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Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.

In the United States, the transportation sector  is the largest single source of greenhouse gas (GHG) and nitrogen oxide (NOx) emissions, and heavy-duty trucks contribute a disproportionately large share. Therefore, the trucking industry has been seeking ways to minimize emissions, such as adopting zero-emission vehicles and improving truck operating strategies to reduce truck miles. Battery-powered vehicles have different limitations than those with internal combustion engines. In this study, researchers from the University of Southern California investigated the adoption of battery electric heavy-duty trucks (BEHDTs) in the short-haul freight movement sector and the drayage industry. Drayage is a short-haul pickup and delivery service for transporting freight among ports, warehouses, and other facilities. With drayage routing, vehicles have limited weight and volume capacities and often make many stops. Routing involves optimizing for multiple factors, like fuel, distance traveled, and timeliness. This brief summarizes the findings from that research and provides implications for the field.View the NCST Project Webpage

Sirtuin 1 (SIRT1) is a histone/protein deacetylase in the cellular response to inflammatory, metabolic, and oxidative stressors. We previously reported that myeloid SIRT1 regulates the inflamed livers canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain. Here, we undertook translational studies in human and mouse orthotopic liver transplantation (OLT) to interrogate the significance of hepatocyte-specific SIRT1 in cold-stored donor livers and liver grafts after reperfusion. In the clinical arm of sixty human OLT patients, hepatic SIRT1 levels in cold-preserved donor livers correlated with the anti-apoptotic Bcl-2 expression. After reperfusion, improved OLT function was accompanied by hepatic SIRT1 levels negatively associated with cleaved caspase-3 expression. In the experimental arm, we compared FLOX-control with hepatocyte-specific SIRT1-KO livers after orthotopic transplantation into WT mouse recipients, parallel with primary murine hepatocyte cultures subjected to cold activation with/without knockdown of SIRT1, GSDME, and IL18Rβ. Indeed, hepatocyte SIRT1 deficiency upregulated apoptosis and GSDME-mediated programmed cell death, deteriorating hepatocellular function and shortening OLT survival. Augmented GSDME processing, accompanied by increased secretion of IL18 by stressed hepatocytes, was prominent in SIRT1-deficient, cold-stored livers. Hepatocyte SIRT1 expression regulated anti-apoptotic Bcl-2/XIAP proteins, suppressed cold stress-triggered apoptosis, and mitigated GSDME licensing to release IL18. Notably, consistent with the ability of IL18 to depress hepatocyte SIRT1 and Bcl-2/XIAP in vitro, IL18 neutralization in vivo prevented hepatocellular damage and restored the anti-apoptotic phenotype in otherwise injury-prone SIRT1-deficient OLTs. In conclusion, this translational study identifies a novel hepatocyte SIRT1-IL18 molecular circuit as a therapeutic target in the mechanism underpinning hepatocyte death pathways in human and mouse liver transplantation.

California has a long history of reducing greenhouse gas (GHG) emissions, and has been working to accelerate the adoption of battery electric heavy-duty trucks (BEHDTs). Unlike diesel heavy-duty trucks (DHDTs), which have hundreds of miles of range per refill, BEHDTs have a restricted, load-dependent driving range, which makes charging planning an important role in the use of BEHDTs as an alternative to DHDTs. This research study investigates a mixed fleet drayage routing problem (MFDRP) with non-linear charging times. The study extends existing mixed fleet drayage routing models by considering multiple charging locations and allowing for more flexible routes for freight pickup and delivery. We formulate the MFDRP as a mixed integer programming model. After linearization and variable elimination, the model can be solved by commercial optimization solvers. However, the model becomes inefficient to solve when the problem size increases. Therefore, we develop a modified adaptive large neighborhood search algorithm, which can solve the problem with hundreds of units of demand in a few CPU minutes. Finally, we simulate one-day drayage operations with different BEHDT shares in the fleet for the years 2022, 2025, and 2030 to assess the potential for substituting DHDTs with BEHDTs. The numerical experiments indicate that employing BEHDTs as substitutes for DHDTs will increase the fleet size under the same level of demand. To reach the maximum share of BEHDTs in the truck fleet, the fleet size increases by 47.2%, 3.4%, and 3.4% in 2022, 2025, and 2030, respectively. Over 50% (90%) CO2 (NOx) emission reductions can be achieved by employing BEHDTs to the maximum share in the fleet.View the NCST Project Webpage

INTRODUCTION: Ischemia-reperfusion injury (IRI) involves a positive amplification feedback loop that stimulates innate immune-driven tissue damage associated with organ procurement from deceased donors and during transplantation surgery. As our appreciation of its basic immune mechanisms has improved in recent years, translating putative biomarkers into therapeutic interventions in clinical transplantation remains challenging. AREAS COVERED: This review presents advances in translational/clinical studies targeting immune responses to reactive oxygen species in IRI-stressed solid organ transplants, especially livers. Here we focus on novel concepts to rejuvenate suboptimal donor organs and improve transplant function using pharmacologic and machine perfusion (MP) strategies. Cellular damage induced by cold ischemia/warm reperfusion and the latest mechanistic insights into the microenvironments role that leads to reperfusion-induced sterile inflammation is critically discussed. EXPERT OPINION: Efforts to improve clinical outcomes and increase the donor organ pool will depend on improving donor management and our better appreciation of the complex mechanisms encompassing organ IRI that govern the innate-adaptive immune interface triggered in the peritransplant period and subsequent allo-Ag challenge. Computational techniques and deep machine learning incorporating the vast cellular and molecular mechanisms will predict which peri-transplant signals and immune interactions are essential for improving access to the long-term function of life-saving transplants.

In today’s world, there is a significant amount of investigation regarding how to efficiently distribute loaded containers from the ports to the consignees. However, to fully maximize the process and become more environmentally friendly, one should also study how to allocate the empty containers created by these consignees. This is an essential part in the study of container movement since it balances out the load flow at each location. The problem of coordinating the container movement to reuse empty containers and lower truck miles is called the “Empty Container Problem”. In this work, the authors develop a scheduling assignment for loaded and empty containers that builds on earlier models but incorporates stochastic (random) future demand. Since this problem is meant to be solved daily and the solution implemented today affects tomorrow’s starting state, incorporating future demand is an important aspect. This report shows that the truck miles needed to satisfy the demand at all locations is reduced by about 4-7% when considering future stochastic demand as opposed to only considering today’s demand. Thus, leading to a cleaner and greener solution, creating less congestion and lowering the impact of freight movement on the environment.View the NCST Project Webpage

T-cell immunoglobulin and mucin (Tim)4 is expressed on APCs, including macrophages, as one of the main amplifiers in the mechanism of liver ischemia-reperfusion injury (IRI) following orthotopic liver transplantation (OLT). Though donor Tim4 selectively expressed on Kupffer cells serves as a checkpoint regulator of innate immune-driven IRI cascades, its role on cells outside the OLT remains unclear. To dissect the role of donor vs. recipient-specific Tim4 signaling in IR-induced stress and hepatocellular function, we employed a murine OLT model utilizing Tim4-knockout (KO) mice as either donor or recipient (WT → WT, WT → Tim4-KO, Tim4-KO → WT). In the experimental arm, disruption of donor Tim4 attenuated IRI-OLT damage, while recipient Tim4-null mutation aggravated hepatic IRI concomitant with disturbed lipid metabolism, enhanced endoplasmic reticulum stress, and activated pro-apoptotic signaling in the grafts. In the in vitro study, murine hepatocytes co-cultured with Tim4-null adipose tissue showed enhanced C/EBP homologous protein (CHOP) expression pattern and susceptibility to hepatocellular death accompanied by activated caspase cascade in response to TNF-α stimulation. In the clinical arm, liver grafts from forty-one transplant patients with enhanced TIM4 expression showed higher body mass index, augmented hepatic endoplasmic reticulum stress, enhanced pro-apoptotic markers, upregulated innate/adaptive immune responses, exacerbated hepatocellular damage, and inferior graft survival. In conclusion, although TIM4 is considered a principal villain in peri-transplant early tissue injury, recipient TIM4 signaling may serve as a savior of IR-triggered metabolic stress in mouse and human OLT recipients.

The urban heat island (UHI) is a crucial factor in developing sustainable cities and societies. Appropriate data collection, analysis, and prediction are essential first steps in studying the effects of the UHI. This research systematically reviewed the papers related to the UHI that have used on-site data collection in the United States and Canada and the papers related to predicting and analyzing this effect in these regions. To achieve this goal, this study extracted 330 articles from Scopus and Web of Science and, after selecting the papers, reviewed 30 papers in detail from 1998 to 2023. The findings of this paper indicated a methodological shift from traditional sensors and data loggers towards more innovative and customized technologies. Concurrently, this research reveals a growing trend in using machine learning, moving from supportive to direct predictive roles and using techniques like neural networks and Bayesian networks. Despite the maturation of UHI research due to these developments, they also present challenges in technology complexity and data integration. The review emphasizes the need for future research to focus on accessible, accurate technologies. Moreover, interdisciplinary approaches are crucial for addressing UHI challenges in an era of climate change. [ABSTRACT FROM AUTHOR]

Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular reactive oxygen species (ROS) results from high levels of oxidative stress (OxS) that occur in response to hepatic ischemia/reperfusion injury (IRI) and metabolic diseases of the liver. Antisense oligonucleotides (ASOs) are an emerging class of gene expression modulators that target RNA molecules by Watson–Crick binding specificity, leading to RNA degradation, splicing modulation, and/or translation interference. Here, we review ASO inhibitor/activator strategies to modulate transcription and translation that control the expression of enzymes, transcription factors, and intracellular sensors of DNA damage. Several small-interfering RNA (siRNA) drugs with N-acetyl galactosamine moieties for the liver have recently been approved. Preclinical studies using short-activating RNAs (saRNAs), phosphorodiamidate morpholino oligomers (PMOs), and locked nucleic acids (LNAs) are at the forefront of proof-in-concept therapeutics. Future research targeting intracellular OxS-related pathways in the liver may help realize the promise of precision medicine, revolutionizing the customary approach to caring for and treating individuals afflicted with liver-specific conditions. [ABSTRACT FROM AUTHOR]

Background/Purpose: The existing risk stratification for early cholecystectomy in patients with acute cholecystitis (AC) is complex. This study aims to establish a simpler risk assessment for surgical complications after cholecystectomy based on age group. Methods: This single‐center retrospective observational study enrolled 350 patients diagnosed with AC who underwent early cholecystectomy within 72 h of diagnosis from 2013 to 2021. Patients were divided into three subgroups based on age: young (<65 years), elderly (65–79 years), and very elderly (≥80 years). Since no mortality was observed, risk factors for the Clavien‐Dindo (CD) grade ≥ II complications were identified within the entire cohort and in each subgroup. Results: There were 120 young, 130 elderly, and 100 very elderly patients. The overall prevalence of complications with CD grade ≥ II was 11.1%. Age and Tokyo Guidelines 18 (TG18) severity were independent risk factors for surgical complications in the whole cohort. Subgroup analysis revealed that there was no independent risk factor in the young group. Meanwhile, age and poor physical status were independent risk factors in the elderly group, and TG18 severity in the very elderly group. Conclusion: Evaluation of only age, physical status, and TG18 severity may be sufficient for risk stratification of surgical complications of AC. [ABSTRACT FROM AUTHOR]