB prime type (sanguineous vs crystalloid). Arterial samples were collected post-sternotomy as a baseline and again at CPB initiation from all patients. In the sanguineous group, CPB prime samples were also collected after buffered ultrafiltration but before CPB initiation. Luminex® measured concentrations of 24 inflammatory mediators for comparison between groups. Statistical analyses were by Mann-Whitney test and Wilcoxon signed-rank test. Data are presented as median [IQR]. RESULTS: Forty consecutive pediatric patients participated. The sanguineous group (n = 26) was younger (4.0 [0.2 - 6.0] vs 48.5 [39.0 - 69.5] months; p = 2.6 × 10-7) and smaller (4.9 [34 - 6.6] vs 17.2 [14.9 - 19.6] kg; p = 2.6 × 10-7) than the crystalloid group (n = 14). Despite this, baseline concentrations of 20 complement and cytokine concentrations were comparable between groups (p > 0.05) while four showed differences between groups (p < 0.05). The sanguineous prime contained supraphysiologic concentrations of complement mediators: C2, C3, C3a, C3b, and C5a. Correspondingly, upon CPB initiation, patients receiving sanguineous prime exhibited a significantly larger burden of C2, C3, C3b, C5, and C5a (p < 0.001) relative to the crystalloid group. Cytokine and chemokine mediators were present at trace levels in the sanguineous prime. CONCLUSIONS: Sanguineous prime contains activated complement that accelerates the inflammatory response at CPB initiation in neonates and infants. Immunomodulatory interventions targeting complement during CPB prime preparation could offer substantial benefits for these vulnerable patients.

Sub-THz and THz Cherenkov radiation source with two-dimensional periodic surface lattice and multistage depressed collector.

We present the theory, concept and design of an efficient, megawatt coherent Cherenkov radiation source based on a two-dimensional periodic surface lattice (2D-PSL) cavity combined with a novel energy recovery system for the generation of highly efficient (> 50%) single-frequency radiation. We demonstrate the scalability of the transverse dimension of the 2D-PSL cavity of the Cherenkov source and thus the potential for efficient, continuous-wave, high-power (> 1 MW) operation; fundamental to the eventual realization of clean, fusion energy. These new sources, with the capacity to operate in the 0.1-10THz range, hold strong promise to address the long-standing "Terahertz gap". By combining a Cherenkov oscillator driven by a non-gyrating beam with an innovative four-stage depressed collector energy recovery system, the overall device efficiency can be increased to be competitive with gyrotrons in the requirements for heating and current drive in fusion plasma. In these Cherenkov devices, the frequency independence of the magnetic guide field enables advantageous frequency scaling without deployment constraints, making them especially attractive for high-impact applications in fusion science, turbulence diagnostics, non-destructive testing and biochemical spectroscopy. The novel energy recovery techniques presented in this paper have broad applicability to many electron-beam driven devices, bringing revolutionary potential to future THz source technologies.

High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson's disease.

Glucocerebrosidase (GCase) is implicated in both a rare, monogenic disorder (Gaucher disease, GD) and a common, multifactorial condition (Parkinson's disease, PD); hence, it is an urgent therapeutic target. To identify correctors of severe protein misfolding and trafficking obstruction manifested by the pathogenic L444P-variant of GCase, we developed a suite of quantitative, high-throughput, cell-based assays. First, we labeled GCase with a small proluminescent HiBiT peptide reporter tag, enabling quantitation of protein stabilization in cells while faithfully maintaining target biology. TALEN-based gene editing allowed for stable integration of a single HiBiT-GBA1 transgene into an intragenic safe-harbor locus in GBA1-knockout H4 (neuroglioma) cells. This GD cell model was amenable to lead discovery via titration-based quantitative high-throughput screening and lead optimization via structure-activity relationships. A primary screen of 10,779 compounds from the NCATS bioactive collections identified 140 stabilizers of HiBiT-GCase-L444P, including both pharmacological chaperones (ambroxol and noninhibitory chaperone NCGC326) and proteostasis regulators (panobinostat, trans-ISRIB, and pladienolide B). Two complementary high-content imaging-based assays were deployed to triage hits: The fluorescence-quenched substrate LysoFix-GBA captured functional lysosomal GCase activity, while an immunofluorescence assay featuring antibody hGCase-1/23 directly visualized GCase lysosomal translocation. NCGC326 was active in both secondary assays and completely reversed pathological glucosylsphingosine accumulation. Finally, we tested the concept of combination therapy by demonstrating synergistic actions of NCGC326 with proteostasis regulators in enhancing GCase-L444P levels. Looking forward, these physiologically relevant assays can facilitate the identification, pharmacological validation, and medicinal chemistry optimization of small molecules targeting GCase, ultimately leading to a viable therapeutic for GD and PD.

Rural-Urban Disparities in Mortality of Patients with Acute Myocardial Infarction and Heart Failure: A Systematic Review and Meta-Analysis.

AIMS: Patients with cardiac disease living in rural areas may face significant challenges in accessing care and studies suggest that living in rural areas may be associated with worse outcomes. However, it is unclear whether rural-urban disparities have an impact on mortality in patients presenting with acute myocardial infarction (AMI) and heart failure (HF). This meta-analysis aimed to assess differences in mortality between rural and urban patients presenting with AMI and HF. METHODS: A systematic search of the literature was performed using PubMed, Embase, MEDLINE and CENTRAL for all studies published until January 16, 2024. A grey literature search was also performed using a manual web search. The following inclusion criteria were applied: (i) studies must compare rural patients to urban patients presenting to hospital with AMI or HF; and (ii) studies must report on mortality. The primary outcome was all-cause mortality. Comprehensive data were extracted including study design, patient characteristics (sex, age and comorbidities), sample size, follow-up period and outcomes. Odds ratios (ORs) were pooled with random-effects model. A subgroup analysis was performed to investigate causes for heterogeneity in which studies were separated based on in-hospital mortality, post-discharge mortality, and region of origin including North America, Europe, Asia and Australia. RESULTS: In total, 37 studies were included (29 retrospective studies, 4 cross-sectional studies and 4 prospective cohort studies) in our meta-analysis; 24 studies for AMI, 11 studies for HF and 2 studies for both AMI and HF. This included a total of 21,107,886 patients with AMI (2,230,264 of which were in rural regions) and 18,434,270 patients with HF (2,655,469 of which were in rural regions). Rural patients with AMI had similar age (mean age 69.8 +/- 5.7; vs 67.5 +/- 5.1) and were more likely to be female (43.2% vs 38.5%) compared to urban patients. Rural patients with HF had similar age (mean age 77.1 +/- 4.4 vs 76.5 +/- 4.2) and were more likely to be female (56.4% vs 49.5%) compared to urban patients. The range of follow-up for the AMI cohort was 0 days to 24 months and the range of follow-up for the HF cohort was 0 days to 24 months. Compared with urban patients, rural patients with AMI had higher mortality rate at follow-up (15.5% vs 13.4%; OR 1.18, 95% CI, 1.13-1.24; I2 = 97%). Compared with urban patients, rural patients with HF had higher mortality rate at follow-up (12.3% vs 11.6%; OR 1.11, 95% CI, 1.11-1.12; I2 = 98%). CONCLUSIONS: To our knowledge, this is the first systematic review and meta-analysis assessing mortality differences between rural and urban patients presenting with AMI and HF. We found that patients living in rural areas had an increased risk of mortality when compared to patients in urban areas. Clinical and policy efforts are required to reduce these disparities.

A total of 37 studies were included in our meta-analysis, involving over 39.5 million patients, and found higher mortality rates in rural patients with AMI and HF compared to those in urban areas. Clinical and policy efforts should focus on improving access to care and outcomes to reduce disparities between rural and urban areas.

Fatty acid derivatization and cyclization of the immunomodulatory peptide RP-182 targeting CD206high macrophages improves anti-tumor activity.

As tumor-associated macrophages (TAMs) exercise a plethora of pro-tumor and immune evasive functions, novel strategies targeting TAMs to inhibit tumor progression have emerged within the current arena of cancer immunotherapy. Activation of the mannose receptor 1 (Mrc1; CD206) is a recent approach that recognizes immune suppressive CD206high M2-like TAMs as a drug target. Ligation of CD206 both induces reprogramming of CD206high TAMs towards a pro-inflammatory phenotype and selectively triggers apoptosis in these cells. CD206-activating therapeutics are currently limited to the linear, 10mer peptide RP-182, 1, which is not a drug candidate. Here we sought to identify a better suitable candidate for future clinical development by synthesizing and evaluating a series of RP-182 analogues. Surprisingly, fatty acid derivative 1a (RP-182-PEG3-K(palmitic acid)) not only showed improved stability but also increased affinity to the CD206 receptor through enhanced interaction with a hydrophobic binding motif of CD206. Peptide 1a showed superior in vitro activity in cell-based assays of macrophage activation which was restricted to CD206high M2-polarized macrophages. Improvement of responses was disproportionally skewed towards improved induction of phagocytosis including cancer cell phagocytosis. 1a reprogrammed the immune landscape in genetically engineered murine KPC pancreatic tumors towards increased innate immune surveillance and improved tumor control, and effectively suppressed tumor growth of murine B16 melanoma allografts.

Accelerated competency-based education in primary care (ACE-PC): a 3-year UC Davis and Kaiser permanente partnership to meet California's primary care physician workforce needs.

PROBLEM: Our nation faces an urgent need for more primary care (PC) physicians, yet interest in PC careers is dwindling. Students from underrepresented in medicine (UIM) backgrounds are more likely to choose PC and practice in underserved areas yet their representation has declined. Accelerated PC programs have the potential to address workforce needs, lower educational debt, and diversify the physician workforce to advance health equity. APPROACH: With support from Kaiser Permanente Northern California (KPNC) and the American Medical Association's Accelerating Change in Medical Education initiative, University of California School of Medicine (UC Davis) implemented the Accelerated Competency-based Education in Primary Care (ACE-PC) program - a six-year pathway from medical school to residency for students committed to health equity and careers in family medicine or PC-internal medicine. ACE-PC accepts 6-10 students per year using the same holistic admissions process as the 4-year MD program with an additional panel interview that includes affiliated residency program faculty from UC Davis and KPNC. The undergraduate curriculum features: PC continuity clinic with a single preceptor throughout medical school; a 9-month longitudinal integrated clerkship; supportive PC faculty and culture; markedly reduced student debt with full-tuition scholarships; weekly PC didactics; and clinical rotations in affiliated residency programs with the opportunity to match into specific ACE-PC residency tracks. OUTCOMES: Since 2014, 70 students have matriculated to ACE-PC, 71% from UIM groups, 64% are first-generation college students. Of the graduates, 48% have entered residency in family medicine and 52% in PC-internal medicine. In 2020, the first graduates entered the PC workforce; all are practicing in California, including 66% at federally qualified health centers, key providers of underserved care.

High-exchange ULTrafiltration to enhance recovery after paediatric cardiac surgery (ULTRA): study protocol for a Canadian double-blinded randomised controlled trial.

INTRODUCTION: Surgical repair is the standard of care for most infants and children with congenital heart disease. Cardiopulmonary bypass (CPB) is required to facilitate these operations but elicits a systemic inflammatory response, leading to postoperative organ dysfunction, morbidity and prolonged recovery after the surgery. Subzero-balance ultrafiltration (SBUF) has been shown to extract proinflammatory cytokines continuously throughout the CPB exposure. We hypothesize that a high-exchange SBUF (H-SBUF) will have a clinically relevant anti-inflammatory effect compared with a low-exchange SBUF (L-SBUF). METHODS AND ANALYSIS: The ULTrafiltration to enhance Recovery After paediatric cardiac surgery (ULTRA) trial is a randomised, double-blind, parallel-group randomised trial conducted in a single paediatric cardiac surgery centre. Ninety-six patients less than 15 kg undergoing cardiac surgery with CPB will be randomly assigned to H-SBUF during CPB or L-SBUF during CPB in a 1:1 ratio with stratification by The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) score 1 and STAT score 2-5. The primary outcome is peak postoperative vasoactive-ventilation-renal score. Time series and peak values of vasoactive-ventilation renal score, vasoactive-inotrope score, ventilation index and oxygenation index will be collected. Secondary clinical outcomes include acute kidney injury, ventilator-free days, inotrope-free days, low cardiac output syndrome, mechanical circulatory support, intensive care unit length of stay and operative mortality. Secondary biomarker data include cytokine, chemokine and complement factor concentrations at baseline before CPB, at the end of CPB exposure and 24 hours following CPB. Analyses will be conducted on an intention-to-treat principle. ETHICS AND DISSEMINATION: The study has ethics approval (#1024932 dated August 31, 2021) and enrolment commenced in September 2021. The primary manuscript and any subsequent analyses will be submitted for peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT04920643.

Evaporation-induced self-assembly of Janus pyramid molecules from fractal network to core-shell nanoclusters evidenced by small-angle X-ray scattering.

Self-assembly of nanoclusters (NCs) is an effective synthetic method for preparing functionalized nanomaterials. However, the assembly process and mechanisms in solutions still remain ambiguous owing to the limited strategies to monitor intermediate assembled states. Herein, the self-assembly process of amphiphilic molecule 4POSS-DL-POM (consisting of four polyhedral oligomeric silsesquioxanes, a dendritic linker, and one polyoxometalate) by evaporation of acetone in a mixed acetone/n-decane solution is monitored by time-resolved synchrotron small-angle X-ray scattering (SAXS). Scattering data assessments, including Kratky analysis, pair distance distribution function, and model fitting, track the self-assembly process of 4POSS-DL-POM from a fractal network to compact NCs, then to core-shell NCs, and finally to superlattice structure. The calculated average aggregation number of a core-shell NC is 11 according to the parameters obtained from core-shell model fitting, in agreement with electron microscopy. The fundamental understanding of the self-assembly dynamics from heterocluster into NCs provides principles to control building block shape and guide target aggregation, which can further promote the design and construction of highly ordered cluster-assembled functional nanomaterials.

Development of quantitative high-throughput screening assays to identify, validate, and optimize small-molecule stabilizers of misfolded ß-glucocerebrosidase with therapeutic potential for Gaucher disease and Parkinson's disease.

Glucocerebrosidase (GCase) is implicated in both a rare, monogenic disorder (Gaucher disease, GD) and a common, multifactorial condition (Parkinson's disease); hence, it is an urgent therapeutic target. To identify correctors of severe protein misfolding and trafficking obstruction manifested by the pathogenic L444P-variant of GCase, we developed a suite of quantitative, high-throughput, cell-based assays. First, we labeled GCase with a small pro-luminescent HiBiT peptide reporter tag, enabling quantitation of protein stabilization in cells while faithfully maintaining target biology. TALEN-based gene editing allowed for stable integration of a single HiBiT-GBA1 transgene into an intragenic safe-harbor locus in GBA1-knockout H4 (neuroglioma) cells. This GD cell model was amenable to lead discovery via titration-based quantitative high-throughput screening and lead optimization via structure-activity relationships. A primary screen of 10,779 compounds from the NCATS bioactive collections identified 140 stabilizers of HiBiT-GCase-L444P, including both pharmacological chaperones (ambroxol and non-inhibitory chaperone NCGC326) and proteostasis regulators (panobinostat, trans-ISRIB, and pladienolide B). Two complementary high-content imaging-based assays were deployed to triage hits: the fluorescence-quenched substrate LysoFix-GBA captured functional lysosomal GCase activity, while an immunofluorescence assay featuring antibody hGCase-1/23 provided direct visualization of GCase lysosomal translocation. NCGC326 was active in both secondary assays and completely reversed pathological glucosylsphingosine accumulation. Finally, we tested the concept of combination therapy, by demonstrating synergistic actions of NCGC326 with proteostasis regulators in enhancing GCase-L444P levels. Looking forward, these physiologically-relevant assays can facilitate the identification, pharmacological validation, and medicinal chemistry optimization of new chemical matter targeting GCase, ultimately leading to a viable therapeutic for two protein-misfolding diseases.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis.

Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. We have generated and characterized new HER2+ BCBM cells (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinically used receptor tyrosine kinase inhibitor (RTKi) Lapatinib blocked phosphorylation of all ErbB1-4 receptors and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), a ligand for ErbB3 and ErbB4 that is abundantly expressed in the brain, was able to rescue Lapatinib-induced apoptosis and clonogenic ability in BCBM94 and in HER2+ BT474. ErbB3 was essential to mediate the NRG1-induced survival pathway that involved PI3K-AKT signalling and the phosphorylation of BAD at serine 136 to prevent apoptosis. High throughput RTKi screening identified the brain penetrable Poziotinib as highly potent compound to reduce cell viability in HER2+ BCBM in the presence of NRG1. Successful in-vivo ablation of BCBM94- and BT474-derived HER2+ brain tumors was achieved upon two weeks of treatment with Poziotinib. MRI revealed BCBM remission upon poziotinib, but not with Lapatinib treatment. In conclusion, we have established a new patient-derived HER2+ BCBM in-vivo model and identified Poziotinib as highly efficacious RTKi with excellent brain penetrability that abrogated HER2+ BCBM brain tumors in our mouse models.

Critical role of water conditions in the responses of autumn phenology of marsh wetlands to climate change on the Tibetan Plateau.

The Tibetan Plateau, housing 20% of China's wetlands, plays a vital role in the regional carbon cycle. Examining the phenological dynamics of wetland vegetation in response to climate change is crucial for understanding its impact on the ecosystem. Despite this importance, the specific effects of climate change on wetland vegetation phenology in this region remain uncertain. In this study, we investigated the influence of climate change on the end of the growing season (EOS) of marsh wetland vegetation across the Tibetan Plateau, utilizing satellite-derived Normalized Difference Vegetation Index (NDVI) data and observational climate data. We observed that the regionally averaged EOS of marsh vegetation across the Tibetan Plateau was significantly (p < .05) delayed by 4.10 days/decade from 2001 to 2020. Warming preseason temperatures were found to be the primary driver behind the delay in the EOS of marsh vegetation, whereas preseason cumulative precipitation showed no significant impact. Interestingly, the responses of EOS to climate change varied spatially across the plateau, indicating a regulatory role for hydrological conditions in marsh phenology. In the humid and cold central regions, preseason daytime warming significantly delayed the EOS. However, areas with lower soil moisture exhibited a weaker or reversed delay effect, suggesting complex interplays between temperature, soil moisture, and EOS. Notably, in the arid southwestern regions of the plateau, increased preseason rainfall directly delayed the EOS, while higher daytime temperatures advanced it. Our results emphasize the critical role of hydrological conditions, specifically soil moisture, in shaping marsh EOS responses in different regions. Our findings underscore the need to incorporate hydrological factors into terrestrial ecosystem models, particularly in cold and dry regions, for accurate predictions of marsh vegetation phenological responses to climate change. This understanding is vital for informed conservation and management strategies in the face of current and future climate challenges.

Phenotype plasticity and altered sensitivity to chemotherapeutic agents in aggressive prostate cancer cells.

In 2023, approximately 288,300 new diagnoses of prostate cancer will occur, with 34,700 disease-related deaths. Death from prostate cancer is associated with metastasis, enabled by progression of tumor phenotypes and successful extracapsular extension to reach Batson's venous plexus, a specific route to the spine and brain. Using a mouse-human tumor xenograft model, we isolated an aggressive muscle invasive cell population of prostate cancer, called DU145J7 with a distinct biophysical phenotype, elevated histone H3K27, and increased matrix metalloproteinase 14 expression as compared to the non-aggressive parent cell population called DU145WT. Our goal was to determine the sensitivities to known chemotherapeutic agents of the aggressive cells as compared to the parent population. High-throughput screening was performed with 5,578 compounds, comprising of approved and investigational drugs for oncology. Eleven compounds were selected for additional testing, which revealed that vorinostat, 5-azacitidine, and fimepinostat (epigenetic inhibitors) showed 2.6-to-7.5-fold increases in lethality for the aggressive prostate cancer cell population as compared to the parent, as judged by the concentration of drug to inhibit 50% cell growth (IC50). On the other hand, the DU145J7 cells were 2.2-to-4.0-fold resistant to mitoxantrone, daunorubicin, and gimatecan (topoisomerase inhibitors) as compared to DU145WT. No differences in sensitivities between cell populations were found for docetaxel or pirarubicin. The increased sensitivity of DU145J7 prostate cancer cells to chromatin modifying agents suggests a therapeutic vulnerability occurs after tumor cells invade into and through muscle. Future work will determine which epigenetic modifiers and what combinations will be most effective to eradicate early aggressive tumor populations.

Holistic Admissions at UC Davis-Journey Toward Equity.

This Viewpoint discusses what higher education institutions can learn from UC Davis when it comes to ensuring equity for their students now that the US Supreme Court has eliminated race-conscious college admissions.

Prey ration, temperature, and predator species influence digestion rates of prey DNA inferred from qPCR and metabarcoding.

Diet analysis is a vital tool for understanding trophic interactions and is frequently used to inform conservation and management. Molecular approaches can identify diet items that are impossible to distinguish using more traditional visual-based methods. Yet, our understanding of how different variables, such as predator species or prey ration size, influence molecular diet analysis is still incomplete. Here, we conducted a large feeding trial to assess the impact that ration size, predator species, and temperature had on digestion rates estimated with visual identification, qPCR, and metabarcoding. Our trial was conducted by feeding two rations of Chinook salmon (Oncorhynchus tshawytscha) to two piscivorous fish species (largemouth bass [Micropterus salmoides] and channel catfish [Ictalurus punctatus]) held at two different temperatures (15.5 and 18.5°C) and sacrificed at regular intervals up to 120 h from the time of ingestion to quantify the prey contents remaining in the digestive tract. We found that ration size, temperature, and predator species all influenced digestion rate, with some indication that ration size had the largest influence. DNA-based analyses were able to identify salmon smolt prey in predator gut samples for much longer than visual analysis (~12 h for visual analysis vs. ~72 h for molecular analyses). Our study provides evidence that modelling the persistence of prey DNA in predator guts for molecular diet analyses may be feasible using a small set of controlling variables for many fish systems.

Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes.

UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Decreased or insufficient ubiquitination can cause or drive aging and many diseases. Therefore, a small-molecule enhancing UBA1 activity could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis, is a potent UBA1 activity enhancer. Auranofin binds to the UBA1's ubiquitin fold domain and conjugates to Cys1039 residue. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of seven representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. These findings suggest that auranofin can serve as a much-needed tool for UBA1 research and therapeutic exploration.

Novel inflammatory mediator profile observed during pediatric heart surgery with cardiopulmonary bypass and continuous ultrafiltration.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with systemic inflammation, featuring increased levels of circulating pro-inflammatory cytokines. Intra-operative ultrafiltration extracts fluid and inflammatory factors potentially dampening inflammation-related organ dysfunction and enhancing post-operative recovery. This study aimed to define the impact of continuous subzero-balance ultrafiltration (SBUF) on circulating levels of major inflammatory mediators. METHODS: Twenty pediatric patients undergoing cardiac surgery, CPB and SBUF were prospectively enrolled. Blood samples were collected prior to CPB initiation (Pre-CPB Plasma) and immediately before weaning off CPB (End-CPB Plasma). Ultrafiltrate effluent samples were also collected at the End-CPB time-point (End-CPB Effluent). The concentrations of thirty-nine inflammatory factors were assessed and sieving coefficients were calculated. RESULTS: A profound increase in inflammatory cytokines and activated complement products were noted in plasma following CBP. Twenty-two inflammatory mediators were detected in the ultrafiltrate effluent. Novel mediators removed by ultrafiltration included cytokines IL1-Ra, IL-2, IL-12, IL-17A, IL-33, TRAIL, GM-CSF, ET-1, and the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL10. Mediator extraction by SBUF was significantly associated with molecular mass < 66 kDa (Chi2 statistic = 18.8, Chi2 with Yates' correction = 16.0, p < 0.0001). There was a moderate negative linear correlation between molecular mass and sieving coefficient (Spearman R = - 0.45 and p = 0.02). Notably, the anti-inflammatory cytokine IL-10 was not efficiently extracted by SBUF. CONCLUSIONS: CPB is associated with a burden of circulating inflammatory mediators, and SBUF selectively extracts twenty of these pro-inflammatory factors while preserving the key anti-inflammatory regulator IL-10. Ultrafiltration could potentially function as an immunomodulatory therapy during pediatric cardiac surgery. Trial registration ClinicalTrials.gov, NCT05154864. Registered retrospectively on December 13, 2021. https://clinicaltrials.gov/ct2/show/record/NCT05154864 .

Continuous Ultrafiltration Enhances Recovery After Adult Cardiac Surgery With Cardiopulmonary Bypass: A Systematic Review and Meta-analysis.

Background: Cardiac surgery with cardiopulmonary bypass is associated with systemic inflammation. Ultrafiltration used throughout the cardiopulmonary bypass time, continuously, is hypothesized to be an immunomodulatory therapy. Methods: A systematic review and meta-analysis of randomized trials investigating continuous forms of ultrafiltration during adult cardiac surgery (CRD42020219309) was conducted and is reported following PRISMA guidelines. MEDLINE, Embase, CENTRAL, and Scopus were searched on November 3, 2021. The primary endpoint was operative mortality, and secondary outcomes included intensive care unit length of stay (ICU LOS), ventilation time, acute kidney injury or renal failure, and pneumonia. Each study was assessed for risk of bias using the Cochrane Risk-of Bias-Tool for Randomized Trials (RoB2) instrument. Outcomes were analyzed with inverse variance random-effects models and assessed for GRADE quality of evidence. Results: Twelve randomized trials consisting of 989 adult patients undergoing coronary, valvular, or concomitant cardiac procedures were included. Compared to controls, patients receiving continuous ultrafiltration had no statistical difference in operative mortality; risk ratio of 0.32 (95% confidence interval [CI]: 0.10-1.03; P = 0.06). Reductions occurred in ICU LOS, by 7.01 hours (95% CI: 1.86-12.15; P = 0.008); ventilation time, by 2.11 hours (95% CI: 0.71-3.51; P = 0.003); and incidence of pneumonia, with a risk ratio of 0.33 (95% CI: 0.15-0.75; P = 0.008). There wasno difference in renal injury. The GRADE quality of evidence for these outcomes ranged from very low to low. Conclusions: Continuous forms of ultrafiltration enhance recovery after adult cardiac surgery by reducing ICU LOS, ventilation time, and incidence of pneumonia. A multicentre randomized trial could confirm and generalize these findings.

Contexte: La chirurgie cardiaque avec pontage cardiopulmonaire est associée à une inflammation généralisée. On croit que l'ultrafiltration utilisée en continu tout au long du pontage cardiopulmonaire pourrait se révéler un traitement immunomodulateur. Méthodologie: Une revue systématique et une métanalyse d'essais avec répartition aléatoire portant sur les formes d'ultrafiltration continue utilisées pendant une chirurgie cardiaque chez l'adulte (CRD42020219309) ont été réalisées, et les résultats sont présentés selon les lignes directrices PRISMA. Les bases de données MEDLINE, Embase, CENTRAL et Scopus ont été interrogées le 3 novembre 2021. L'étude avait pour critère d'évaluation principal la mortalité pendant la chirurgie, et pour critères secondaires, la durée du séjour aux soins intensifs, la durée de ventilation, la survenue de lésions rénales aiguës ou d'insuffisance rénale et la pneumonie. Pour chaque étude, le risque de biais a été évalué à l'aide de l'instrument Risk-of Bias-Tool for Randomized Trials (RoB2) du réseau Cochrane. Les résultats ont été analysés à l'aide de modèles à effets aléatoires selon l'inverse de la variance, et la qualité des données a été évaluée selon l'échelle GRADE. Résultats: Ont été incluses les données de douze essais avec répartition aléatoire auxquels ont pris part 989 patients adultes ayant subi une intervention chirurgicale coronarienne ou valvulaire, ou une chirurgie cardiaque concomitante. Le taux de mortalité enregistré pendant la chirurgie chez les patients qui avaient reçu une ultrafiltration continue ne s'est pas avéré statistiquement différent de celui relevé chez les témoins; rapport de risque = 0,32 (intervalle de confiance [IC] à 95 % : 0,10 à 1,03; p = 0,06). La durée du séjour aux soins intensifs a diminué de 7,01 heures (IC à 95 % : 1,86 à 12,15; p = 0,008), et le temps de ventilation, de 2,11 heures (IC à 95 % : 0,71 à 3,51; p = 0,003); l'incidence de pneumonie a également baissé (rapport de risques = 0,33 [IC à 95 % : 0,15 à 0,75; p = 0,008]). Aucune différence n'a été observée sur le plan des lésions rénales. La qualité des données selon l'échelle GRADE pour ces résultats allait de faible à très faible. Conclusions: L'ultrafiltration continue améliore le rétablissement après une chirurgie cardiaque chez l'adulte en réduisant la durée du séjour aux soins intensifs, le temps de ventilation et l'incidence de pneumonie. Un essai multicentrique à répartition aléatoire pourrait confirmer et généraliser ces conclusions.

Frontiers in the Application of RF Vacuum Electronics.

The application of radio frequency (RF) vacuum electronics for the betterment of the human condition began soon after the invention of the first vacuum tubes in the 1920s and has not stopped since. Today, microwave vacuum devices are powering important applications in health treatment, material and biological science, wireless communication-terrestrial and space, Earth environment remote sensing, and the promise of safe, reliable, and inexhaustible energy. This article highlights some of the exciting application frontiers of vacuum electronics.